Cu(OTf)2-Mediated Cross-Coupling of Nitriles and N-Heterocycles with Arylboronic Acids to Generate Nitrilium and Pyridinium Products**

Article abstract of DOI:10.1002/anie.202016811

Metal-catalyzed C–N cross-coupling generally forms C?N bonds by reductive elimination from metal complexes bearing covalent C- and N-ligands. We have identified a Cu-mediated C–N cross-coupling that uses a dative N-ligand in the bond-forming event, which, in contrast to conventional methods, generates reactive cationic products. Mechanistic studies suggest the process operates via transmetalation of an aryl organoboron to a Cu^II complex bearing neutral N-ligands, such as nitriles or N-heterocycles. Subsequent generation of a putative Cu^III complex enables the oxidative C–N coupling to take place, delivering nitrilium intermediates and pyridinium products. The reaction is general for a range of N(sp) and N(sp²) precursors and can be applied to drug synthesis and late-stage N-arylation, and the limitations in the methodology are mechanistically evidenced.

Full text of DOI:10.1002/anie.202016811

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How to cite: Angew. Chem. Int. Ed. 2021, 60, 7935–7940
International Edition:
German Edition:
doi.org/10.1002/anie.202016811
doi.org/10.1002/ange.202016811
Cross-Coupling
Cu(OTf)2-Mediated Cross-Coupling of Nitriles and N-Heterocycles
with Arylboronic Acids to Generate Nitrilium and Pyridinium
Products**
Nicola L. Bell+, Chao Xu+, James W. B. Fyfe, Julien C. Vantourout, Jeremy Brals, Sonia Chabbra,
Bela E. Bode, David B. Cordes, Alexandra M. Z. Slawin, Thomas M. McGuire, and
Allan J. B. Watson*
Abstract: Metal-catalyzed C–N cross-coupling generally
chemicals, natural products, and materials.[1–8] The develop-
À
À
forms C N bonds by reductive elimination from metal
ment of new or improved processes for C N bond construc-
complexes bearing covalent C- and N-ligands. We have
identified a Cu-mediated C–N cross-coupling that uses a dative
N-ligand in the bond-forming event, which, in contrast to
conventional methods, generates reactive cationic products.
Mechanistic studies suggest the process operates via trans-
metalation of an aryl organoboron to a CuII complex bearing
neutral N-ligands, such as nitriles or N-heterocycles. Subse-
quent generation of a putative CuIII complex enables the
oxidative C–N coupling to take place, delivering nitrilium
intermediates and pyridinium products. The reaction is general
for a range of N(sp) and N(sp2) precursors and can be applied
to drug synthesis and late-stage N-arylation, and the limitations
in the methodology are mechanistically evidenced.
tion remains a continual inspiration for metal-based reaction
development. Despite a broad diversity and subtlety in the
mechanism of these methods, the basic premise of the
reaction involves a series of individual mechanistic steps,
e.g., oxidative addition, transmetalation, and/or deprotona-
tion, to allow access to a key metal complex bearing formally
anionic, covalently bound C- and N-ligands (Scheme 1a). This
complex undergoes reductive elimination to deliver a neutral
product, which is produced regardless of whether the catalysis
itself is electroneutral (e.g., the Buchwald-Hartwig or Ull-
mann-Goldberg reactions) or oxidative (e.g., the Chan-Lam
reaction).[6–9]
In these processes, the N-ligand originates from a precur-
sor amine or amine-derived substrate bearing at least one
À
Introduction
functionalizable N H, which undergoes deprotonation at
some stage in the reaction mechanism to deliver the required
anionic N-ligand. This limits the scope of established pro-
Transition metal-mediated C-N cross-coupling is an
essential synthetic method, used extensively throughout the
chemical industry for the synthesis of pharmaceuticals, agro-
À
cesses to substrates with at least one N H.
However, it should be noted that the direct N-arylation of
substrates without a functionalizable site is known. N-
arylation of nitriles and N-heterocycles has been achieved
with or without transition metal activators, for example, using
diaryliodonium salts.[10,11] With Cu-promoted processes,[10,11]
these are mechanistically ambiguous, with no evidence for
[*] Dr. N. L. Bell,[+] Dr. C. Xu,[+] Dr. J. W. B. Fyfe, J. Brals, S. Chabbra,
Dr. B. E. Bode, Dr. D. B. Cordes, Prof. A. M. Z. Slawin,
Dr. A. J. B. Watson
EaStCHEM, School of Chemistry
University of St Andrews
North Haugh, St Andrews, Fife, KY16 9ST (UK)
E-mail: aw260@st-andrews.ac.uk
J. C. Vantourout
GlaxoSmithKline, Medicines Research Centre
Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY (UK)
Dr. T. M. McGuire
AstraZeneca
Darwin Building, Unit 310
Cambridge Science Park, Milton Road, Cambridge, CB4 0WG (UK)
[+] These authors contributed equally to this work.
