Ligand-Promoted Non-Directed C?H Cyanation of Arenes

Article abstract of DOI:10.1002/chem.201805772

This article reports the first example of a 2-pyridone accelerated non-directed C?H cyanation with an arene as the limiting reagent. This protocol is compatible with a broad scope of arenes, including advanced intermediates, drug molecules, and natural products. A kinetic isotope experiment (k_H/k_D=4.40) indicates that the C?H bond cleavage is the rate-limiting step. Also, the reaction is readily scalable, further showcasing the synthetic utility of this method.

Full text of DOI:10.1002/chem.201805772

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Accepted Article
Title: Ligand-Promoted Non-Directed C–H Cyanation of Arenes
Authors: Luo-Yan Liu, Kap-Sun Yeung, and Jin-Quan Yu
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To be cited as: Chem. Eur. J. 10.1002/chem.201805772
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DOI: 10.1002/anie.200((will be filled in by the editorial staff))
C–H Activation
Ligand-Promoted Non-Directed C–H Cyanation of Arenes
Luo-Yan Liu, Kap-Sun Yeung and Jin-Quan Yu*
Abstract: We herein report the first example of a 2-pyridone
accelerated non-directed C−H cyanation with an arene as the
limiting reagent. This protocol is compatible with a broad scope of
arenes, including advanced intermediates, drug molecules, and
natural products. A kinetic isotope experiment (kH/kD = 4.40)
indicates that the C–H bond cleavage is the rate-limiting step. Also,
the reaction is readily scalable, further showcasing the synthetic
utility of this method.
C
yanoarenes are abundant in natural products, drug
molecules, and advanced synthetic intermediates.1 The cyano
functional group is highly versatile in organic synthesis and can be
readily converted to carboxyl, carbonyl, amino, and other
heterocyclic groups.2 Thus, installation of cyano groups in a direct
and facile manner is of high interest. However, introduction of
cyano groups onto arenes have traditionally relied heavily on the
Sandmeyer reaction and other transition-metal-mediated cross-
coupling reactions with aryl halides.3 The use of highly reactive
diazonium intermediate and the requirement to prefunctionalize
arenes render these traditional methods undesirable and inefficient,
often with limited scope and functional group tolerance.
Figure 1. (a) Previous work about transition-metal-catalyzed directed C(sp2)–H
cyanation. (b) Non-directed cyanation of arenes via radical mechanism (c) Ligand-
accelerated non-directed C(sp2)–H olefination of arenes. (d) Ligand-accelerated non-
directed C(sp2)–H cyanation of arenes.
On the other hand, direct C–H cyanation of arenes offers a
potentially superior alternative. In the past decade, tremendous
efforts have been devoted to the development of directed C–H
cyanation of arenes. Pyridines, pyrimidines, and oximes have been
employed as directing groups for ortho C–H cyanation with Pd, Ru,
Rh, and Co catalysts (Fig. 1a).4 A meta-selective C–H cyanation
has been realized using a U-shaped template.5 More recently, two
examples of non-directed C–H cyanation of arenes through radical
pathways have also been achieved (Fig. 1b).6 In a continuing effort
to improve the reactivity and selectivity of non-directed C–H
functionalizations of arenes, we have successively discovered 2,6-
dialkyl pyridine ligands7 that can accelerate non-directed C–H
olefination of electron-deficient arenes and electron-deficient 2-
pyridone ligands8 that can enable C–H olefination with arenes as the
limiting reagent (Fig. 1c).
Table1. Ligand Evaluation a,b
Guided by these ligand developments, we wondered whether
these ligands could be used to enable C–H cyanation. We began our
study by treating the model substrate mesitylene (1.0 equiv.) with
Pd(OAc)2 (10 mol%), AgCN (1.1 equiv., cyanide source), and
AgOAc (3.0 equiv.) in HFIP (solvent) at 100 oC. Encouragingly, the
desired C(sp2)–H cyanation product was detected in 18% yield. We
first evaluated several mono-dentate pyridine-based ligands (L1-L3),
which have been shown to promote C–H activation.9 However,
[]
L.-Y. Liu, Prof. Dr. J.-Q. Yu
Department of Chemistry, The Scripps Research Institute (TSRI)
10550 North Torrey Pines Road, La Jolla, CA 92037 (USA)
E-mail: yu200@scripps.edu
[a] Conditions: mesitylene (0.2 mmol, 1.0 equiv), Pd(OAc)2 (10 mol%), ligand (20
mol%), AgOAc (3.0 equiv), AgCN (1.1 equiv.), HFIP (0.5 mL), 100 oC, under air, 24 h.
See SI for work up procedures. [b] The yield was determined by 1H NMR analysis of
the crude product using CH2Br2 as the internal standard.
