Ruthenium-catalysedmeta-selective CAr-H bond alkylationviaa deaminative strategy

Article abstract of DOI:10.1039/d1cc00039j

The use of aliphatic amines as alkylating reagents in organic synthesisviaC-N bond activation remains underdeveloped. We herein describe a novel ruthenium-catalysed and directing-group assisted protocol for the synthesis ofmeta-alkylated arenesviadual C-H and C-N activation. Bench-stable and easily handled redox-active Katritzky pyridinium salts derived from abundant amines and amino acid species were used as alkyl radical precursors. This catalytic reaction could accommodate a broad range of functional groups and provide access to variousmeta-alkylated products.

Full text of DOI:10.1039/d1cc00039j

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Ruthenium-catalysed meta-selective CAr–H bond
alkylation via a deaminative strategy†
Cite this: Chem. Commun., 2021,
57, 3411
Ze-Fan Zhu, Guang-Le Chen and Feng Liu
*
Received 4th January 2021,
Accepted 26th February 2021
DOI: 10.1039/d1cc00039j
rsc.li/chemcomm
The use of aliphatic amines as alkylating reagents in organic synthesis meta-C–H alkylation via ruthenium catalysis to meet various
via C–N bond activation remains underdeveloped. We herein describe demands is still required.
a novel ruthenium-catalysed and directing-group assisted protocol
The generation of alkyl radicals from naturally abundant
for the synthesis of meta-alkylated arenes via dual C–H and C–N and inexpensive feedstocks is highly important for synthetic
activation. Bench-stable and easily handled redox-active Katritzky chemistry. Although aliphatic amines are widely found in
pyridinium salts derived from abundant amines and amino acid synthetic chemicals and bioactive molecules, their utilizations
species were used as alkyl radical precursors. This catalytic reaction as the alkylation reagents in organic synthesis remain
could accommodate a broad range of functional groups and provide underdeveloped.15 In recent years, bench-stable Katritzky salts,
access to various meta-alkylated products.
readily obtained from the condensation of primary amines with
2,4,6-triphenylpyrylium in one step, have been employed as the
The conversion of C–H bonds into C–C and C–heteroatom bonds is efficient alkyl radical precursors via C–N bond cleavage in a
an efficient and powerful approach for rapid generation of complex
molecules from simpler ones.1 However, the control of site selec-
tivity in molecules that contain diverse C–H bonds with electronic
and steric similarity remains a critical challenge in organic
synthesis.2 Directing-group-assisted transition-metal catalysis has
been identified as an effective strategy toward proximity-driven
ortho-selective C–H functionalization,3 which is well established. In
contrast, methods for remote meta-selective C–H activation remain
underdeveloped.4–6 The ruthenium-catalyzed s-activation strategy,
representatively developed by Ackermann, Frost and others in
recent years,7–13 has proven valuable for radical-type meta-
selective C–H functionalization through an ortho/para fashion, thus
enabling access to the alkylated,8,9 acylated,10 sulfonated,11
brominated,12 and nitrated13 products. Note that tertiary and
secondary alkyl halides could act as the efficient alkyl radical
precursors for the meta-selective C–H alkylation (Scheme 1a)8 but
the reaction of unactivated primary alkyl halides via ruthenium
catalysis led to the ortho-C–H alkylation.8b,14 Despite these signifi-
cant advances in the field, the development of new methods for
Jiangsu Key Laboratory of Neuropsychiatric Diseases and Department of Medicinal
Chemistry, College of Pharmaceutical Sciences, Soochow University,
199 Ren-Ai Road, Suzhou, Jiangsu 215123, People’s Republic of China.
E-mail: fliu2@suda.edu.cn
† Electronic supplementary information (ESI) available: Experimental details,
characterization data, and copies of 1H, 13C and 19F NMR spectra for all
Scheme 1 Radical deaminative arylation of pyridinium salts and meta-C–H
alkylation of arenes.
compounds. See DOI: 10.1039/d1cc00039j
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Table 1 Substrate scope with respect to CAr–H bondsab
number of reactions.16 In 2017, Watson and co-workers described
that Katritzky salts could act as amine-derived alkyl electrophiles
in Ni-catalyzed deaminative cross-coupling reactions with aryl-
boronic acids (Scheme 1b).17 This reaction proceeded with the
generation of alkyl radicals through a single-electron reduction
and fragmentation process. Recently, Ni-catalyzed reductive cross-
coupling of aryl halides with Katritzky salts, which was indepen-
dently developed by the groups of Watson,18a Martin,18b
Rueping,18c Pan,19 and Molander,20 has also been applied suc-
cessfully to C(sp3)–CAr bond formation (Scheme 1c). Besides,
Glorius’s group developed a photoredox-mediated alkylation of
heteroarenes with Katritzky salts via homolytic aromatic substitu-
tion (Scheme 1d).21 This Minisci arylation represents another
radical strategy to convert the ubiquitous NH2 moiety.