[**] A previous version of this manuscript has been deposited on
a preprint server (https://doi.org/10.26434/chemrxiv.13399307.v1).
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
https://doi.org/10.1002/anie.202016811.
ꢀ 2021 The Authors. Angewandte Chemie International Edition
published by Wiley-VCH GmbH. This is an open access article under
the terms of the Creative Commons Attribution License, which
permits use, distribution and reproduction in any medium, provided
the original work is properly cited.
Scheme 1. a) General approach to cross-coupling. b) This work: cross-
coupling to unconventional substrates. Ar=aryl, TM=transition met-
al.
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a metal-centered reductive elimination. These processes have
also been rationalized as direct arylation using the increased
electrophilicity of the aryl transfer reagent via Lewis acid
activation.[12] More specifically, while CuI has been shown to
slightly accelerate aryl transfer with diaryliodoniums, these
processes also proceed effectively without CuI,[13,14] consistent
with observed general reactivity of this class of reagents[15]
and related reactive aryl transfer reagents, such as aryldiazo-
nium salts.[16]
Here, we report the discovery, mechanistic rationale,
example scope, and limitations of a Cu-mediated C-N cross-
coupling method that promotes reductive elimination to
neutral N-ligands, such as nitriles and N-heterocycles gen-
erating reactive cationic products (Scheme 1b).
Results and Discussion
During investigations to rationalize the reactivity of CuII
sources in standard Chan-Lam reactions, the amide product
3a was identified in good yield when the reaction of
arylboronic acid 1 with aniline was attempted with Cu(OTf)2
in MeCN as solvent (Scheme 2a). A similar observation was
made by Sanford during studies of fluorodeboronation, which
also used stoichiometric Cu(OTf)2 (4 equiv) in MeCN
(Scheme 2b).[17] We were intrigued by this observation since
hydrolysis of MeCN to acetamide followed by Chan-Lam-
type N-arylation seemed unlikely— we have previously at-
tempted Chan-Lam arylations of amides using Cu(OTf)2 and
found this to be problematic (vide infra). Consequently, we
sought to understand the origin of this coupling process.
Control experiments indicated the possibility of an
alternative pathway. The Chan-Lam arylation of acetamide
6 using Cu(OTf)2 in PhMe does not provide the N-aryl
product. Instead, the products of aryl-boronic acid oxidation
and protodeboronation were observed and represented the
almost complete mass balance (Scheme 3a)— protodeboro-
nation was also noted as an issue in Sanfordꢀs study[17] and is
a common problem for Cu-mediated reactions of organo-
borons.[18,19] Separate experiments (Table S1) indicated that
the same conditions did not lead to nitrile hydrolysis.[20] The
competition reaction of 1 with acetamide and D3CCN in the
presence of Cu(OTf)2 led to the deuterated acetamide
product 3b exclusively, further supporting the absence of
a Chan-Lam pathway and indicating selectivity for nitrile
(Scheme 3b).
Scheme 3. Control reactions. Ar1 =p-PhC6H4; Ar2 =p-(F3CO)C6H4.
To rationalize these initial observations, we considered
a reaction pathway that proceeded via formation of a nitrilium
intermediate formed by Cu-mediated N-arylation of the
nitrile. N-arylation of nitriles is known using highly reactive
aryl transfer agents, such as iodonium and diazonium
salts;[10,16] however, oxidative coupling of nitriles with aryl-
boronic acids is unknown. Accordingly, we sought to establish
if an oxidative coupling pathway was operational.
Treatment of Cu(OTf)2 with H2O in MeCN leads to
a stable and isolable complex CuII(OTf)2(H2O)2(MeCN)2
(10a, Scheme 3c).[21] Heating this complex with 1 lead to
the observed acetamide 3a, which we propose proceeds
through nitrilium 11a, suggesting possible formation and
involvement of 10a in the reaction.[22]
Nitrilium ions are highly reactive electrophiles capable of
a variety of bond forming processes with nucleophiles;[23]
however, extensive experimentation to intercept the pro-
posed nitrilium 11a were unsuccessful and afforded a mixture
of amide and returned starting material (Tables S2 and S3).
We therefore attributed amide formation to hydrolysis of the
nitrilium with H2O present in the reaction mixture, arising
either from boroxine formation from 1 or Cu-bound H2O in
10a— H2O could not be excluded in preparation of stoichio-
metric Cu(OTf)2 nitrile complexes as noted above.
Independent preparation of stable nitrilium 11c[24] and
treatment with 10a led to instantaneous hydrolysis, high-
Scheme 2. Observations of Cu-mediated nitrile arylation. [a] Deter-
mined by HPLC. Ar1 =p-PhC6H4. Tf=trifluoromethylsulfonyl.