Dr. Kap-Sun Yeung
Discovery Chemistry, Bristol-Myers Squibb Research and Development,
5 Research Parkway, Wallingford, CT 06492 (USA)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/anie.201xxxxxx.
1
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10.1002/chem.201805772
Chemistry - A European Journal
only trace amounts of product were observed. Based on our previous
studies on non-directed C(sp2)–H olefination promoted by electron-
deficient 2-pyridone ligands, we set out to extensively screen 2-
pyridone ligands for this non-directed C(sp2)–H cyanation reaction.
The addition of a simple 2-pyridone ligand suppressed the reactivity
(L4). To our delight, the use of 5-nitro-2-pyridone, which has
previously demonstrated efficiency for γ-C(sp3)–H arylation,10
slightly increased the yield to 25% (L5). Incorporation of a
trifluoromethyl or a nitro group at the 3 position of L5 led to lower
yields (L6, L7). A significant drop in reactivity was observed with
3-nitro-2-pyridone (L8). Intriguingly, the yield increased to 77%
when a trifluoromethyl group was installed at the 5-position of L8
(L9). The replacement of 5-CF3 in L9 with 5-Cl further improved
the yield to 87% (L10). However, the use of 3,5-dichloro-2-
pyridone resulted in loss of reactivity (L11). These results suggest
that this cyanation reaction is exceptionally sensitive to the steric
and electronic environments of the 2-pyridone ligands. Other
structural variations of 2-pyridone ligands resulted in low reactivity
(L12-L15) (Table 1).
been examined, such as oxidants, solvents, and temperature. Further,
minimal products were afforded with KCN, K3Fe(CN)6, and
TMSCN as the cyanation reagents. Oxidants other than AgOAc only
provided trace products, while other variations of the reaction
parameters resulted in inferior reactivity.
With the optimal reaction conditions established, we next
explored the scope of arenes for this non-directed cyanation reaction.
Extensive screening of 2-pyridone ligands proved that L9 gave
similar even higher yields than L10 in some cases, thus both of the
two ligands were used to explore the substrate scope of this reaction.
Electron neutral to rich arenes such as simple benzene, alkyl
substituted benzenes, and alkoxy benzenes consistently afforded the
mono-cyanated products in good yields (2a−2q, 2t−2u). The mono
selectivity could be explained by the electron-deficient nature of
cyanated arenes. Mono-alkylated arenes were cyanated at the less
Table 3. Substrate Scope a,b
With the optimal ligand L10 identified, we next examineed
different cyanide sources and their loadings (Table 2). We first
tested several commercially available cyanide salts and found that
increasing the loading of AgCN to 2.0 equivalents from 1.1
equivalents decreased yield to 50% from 84%, presumably due to
palladium catalyst deactivation by excess cyanide coordination.11
Screening of two other cyanide sources showed that CuCN and
Zn(CN)2 gave lower yields. Other reaction parameters have also
Table 2. Optimization of Reaction Conditions a,b,c
[a] Conditions: o-xylene (0.2 mmol, 1.0 equiv), Pd(OAc)2 (10 mol%), ligand (20
mol%), AgOAc (3.0 equiv), AgCN (1.1 equiv.), HFIP (0.5 mL), 100 oC, under air, 24 h.
See SI for work up procedures. [b] The yield was determined by 1H NMR analysis of
the crude product using CH2Br2 as the internal standard. [c] The product was isolated as
a mixture of two isomers: 3-cyano and 4-cyano o-xylene.
2
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To further examine the practicality of this reaction, we also
examined cyanation on advanced intermediates and biologically
relevant substrates (2v−2x, 2ab−2ac). Gladly, O, S, N- heterocycles
could be cyanated in good yields. Interestingly, for both
dibenzofuran and dibenzothiophene, cyanation proceeded
sleectively at the 4 position, while olefination occurred at the 2
position in our previous studies for non-directed olefination.ref This
suggests that electronic effect is more important to selectivity
compared to steric effect in this cyanation reaction. Some natural
products and drug molecules can also be cyanated under the optimal
conditions in moderate to good yields (2z, 2aa, 2ad). 2-Alkyl/aryl
anisoles were observed to give better selectivity (2ae−2aj), which
could be rationalized by a combination of electronic effect and steric
effect (Table 3).
To further showcase the synthetic utility of this method, non-
directed cyanation of mesitylene (1h) was carried out on 10.0 mmol
scale, yielding the desired product in 62% yield (Fig. 2a).