Motivated by the advantages of alkyl amine derivatives as alkyla-
tion reagents, we wondered whether the combination of C–N bond
activation and meta-CAr–H functionalization could be adapted to
synthesis of functionalized aromatic rings. In continuation of our
research effort on radical transformation of alkylpyridinium salts,22
we herein report the first example of ruthenium-catalyzed dual
activation of a C–N bond and C–H bond for meta-CAr–C(sp3) bond
formation (Scheme 1e). This protocol allows an array of alkyl
groups to be installed, providing a general method for the
transformation of amino groups into various aryl moieties.
After examining various conditions with respect to Ru
catalysts, inorganic bases, solvents, and ligands (see the ESI,†
Table S1, entries 1–19), we were pleased to find that, with
5 mol% of [RuCl2(p-cymene)]2 (10 mol% of [Ru]) as the catalyst,
2 equiv. of K2CO3 as the base, 30 mol% of camphorsulfonic acid
(CSA) and 10 mol% of PPh3 as the synergistic ligands, and 1,
4-dioxane (0.25 M) as the solvent, the catalytic reaction readily
offered the desired meta-alkylated product 3a in 91% yield
(Table S1, ESI,† entry 13). Variation in other commonly used
Ru catalysts, such as Ru3(CO)12, RuCl3Á3H2O, and RuCl2(PPh3)3,
provided lower chemical yield than [RuCl2(p-cymene)]2 under
a
Reaction conditions: a mixture of 1 (0.2 mmol), 2a (0.3 mmol),
[RuCl2(p-cymene)]2 (5 mol%), CSA (camphorsulfonic acid, 30 mol%),
K2CO3 (0.4 mmol) and PPh3 (10 mol%) in 1,4-dioxane (0.8 mL, used
without dehydration) was stirred at 120 1C (oil bath, sealed tube) for 48–72 h.
otherwise identical reaction conditions (Table S1, ESI,† entries b Isolated yields. c 1a (1.2 mmol, 186 mg) and 2a (1.8 mmol, 1.0 g).
17–19). The control experiments revealed that the ruthenium
catalyst and ligands were all essential for the success of the
reaction (Table S1, ESI,† entries 20–22).
To demonstrate the synthetic utility of this protocol, the reaction
With the optimized reaction conditions in hand, we aimed to using 1.2 mmol of 1a and 1.8 mmol (1.0 g) of 2a was performed
survey the scope and limitations of this strategy for meta-CAr–H under the standard conditions. The reaction still proceeded
alkylation with Katritzky salts. As shown in Table 1a, the reaction smoothly, offering the desired product 3a in 78% yield.
could accommodate a range of functional groups on the aromatic
To explore the further practicability of this deaminative
ring (3b–d and 3f–g) or the chelating pyridine ring (3h–i) regard- strategy, we examined the reaction of 2-arylpyridines (1) with
less of their electronic properties. Remarkably, the bromine atom various primary amine-derived redox-active Katritzky salts (2).
is well reserved in this Ru-catalyzed reaction (3c). As might be As depicted in Table 2, a broad range of acyclic, cyclic and
expected, blocking one of the meta-positions on the phenyl ring heterocyclic alkylpyridiniums were accommodated well by this
led to only trace amount of alkylated product being detected in Ru-catalyzed radical reaction, furnishing the desired meta-
the reaction (3e). Note that these experimental findings (e.g. 3e alkylated products in reasonable yields (4a–p). Note that the
and 3f) could indicate that the reaction is sensitive to the steric efficiency of the electrophilic radicals (4a–c) is better than
interactions. We next turned our attention to the investigation of that of the nucleophilic radicals (4h and 4p) when using
different directing groups (Table 1b). We were delighted to 2-phenylpyridine as the coupling partner. This protocol exhi-
find that the isoquinoline-, pyrimidine-, pyrazole-, and purine- bits excellent functional group compatibility, with, for example,
containing substrates could efficiently deliver the desired pro- amides/sulfonamides (4c and 4l–m), sulfides (4e), and
ducts (3j–m). Unfortunately, under similar reaction conditions, unmasked hydroxyl groups (4g) being well tolerated. Strikingly,
our efforts to achieve the alkylated products 3n–p were unsuccessful. the reaction of unactivated primary alkyl Katritzky salts via the
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Table 2 Substrate scope of alkylpyridinium saltsab
Scheme 2 Competitive experiments.
