A Mild and Direct Site-Selective sp2 C-H Silylation of (Poly)Azines

Article abstract of DOI:10.1021/jacs.8b12063

A base-mediated protocol that allows for the site-selective sp² C-H silylation of azines is described. This method is distinguished by its mild conditions, simplicity and excellent site-selective modulation for a diverse set of azines, even in the context of late-stage functionalization, while exhibiting orthogonal reactivity with classical silylation reactions.

Full text of DOI:10.1021/jacs.8b12063

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A Mild & Direct Site-Selective sp2 C–H Silylation of (Poly)Azines
Yiting Gu, Yangyang Shen, Cayetana Zarate, and Ruben Martin
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 18 Dec 2018
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A Mild & Direct Site-Selective sp2 C–H Silylation of (Poly)Azines
Yiting Gu,†£‡ Yangyang Shen, †£‡ Cayetana Zarate,†£ and Ruben Martin†§*
†Institute of Chemical Research of Catalonia (ICIQ), The Barcelona Institute of Science and Technology, Av. Països
Catalans 16, 43007 Tarragona, Spain
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£ Universitat Rovira i Virgili, Departament de Química Analítica i Química Orgànica, c/Marcel·lí Domingo, 1, 43007
Tarragona, Spain
§ ICREA, Passeig Lluís Companys, 23, 08010, Barcelona, Spain
Supporting Information Placeholder
remain currently confined to C3-selective processes with
ABSTRACT: A base-mediated protocol that allows for
noble Ir or Ru catalysts (Scheme 1, path b).10 Therefore,
the site-selective sp2 C–H silylation of azines is
at the outset of our investigations it was unclear whether
described. This method is distinguished by its mild
a switchable C2/C4–H silylation of pyridines could be
conditions, simplicity and excellent site-selective
developed without steric and electronic bias.11 If
modulation for a diverse set of azines, even in the context
successful, we recognized that such a pathway would give
of late-stage functionalization, while exhibiting
access to elusive silylated advanced pharmaceutical
orthogonal reactivity with classical silylation reactions.
ingredients (APIs) with predictable reactivity and site-
selectivity. As part of our interest in catalytic C–Si bond-
The prevalence of (poly)azines in pharmaceuticals and
formations,12 we report herein the successful realization
biologically-active molecules have challenged chemists
of this goal (Scheme 1, bottom). Our protocol is
characterized by its simplicity, mild conditions and a
to design site-selective C–H functionalizations of these
heterocycles.1,2 At present, these techniques typically rely
predictable site-selectivity pattern, even in the context of
on two-step procedures via preactivated (poly)azine
intermediates (Scheme 1, path a).3 Despite the advances
late-stage silylation of azine drugs, that can be modulated
realized,2-3 a switchable and direct site-selective C–H
functionalization capable of forging C–heteroatom bonds
in (poly)azines still remains largely unexplored.4 For
example, C4-selective functionalization is not as
commonly practiced as one might initially anticipate, thus
constituting a worthwhile endeavour.4-6
by a judicious choice of the solvent employed while
obviating the need for transition metal complexes or
prefunctionalized substrates. Preliminary mechanistic
studies suggest the intermediacy of silyl anions, offering
orthogonal reactivity with existing silylation techniques.
Table 1. Optimization of the Reaction Conditions.a
Scheme 1. Forging C–Heteroatom Bonds in (Poly)Azines.
Driven by the versatility of (hetero)aryl silanes as
synthons in organic synthesis and their interest in
medicinal and material science,7 the recent years have
witnessed the design of metal-catalyzed sp2 C–H
silylation reactions.8 While the coupling of electron-rich
or electron-neutral (hetero)arenes has become routine,8,9
sp2 C–H silylation strategies of electron-deficient azines
a
1a (0.40 mmol), Et3SiBPin (0.40 mmol), KHMDS (1
b
equiv), DME (2 mL) at rt. GC yields using decane as
internal standard. c Isolated yield.
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Our study began by evaluating the direct C4–silylation of
Page 2 of 6
aliphatic or aromatic substituents at either C2 (5a, 5e-5h,
5k) or C3 (5b-5d, 5g-5j, 5l-o), even with particularly
sterically-hindered combinations (5c, 5d).17 As
anticipated, substituents at C4 gave rise to C2–silylated
compounds (5p-5s). Notably, pyrazines (5u), pyridimines
(5t), imidazo[1,2-b]pyridazines (5v), pyridimines (5w) or
quinolines (5x) posed no problems. Equally interesting