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lighting the lability of Cu-bound H2O (Scheme 3d). To probe
the origin of H2O in the acetamide product, we undertook
labelling experiments. Addition of H218O to the reaction of
10a with 1 led to 41% 18O incorporation in the product 3c,
consistent with the 16O:18O stoichiometry (Scheme 3e).
Preparation of 18O-labelled complex 10b was successful;
however, the 18O incorporation could not be quantified due to
lability of the dative ligands. Indeed, despite obtaining crystal
structure data of 10a and 10b (identical), HRMS analyses
were uniformly unsuccessful. Use of 10b in the absence of
additional H2O gave 3c in comparable yield to the reaction of
10a and with 60% 18O incorporation (Scheme 3 f).
The inability to trap the nitrilium by any nucleophile other
than H2O suggests that nitrilium quenching may be occurring
from H2O in solution, a Cu aquo species (e.g., 10a/10b), or
from a CuI complex liberated after reductive elimination
(e.g., 13, Scheme 3 f).
key CuIII intermediate 17a with [17a–TfOÀ] (17b) found,[26–28]
allowing formation of the nitrilium product 11 (11b found).
Mass ions consistent with the proposed CuI aquo complex 18a
were detected (18b), consistent with the quenching proposal
outlined in Scheme 3 f. Stoichiometric Cu(OTf)2 was exclu-
sively effective— other Cu sources failed to promote the
reaction (Table S7). Extensive investigation failed to allow
this process to operate with catalytic Cu(OTf)2— the addition
of terminal oxidants led to issues of organoboron oxidation
and rendering Cu turnover (Scheme 4, dotted line) irrelevant
(Table S9). The same turnover issues in systems using Cu-
(OTf)2 and CuOTf have been observed in C-F bond
formation by Sanford[17] and Hartwig,[29] respectively, where
3–4 equivalents of Cu were necessary for reaction efficiency.
This problem remains unresolved for many Cu(OTf)2-based
processes.[30]
The proposed nitrilium ions were observable by HRMS;
however, the inability to intercept the proposed nitrilium with
other nucleophiles was unsatisfactory. Specifically, this invites
To further substantiate this nitrilium proposal, HRMS
analysis of reaction mixtures identified a series of mass ions
that allowed the following mechanism to be proposed
(Scheme 4).[25]
À
further scrutiny of the proposed key C N bond forming event
in Scheme 4— the potential for an on-metal hydrolysis cannot
À
We propose that Cu(OTf)2 forms 10a (crystal structure
obtained from reaction mixtures). Loss of TfOH and H2O
gives 14a–mass ions consistent with [14a–MeCN] (14b) and
[14a–H2O] (14c) were found. Transmetalation then gives 16a
(16b found), possibly via a pathway consistent to the Chan-
Lam amination (15).[26] Disproportionation of 16a gives the
be excluded. We therefore sought to demonstrate the C N
bond forming process using a system that would allow
À
unambiguous identification C N bond formation produced
from reductive elimination to a neutral N-ligand on CuIII.
Treatment of Cu(OTf)2 with DMAP allowed formation of
CuII(OTf)2(DMAP)4 19 and its structure unambiguously
confirmed by X-ray (Scheme 5).
Complex 19 is similar to the nitrile complex 10a; however,
this can be prepared without aquo ligands. Under the same
reaction conditions used in Scheme 3c, 19 leads to a similar
À
C N bond formation giving N-aryl pyridinium 20 and in
similar yield to the nitrile process. 20 was characterized
unambiguously by spectroscopy and X-ray, providing strong
support for C-N cross-coupling via CuIII. We propose this
reaction to follow a similar course to that proposed in
Scheme 4. Single electron pathways via oxidation of DMAP
by CuII were proposed to be unlikely based on oxidation
potentials and EPR analysis (vide infra).[33–35]
Despite evidence for the feasibility of reductive elimina-
tion from (aryl)CuIII complexes yielding N-aryl ammonium
products,[36,37] the equivalent N(sp3) cross-coupling under the
conditions reported here did not afford the desired C-N(sp3)
bond. We attribute this to competing amine oxidation by
CuII;[38] this was substantiated by EPR studies, which showed
quenching of CuII and, in the case of N-methylpyrrolidine,
a radical species could be observed (Scheme 6a). Addition of
tertiary amines to the optimized DMAP N-arylation process
Scheme 5. Cross-coupling to N(sp2) via DMAP complex 19. Ar1 =p-
PhC6H4, DMAP=4-dimethylaminopyridine.
Scheme 4. Proposed mechanism with observed HRMS mass ions.