counterparts (Scheme 2, eqn (3) and (4)). Interestingly, fluorine-
containing substrate 1b is more reactive than 2-phenylpyridine (1a)
in both cases (eqn (1) and (3)). This could be attributed to the
conjugative effect of the F-atom to activate its ortho positions. These
phenomena suggest that a simple electrophilic substitution type
mechanism could be unlikely. On the other hand, with TEMPO
((2,2,6,6-tetramethylpiperidin-1-yl)oxyl) as a radical scavenger, the
reaction did not lead to the formation of the desired product 3a (see
the ESI†). This result could support the involvement of a radical
process.
a
Reaction conditions: a mixture of 1 (0.2 mmol), 2 (0.3 mmol),
[RuCl2(p-cymene)]2 (5 mol%), CSA (30 mol%), K2CO3 (0.4 mmol) and
Furthermore, we prepared the well-defined cyclometalated
ruthenium complex 5,8c which showed high catalytic activity
as [RuCl2(p-cymene)]2 under similar reaction conditions
(Scheme 3). On the basis of the observations and previous
reports,8,9 a proposed mechanism of the catalytic transforma-
PPh3 (10 mol%) in 1,4-dioxane (0.8 mL, used without dehydration) was
stirred at 120 1C (oil bath, sealed tube) for 48–72 h. Isolated yields.
b
Diastereoselectivity ratio (dr) and regioisomeric ratio (m : o) determined
from the 1H NMR spectra.
Ru catalytic system could afford both meta-C–H and ortho-C–H tion is depicted in Scheme 3. The in situ generated ruthe-
alkylation products (4o–p), while the reaction of unactivated nium(II) complex A undergoes single-electron transfer (SET) to
primary alkyl halides led to ortho-C–H alkylation as the exclu- Katritzky salt 2 to offer the ruthenium(III) complex B, as well as
sive reaction pattern under similar conditions.8b,14
the corresponding alkyl radical, which attacks on the arene
To gain further understanding of the reaction mode, we moiety at the activated position para to ruthenium, delivering
performed intermolecular competition experiments between
differently substituted phenylpyridines (Scheme 2). When
using the Katritzky salt 2a derived from amino acid ester as
the adduct species C. Subsequently, ligand to metal charge
transfer and re-aromatization leads to the ruthenacycle
D. Finally, ligand exchange could provide the desired meta-
the alkylating reagent, the results revealed that electron-rich alkylated product 3 or 4 and thus regenerate the ruthenium(III)
methoxy-substituted arene 1d was the most reactive substrate complex A to close the catalytic cycle.
(Scheme 2, eqn (1) and (2)). In contrast, the experimental data
In summary, we have described a novel method towards
obtained from the competitive reactions of Katritzky salt 2h meta-decorated arenes that is based on an unprecedented
demonstrated that electron-deficient arenes could be inherently ruthenium-catalyzed dual activation of C–N and C–H bonds.
more reactive than their electron-neutral or electron-rich
The readily available redox-active Katritzky pyridinium salts
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5 meta-CAr–H functionalization via a steric control pattern, see:
(a) D. W. Robbins and J. F. Hartwig, Angew. Chem., Int. Ed., 2013,
52, 933; (b) B. M. Partridge and J. F. Hartwig, Org. Lett., 2013, 15, 140.
6 meta-CAr–H functionalization via
a transient mediator, see:
(a) H. Shi, A. N. Herron, Y. Shao, Q. Shao and J.-Q. Yu, Nature, 2018,
558, 581; (b) G. Cheng, P. Wang and J.-Q. Yu, Angew. Chem., Int. Ed.,
2017, 56, 8183; (c) J. Ye and M. Lautens, Nat. Chem., 2015, 7, 863;
(d) Z. Dong, J. Wang and G. Dong, J. Am. Chem. Soc., 2015, 137, 5887.
7 For a review, see: J. A. Leitch and C. G. Frost, Chem. Soc. Rev., 2017,
46, 7145.
