Versatile ruthenium(ii)-catalyzed C-H cyanations of benzamides

Article abstract of DOI:10.1039/c3cc49502g

Direct cyanations of arenes and heteroarenes bearing only weakly coordinating amides were accomplished using a robust ruthenium(ii) catalyst. The user-friendly C(sp²)-H activation occurred with the assistance of carboxylate with high site-selectivity, excellent functional group tolerance and ample scope.

Full text of DOI:10.1039/c3cc49502g

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Versatile ruthenium(II)-catalyzed C–H cyanations
of benzamides†
Cite this: Chem. Commun., 2014,
50, 1878
Weiping Liu and Lutz Ackermann*
Received 15th December 2013,
Accepted 2nd January 2014
DOI: 10.1039/c3cc49502g
www.rsc.org/chemcomm
Direct cyanations of arenes and heteroarenes bearing only weakly as oxazolines, oximes, pyrazoles or pyridines.17–19 Herein, we wish to
coordinating amides were accomplished using a robust ruthenium(II) disclose an alternative strategy, which involves the use of relatively
catalyst. The user-friendly C(sp2)–H activation occurred with the inexpensive20 ruthenium(II) catalysts21 for the first time for C(sp2)–H
assistance of carboxylate with high site-selectivity, excellent func- cyanations. Importantly, the versatile ruthenium catalyst enabled
tional group tolerance and ample scope.
expedient C–H cyanations with easily accessible N-cyano-N-phenyl-
p-toluenesulfonamide (NCTS, 2) as the most user-friendly cyanation
Aromatic nitriles constitute key structural motifs of important phar- reagent for the functionalization of only weakly coordinating22 aro-
maceuticals, dyes, agrochemicals and natural products.1–3 The cyano matic and heteroaromatic amides – key structural scaffolds in organic
group serves as a versatile functional group that can easily be synthesis and medicinal chemistry.
transformed into amines, ketones or aldehydes, among others.4
We initiated our studies by probing the effect of different
The syntheses of aryl nitriles continue to rely on classical approaches, additives and solvents on the envisioned C–H bond cyanation
such as the Sandmeyer5 or the Rosenmund–von Braun reaction,6,7 using synthetically useful benzamide 1a (Table 1).
which have severe limitations, including the use of stoichiometric or
Thus, [RuCl2(p-cymene)]2 enabled the desired direct cyanation
even super-stoichiometric amounts of metal cyanides as well as harsh when using both AgSbF6 and AgOAc as additives in DCE as the
reaction conditions. An alternative approach is represented by transi-
tion metal-catalyzed cyanations of aryl halides or boronic acids under
milder reaction conditions.8 These catalyzed coupling reactions
thereby also display a considerably improved functional group
tolerance. However, this strategy exploits prefunctionalized sub-
strates, the preparation of which requires numerous functional group
interconversions and generates undesired waste.
Table 1 Optimization of C–H cyanation with benzamide 1aa
The catalytic activation of otherwise inert C(sp2)–H bonds as latent
functional groups has in recent years emerged as an increasingly
viable tool for improving the atom- and step-economy of organic
synthesis.9 Thus, Yu developed direct cyanations of 2-
Entry
Additive
Solvent
Yield (%)
1
2
AgOAc
Cu(OAc)2
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
KOAc
DCE
DCE
DCE
DCE
77 (70)
30
3b
80 (67)
o5
arylpyridines.10,11 The research groups of Jiao12 and Chang13 reported 4c
5d
DCE
67 (54)
38
on oxidative cyanations of electron-rich substrates with nonmetallic
6
7
8
1,4-Dioxane
o-Xylene
Toluene
DMF
DCE
DCE
DCE
DCE
DCE
cyano-group sources in the presence of stoichiometric sacrificial
21
23
oxidants,14,15 while Hartwig disclosed a two-step iridium-catalyzed
borylation/copper-mediated cyanation protocol.16 Very recently,
rhodium-catalyzed C–H cyanations of arenes were accomplished,
9
o2
10e
11
o2
o5
albeit exploiting rather strongly coordinating directing groups, such 12
CsOAc
NaOAc
NaOAc
17
13
90 (80)
95 (84)
14 f
Institut fuer Organische und Biomolekulare Chemie, Georg-August-Universitaet,
Tammannstrasse 2, 37077 Goettingen, Germany.
a
Reaction conditions: 1a (0.5 mmol), 2 (1.0 mmol), [RuCl2( p-cymene)]2
E-mail: Lutz.Ackermann@chemie.uni-goettingen.de
(5.0 mol%), AgSbF6 (20 mol%), additive (20 mol%), solvent (2.0 mL),
† Electronic supplementary information (ESI) available: Experimental proce-
dures, characterization data, and 1H and 13C NMR spectra of products. See