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Following optimization (Tables S7–S11), a general process
was developed for the coupling of arylboronic acids with
nitriles and N-heterocycles— a selection of products is
provided in Scheme 7 (for additional substrates see
Scheme S15).[46] The process tolerates a variety of functional
groups on both the nitrile and arylboronic acid, with standard
structural and electronic variations examined in this example
scope. The nitrilium process is an unusual amidation protocol
(essentially an aryl Ritter reaction) providing a new approach
to this ubiquitous motif; however, the heterocycle N-arylation
process allows access to products that cannot be made easily
using any established method, providing novel opportunities
for synthetic design. In general, the scope of the boronic acid
was very good for arylboronic acids, with some lower yields
observed using heteroaromatic species consistent with estab-
lished limitations with these substrates.[47] Alkylboronic acids
were tolerated only in the N-heterocycle process (e.g.,
product 45); no desired products were observed in the
equivalent nitrilium reactions. For the nitrilium process, the
C-N cross-coupling could be achieved using the nitrile as
solvent where practical (e.g., for MeCN, EtCN), otherwise
PhMe was the preferred medium for both the nitrilium and N-
heterocycle processes. While generally effective, solubility
issues can present with certain arylboronic acids in PhMe
resulting in lower yields (e.g., 29–31). With regards the N-
heterocycle process, the reaction was broadly tolerant to the
nature of the heterocycle, although higher yields were
obtained with more electron-rich compounds, which may be
expected based on the oxidative coupling process. The issue of
lower yields with substrates bearing ortho-substitution was
replicated (e.g., 27 and 40) and is again consistent with
observations in Cu-mediated oxidative coupling processes.[9]
As discussed above for the nitrile process, stoichiometric
Cu(OTf)2 was also needed for the heterocycle process, which
perhaps offers some explanation for the lack of observable
reinsertion into the N-aryl pyridinium products. Additional
demonstrations of utility are provided in Scheme 7c-g. The C-
N coupling process can be applied to the N-arylation of non-
aryl N(sp2) including the common organic base DBU as well
as the Lewis base organocatalyst (À)-tetramisole to afford
compounds 52 and 53, respectively (Schemes 7c and d).
The ability to induce direct N-arylation of N-heterocycles
allows a significantly shorter route to non-symmetrical NHCs
by N-arylation of N-aryl imidazoles such as 54, which
proceeds via the expected complex 55 to deliver imidazolium
salt 56 (Scheme 7e; see also 50 and 51 in Scheme 7b for alkyl/
aryl imidazolium).[11] Lastly, the process can be used in
synthesis, for example using the nitrilium process to access
pharmaceutically relevant amides, such as the Tolvaptan
intermediate 57 (Scheme 7 f) and for late-stage functionali-
zation, for example N-arylation of the agrochemical Pyri-
proxyfen, giving product 58 (Scheme 7g).
Scheme 6. Limitations of the Cu-mediated arylation with R3N. Ar3 =4-
MeC6H4. Ar4 =4-FC6H4. [a] vs. Fc+/0 [39] [b] vs. SCE.[40] [c] vs. SCE.[41]
.
[d] vs. SCE.[42] [e] vs. SCE.[43] [f] Determined by 1H NMR analysis.
Fc =ferrocene, SCE=saturated calomel electrode.
had variable effects on the observed yield (Scheme 6b). For
example, PhNMe2 almost completely reduced CuII and
lowered yield of 21 by approximately half; however, n-
butylaziridine reduced approx. 25% of CuII yet had no impact
on the yield of 21. Little reduction of CuII by TMEDA was
observed by EPR and the arylation reaction was instead
impaired by formation of a series of novel but unreactive
bidentate complexes (Scheme S12). As expected, DMAP did
not significantly reduce CuII.
Moreover, in the presence of unsubstituted anilines, an
alternative oxidative coupling pathway becomes evident via
formation of 1,2-diarylhydrazines (22) and azobenzenes (23)
(Scheme 6c). This is clearly mechanistically related to pre-
viously reported Cu-mediated N-N coupling reactions.[44,45]
Consistent with these previous reports, our EPR data suggests
that these processes proceed via single electron oxidation of
the aniline by CuII; however, importantly, the resulting
aminium radical does not appear to be free in solution and
attempts to intercept these species were universally unsuc-
cessful (Table S6). In contrast to a previously proposed
mechanism,[44] our data suggests formation of the N N bond
À
at the metal or within the solvent cage. This would deliver the
symmetrical hydrazine product, consistent with previous
observations.[44,45] As an adjunct to the main work described Conclusion
here, additional control experiments have shown facile
oxidation of the hydrazine to the azobenzene by Cu(OTf)2
aligning with the experimental data observed across these
separate studies (Scheme S14).[44,45]
In summary, the data provided establishes a framework
for oxidative C-N cross-coupling of arylboronic acids with
neutral N-ligands. Importantly, mechanistic data supports
7938
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