8 (a) K. Korvorapun, R. Kuniyil and L. Ackermann, ACS Catal., 2020,
10, 435; (b) A. Sagadevan and M. F. Greaney, Angew. Chem., Int. Ed.,
2019, 58, 9826; (c) P. Gandeepan, J. Koeller, K. Korvorapun, J. Mohr
and L. Ackermann, Angew. Chem., Int. Ed., 2019, 58, 9820;
(d) F. Fumagalli, S. Warratz, S.-K. Zhang, T. Rogge, C. Zhu,
A. C. Stu¨ckl and L. Ackermann, Chem. – Eur. J., 2018, 24, 3984;
(e) K. Korvorapun, N. Kaplaneris, T. Rogge, S. Warratz, A. C. Stu¨ckl
and L. Ackermann, ACS Catal., 2018, 8, 886; ( f ) J. Li, K. Korvorapun,
S. De Sarkar, T. Rogge, D. J. Burns, S. Warratz and L. Ackermann,
Nat. Commun., 2017, 8, 15430; (g) Z.-Y. Li, L. Li, Q.-L. Li, K. Jing,
H. Xu and G.-W. Wang, Chem.
– Eur. J., 2017, 23, 3285;
(h) A. J. Paterson, C. J. Heron, C. L. McMullin, M. F. Mahon,
N. J. Press and C. G. Frost, Org. Biomol. Chem., 2017, 15, 5993;
(i) Z. Ruan, S.-K. Zhang, C. Zhu, P. N. Ruth, D. Stalke and
L. Ackermann, Angew. Chem., Int. Ed., 2017, 56, 2045; ( j) J. Li,
S. Warratz, D. Zell, S. De Sarkar, E. E. Ishikawa and L. Ackermann,
J. Am. Chem. Soc., 2015, 137, 13894; (k) A. J. Paterson, S. S. John-
Campbell, M. F. Mahon, N. J. Press and C. G. Frost, Chem. Commun.,
2015, 51, 12807; (l) N. Hofmann and L. Ackermann, J. Am. Chem.
Soc., 2013, 135, 5877.
9 (a) X.-G. Wang, Y. Li, H.-C. Liu, B.-S. Zhang, X.-Y. Gou, Q. Wang,
J.-W. Ma and Y.-M. Liang, J. Am. Chem. Soc., 2019, 141, 13914;
(b) G. Li, D. Li, J. Zhang, D.-Q. Shi and Y. Zhao, ACS Catal., 2017,
7, 4138; (c) B. Li, S.-L. Fang, D.-Y. Huang and B.-F. Shi, Org. Lett., 2017,
19, 3950.
Scheme 3 Control experiment and proposed mechanism.
10 K. Jing, Z.-Y. Li and G.-W. Wang, ACS Catal., 2018, 8, 11875.
11 O. Saidi, J. Marafie, A. E. W. Ledger, P. M. Liu, M. F. Mahon,
derived from abundant amines were used as efficient radical
precursors for remote CAr–H bond alkylation. The reaction
works well with a range of N-containing directing groups, such
as pyridine, pyrimidine, pyrazole, isoquinoline, and purine.
This catalytic reaction displays an excellent functional group
tolerance and could be applicable to the introduction of a
variety of alkyl moieties.
¨
G. Kociok-Kohn, M. K. Whittlesey and C. G. Frost, J. Am. Chem. Soc.,
2011, 133, 19298.
12 (a) C. J. Teskey, A. Y. W. Lui and M. F. Greaney, Angew. Chem., Int.
Ed., 2015, 54, 11677; (b) Q. Yu, L. Hu, Y. Wang, S. Zheng and
J. Huang, Angew. Chem., Int. Ed., 2015, 54, 15284.
13 Z. Fan, J. Ni and A. Zhang, J. Am. Chem. Soc., 2016, 138, 8470.
14 (a) L. Ackermann, N. Hofmann and R. Vicente, Org. Lett., 2011,
´
13, 1875; (b) L. Ackermann, P. Novak, R. Vicente and N. Hofmann,
Angew. Chem., Int. Ed., 2009, 48, 6045.
The authors acknowledge the Natural Science Foundation of
the Jiangsu Higher Education Institutions of China (Grant No.
18KJA350001) and the Priority Academic Program Development
of the Jiangsu Higher Education Institutes (PAPD).