DOI: 10.1039/c3cc49502g
120 1C, 18 h; GC-conversion, isolated yields are given in parentheses.
b
c
d
e
AgOAc (30 mol%). Without AgSbF6. AgSbF6 (30 mol%). Without
f
[RuCl2( p-cymene)]2. 24 h.
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Scheme 1 Effect of N-substituents on C–H cyanations.
solvent (entries 1–5). DCE proved to be the solvent of choice (entries 1
and 6–9), while a test reaction illustrated that the C–H bond activation
did not occur in the absence of the ruthenium catalyst (entry 10).
Among a set of representative metal acetate additives,23,24 NaOAc
furnished the highest yields of the product 3a (entries 11–14).
With the optimized catalytic system in hand, we explored the
effect exerted by the N-substituent at the amide moiety (Scheme 1). A
variety of tertiary amides 1a–1f proved to be suitable substrates with
optimal results being accomplished with the sterically hindered
substrate 1a.25 A comparable catalytic efficacy was obtained when
performing the C–H bond cyanation on a larger 5 mmol scale.
Subsequently, we tested the scope of the catalytic system for the
cyanation of aromatic amides 1 (Scheme 2). The robust ruthenium(II)
complex proved to be highly chemo-selective. Thus, the catalyst
tolerated a set of valuable electrophilic functional groups, such as ester,
fluoro, chloro, bromo and even iodo groups, which should be invalu-
able for the further diversification of the thus obtained products 3.
Scheme 3 C–H cyanation with heteroaromatic amides 1.
The user-friendly ruthenium(II) catalyst was not limited to the
functionalization of arenes. Indeed, challenging heteroaromatic
substrates 1p–1u were efficiently directly functionalized both at
positions C–2 (Scheme 3a) as well as C–3 (Scheme 3b). Thereby,
cyanated thiophenes, furanes, benzothiophenes, benzofuranes
and indoles were obtained in a chemo- and site-selective fashion.
The well-defined ruthenium(II) biscarboxylate complex 426 dis-
played a catalytic activity comparable to the one observed when using
the in situ generated system, notably even in the absence of NaOAc
(Scheme 4).
In consideration of the unique chemo-selectivity and outstanding
efficacy of our ruthenium catalyst, we became interested in delineat-
ing its mode of action. To this end, intramolecular competition
experiments with meta-substituted substrates 1v–1x revealed a con-
siderable secondary directing group effect27 exerted by a methoxy
substituent and, even more pronounced, by a fluoro group present in
benzamides 1w and 1x, respectively (Scheme 5).
Intermolecular competition experiments between differently deco-
rated amides indicated electron-rich arenes to be preferentially
converted (Scheme 6), which can be rationalized in terms of an
electrophilic-type activation mode of the cationic ruthenium species.
In support of this hypothesis, we observed a rather low kinetic
isotope effect (KIE) of kH/kD E 1.2 (see the ESI†). Moreover, C–H
bond activation conducted in the presence of D2O as the cosolvent
Scheme 2 Scope of ruthenium-catalyzed C–H cyanation with amides 1.
Scheme 4 Well-defined complex 4 as the catalyst.
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insertion of NCTS (2) give rise to key intermediate 7. Subsequently,
b-elimination provides the desired product 3, while proto-demetalation
regenerates the cationic ruthenium(II) carboxylate catalyst 5.
In summary, we have reported on the use of relatively
inexpensive ruthenium-catalyzed C(sp2)–H bond cyanation on
arenes for the first time. The robust direct cyanation29,30
occurred site-selectively on synthetically useful aromatic and
heteroaromatic amides with ample scope. Experimental mecha-
nistic studies provided strong support for a reversible C–H
metalation mechanism by a cationic ruthenium(II) complex.
Support from the European Research Council under the European
Community’s Seventh Framework Program (FP7 2007–2013)/ERC
Grant agreement no. 307535 and the Chinese Scholarship Council
(fellowship to W.L.) is gratefully acknowledged.
Scheme 5 Intramolecular competition experiments with meta-substituted
arenes 1.
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Scheme 7 H/D exchange reaction.
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(Scheme 7).
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Scheme 8 Plausible catalytic cycle.
1880 | Chem. Commun., 2014, 50, 1878--1881
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´
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