[a] Conditions: 1 (0.2 mmol, 1.0 equiv), Pd(OAc)2 (10 mol%), L9 (20 mol%), AgOAc
(3.0 equiv), AgCN (1.1 equiv.), HFIP (0.5 mL), 100 oC, under air, 24 h. See SI for work
up procedures. [b] The product was isolated as mixture of regio-isomers. [c] 3.0 equiv.
of benzene were used. [d] 8.0 equiv. of substrates were used. [e] The reaction was
conducted at 120 oC. [f] 15 mol% Pd(OAc)2 were used instead of 10 mol%. [g] 20 mol%
Pd(OAc)2 were used instead of 10 mol%. [h] L10 was used instead of L9. [i] The
reaction was conducted at 90 oC for 12 h.
Figure 2. (a) Scale-up reaction. (b) Primary kinetic isotope effect.
sterically hindered meta and para positions, providing meta- and
para-isomers as the main products (2b−2d). Arenes with bulkier
substituents such as tert-butyl group (2d) afforded considerably
better para site selectivity. Di-alkylated and tri-alkylated arenes all
provided the mono-cyanated products in good yields with various
selectivities depending on the substitution patterns of the alkylated
arenes (2e−2h). Strong electron-donating substituents such as
alkoxy groups, only provide ortho- and para-cyanated isomers,
owing to its electronic effect. The bulkier silyl-protected phenol
gave para-cyanated product as the main isomer because of steric
effect (2p and 2q). Naphthalene also provided the cyanated pruducts
in 73% yield, with a 2.0/1.0 selectivity ratio (α/β) (2l). This non-
directed cyanation occurred selectively on the relative electron-rich
arene for diaryl substrates (2m). For 2-chloroanisole and 3-
chloroanisole (2n and 2o), the yields dropped to only 20% under the
same conditions due to the electron-withdrawing effect of the
chloride on the benzene ring. However, heating up the reaction to
120 oC improved yields to 64% and 50% respectively. Electron-
deficient arenes such as chlorobenzene and methyl benzoate, are
unreactive to this reaction condition, thus 8.0 equiv. of arenes and
1.0 equiv. of cyanide were used to secure 45% and 50% yields
respectively (2s and 2t).
Figure 3. Proposed mechanism
3
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10.1002/chem.201805772
Chemistry - A European Journal
Soc. Jpn. 1975, 48, 3298; (c) J. R. Dalton, S. L. Regen, J. Org. Chem.
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To gain insight into the reaction mechanism, we carried out kinetic
isotope effect (KIE) experiments. Intermolecular one-pot and
parallel experiments provided a PH/PD value of 4.29 and a kH/kD
value of 4.40, respectively, which suggest that the C–H activation
step is rate-limiting step (Fig. 2b).
A plausible catalytic cycle is outlined in Figure 4. 2-pyridone
ligand functions as an analogue of OAc and accelerates C–H
cleavage to form intermediate II. Ligand Exchange of CN- between
AgCN and Pd complex intermediate II forms III. Then reductive
elimination from III provides the desired product (Fig. 3).
In summary, we have developed the first example of a Pd-
catalyzed non-directed cyanation of arenes, enabled by an electron-
deficient 2-pyridone ligands. The reaction features broad substrate
scope and high functional group compatibility, exemplified by
successful C–H cyanation of a range of complex molecules.
Currently, we are attempting to achieve better site selectivity for
non-directed C–H activation through ligand design.
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Received: ((will be filled in by the editorial staff))
Published online on ((will be filled in by the editorial staff))
[6] (a) J. B. Mcmanus, D. A. Nicewicz, J. Am. Chem. Soc. 2017, 139,
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Acknowledgement
[7] Y.-H. Zhang, B.-F. Shi, J.-Q. Yu, J. Am. Chem. Soc. 2009, 131, 5072.
We gratefully acknowledge The Scripps Research Institute, Bristol-
Meyers Squibb, and the NIH (NIGMS, 2R01GM084019) for
financial support.
[8] P. Wang, P. Verma, G.-Q. Xia, J. Shi, J. X. Qiao, S. Tao, P. T. W.
Cheng, M. A. Poss, M. E. Farmer, K.-S. Yeung, J.-Q. Yu, Nature
2017, 551, 489.
Keywords: cyanation · C–H activation · palladium · 2-pyridone
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4
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10.1002/chem.201805772
Chemistry - A European Journal
C–H Activation
L.-Y. Liu, K.-S. Yeung, J.-Q. Yu*
__________ Page – Page
Ligand-Accelerated Non-Directed C–
H Cyanation of Arenes
We herein report the first example of a 2-pyridone accelerated non-directed C−H
cyanation with an arene as the limiting reagent. This protocol is compatible with a
broad scope of arenes, including advanced intermediates, drug molecules, and
natural products. A kinetic isotope experiment (kH/kD = 4.40) indicates that the C–H
bond cleavage is the rate-limiting step. Also, the reaction is readily scalable, further
showcasing the synthetic utility of this method.
5
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10.1002/chem.201805772
Chemistry - A European Journal
6
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