15 Electronic or strain activation of the C(sp3)–N bond, see:
(a) C. H. Basch, K. M. Cobb and M. P. Watson, Org. Lett., 2016,
18, 136; (b) T. Moragas, M. Gaydou and R. Martin, Angew. Chem., Int.
Ed., 2016, 55, 5053; (c) J. Hu, H. Sun, W. Cai, X. Pu, Y. Zhang and
Z. Shi, J. Org. Chem., 2016, 81, 14; (d) Y.-Q.-Q. Yi, W.-C. Yang,
D.-D. Zhai, X.-Y. Zhang, S.-Q. Li and B.-T. Guan, Chem. Commun.,
2016, 52, 10894; (e) Y. Gui and S.-K. Tian, Org. Lett., 2017, 19, 1554;
Conflicts of interest
The authors declare no competing financial interest.
References
1 (a) J. Wencel-Delord and F. Glorius, Nat. Chem., 2013, 5, 369;
(b) L. McMurray, F. O’Hara and M. J. Gaunt, Chem. Soc. Rev., 2011,
40, 1885.
´
´
( f ) M. Guisan-Ceinos, V. Martın-Heras and M. Tortosa, J. Am. Chem.
Soc., 2017, 139, 8448.
16 For a review, see: F.-S. He, S. Ye and J. Wu, ACS Catal., 2019, 9, 8943.
17 (a) J. Liao, W. Guan, B. P. Boscoe, J. W. Tucker, J. W. Tomlin,
M. R. Garnsey, J. J. Piane and M. P. Watson, Org. Lett., 2018,
20, 3030; (b) C. H. Basch, J. Liao, J. Xu, J. J. Piane and
M. P. Watson, J. Am. Chem. Soc., 2017, 139, 5313.
18 (a) J. Liao, C. H. Basch, M. E. Hoerrner, M. R. Talley, B. P. Boscoe,
J. W. Tucker, M. R. Garnsey and M. P. Watson, Org. Lett., 2019,
21, 2941; (b) R. Martin-Montero, V. R. Yatham, H. Yin, J. Davies and
R. Martin, Org. Lett., 2019, 21, 2947; (c) H. Yue, C. Zhu, L. Shen, Q. Geng,
K. J. Hock, T. Yuan, L. Cavallo and M. Rueping, Chem. Sci., 2019, 10, 4430.
19 S. Ni, C. Li, Y. Mao, J. Han, Y. Wang, H. Yan and Y. Pan, Sci. Adv.,
2019, 5, eaaw9516.
2 R. G. Bergman, Nature, 2007, 446, 391.
3 (a) K. M. Engle, T.-S. Mei, M. Wasa and J.-Q. Yu, Acc. Chem. Res.,
2012, 45, 788; (b) meta-CArÀH functionalization through an
auxiliary-coordinated process, see: T. W. Lyons and M. S. Sanford,
Chem. Rev., 2010, 110, 1147.
4 (a) meta-CAr–H functionalization through an auxiliary-coordinated
process, see: R. Jayarajan, J. Das, S. Bag, R. Chowdhury and D. Maiti,
Angew. Chem., Int. Ed., 2018, 57, 7659; (b) Z. Zhang, K. Tanaka and
J.-Q. Yu, Nature, 2017, 543, 538; (c) S. Bag, R. Jayarajan, U. Dutta,
R. Chowdhury, R. Mondal and D. Maiti, Angew. Chem., Int. Ed., 2017,
20 J. Yi, S. O. Badir, L. M. Kammer, M. Ribagorda and G. A. Molander,
Org. Lett., 2019, 21, 3346.
21 F. J. R. Klauck, M. J. James and F. Glorius, Angew. Chem., Int. Ed.,
2017, 56, 12336.
56, 12538; (d) A. Maji, B. Bhaskararao, S. Singha, R. B. Sunoj and 22 (a) Z.-F. Zhu, J.-L. Tu and F. Liu, Chem. Commun., 2019, 55, 11478;
D. Maiti, Chem. Sci., 2016, 7, 3147; (e) Y. Kuninobu, H. Ida, M. Nishi
and M. Kanai, Nat. Chem., 2015, 7, 712.
(b) Z.-F. Zhu, M.-M. Zhang and F. Liu, Org. Biomol. Chem., 2019,
17, 1531; (c) M.-M. Zhang and F. Liu, Org. Chem. Front., 2018, 5, 3443.
This journal is © The Royal Society of Chemistry 2021
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