was the observation that ketones (5f), free amines (5k, 5l)
or aryl chlorides (5m) do not interfere with C–Si bond-
formation. The latter is particularly noteworthy, leaving
ample room for further functionalization via cross-
coupling reactions.20 Importantly, 5p could be scaled up
without compromising neither yield nor regioselectivity.
As for Table 1 (entry 11), site-selectivity could be tuned
and controlled by subtle modulation of the electronic
properties of bipyridine cores via N-oxide derivatives (5y,
5z).18,19
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pyridine (1a) with Et3SiBPin (Table 1). After some
experimentation,13 we found that a transition metal-free
protocol consisting of KHMDS in DME at rt afforded 2a
in 74% isolated yield with excellent C4:C2 (10:1) ratio
(entry 1). Interestingly, a strong solvent effect (entries 1-
4) was noticed. Specifically, C4 silylation was
predominantly observed with bidentate solvents (entries
1-2) whereas the use of HMPA or 1a as solvent eroded
both yield and selectivity (entries 3-4). Equally striking
was the influence of the base and escorting counterion,
thus revealing the non-innocent behavior of these
variables on both reactivity and site-selectivity (entries 5-
8).14 Moreover, Et3SiH as silyl source failed to provide 3a
(entry 9)15,16 whereas good yields and selectivities were
obtained under air (entry 10), thus constituting a bonus in
practical terms.17 Interestingly, the utilization of N-oxide
derivatives resulted in 3a as single regioisomer in 61%
yield (entry 11).18,19
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Scheme 2. Late-Stage Silylation of Azine Drugs.
Table 2. Site-Selective Silylation of Azines. a,b
a
b
As Table 1 (entry 1). Isolated yields, average of two
c
d
e
independent runs. KHMDS (2 equiv). 0 ºC. 5 mmol
scale. f From N-oxide derivative. g C4:C5 = 2.7:1.
As evident from the results compiled in Table 2,
systematic structural editing revealed that the C–H
silylation can be applied to a wide number of azines. C4–
silylated pyridines were invariably obtained in good
yields and site-selectivities with azines possessing
The flexibility and generality of our site-selective
silylation suggested that our protocol should be
applicable within the context of late-stage silylation of
azine drugs without requiring additional processing. As
shown in Scheme 2, this turned out to be the case. C2–
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and C3–substituted pyridine drugs such as Doxylamine,
selectivity found with dioxane in the presence of DME or
18-crown-6, with the latter providing exclusive access to
2a.13
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Loratadine, Estrone and Nicotine exclusively delivered
the corresponding C4-silylated pharmaceuticals (6, 8, 9
and 12) in good yields and site-selectivities.17 As evident
from NMR spectroscopy,13 C2–Si bond-formation was
solely obtained from Metyrapone (7) at the most electron-
poor pyridyl backbone. A similar C2-selectivity pattern
was observed with antiretroviral Nevirapine (10), an
observation that could be confirmed by X-ray
crystallography.21 Exhaustive C4-silylation could be
applied to TmPyPB (11) whereas late-stage silylation was
within reach for pyridimine-containing drugs such as
Piribedil or Buspirone, affording 13 and 14 in good yields
– the latter on a gram scale –, as the only observable
products.
Scheme 4. Intermediacy of Silyl Anion Species.
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Scheme 3. Regiodivergent Silylation of Pyridines.
The data summarized above suggest a scenario based on
an initial complexation of the azine to K+ and the
intermediacy of silyl anion species.28,29 This notion is
supported by the reactivity found with 15 with Et3SiBPin
(Scheme 4, right pathways). As shown, dearomatization
was observed upon quenching with D2O or Me3SiCl (18-
19), whereas their aromatized congeners (20-21) were
cleanly obtained upon subsequent oxidation. To put these
results into perspective, 16 and 17 were exclusively
observed from 15 via KOtBu/Et3SiH-mediated
silylation15a or Ni-catalyzed C–O cleavage (left
pathways),12b thus showing the complementarity and
orthogonal reactivity with other silylation events.30,31 The
results shown in Scheme 5 further illustrates the
prospective potential of our protocol, either using
silylated azines as
a means to effect unusual
defluorinative C–H silylations via nucleophilic attack and
two consecutive [1,3]-H shifts (22)32 or as handles for
subsequent functionalization (23-24).33
The non-negligible role exerted by both the solvent and
escorting counterion suggested that C4-selectivity might
be dictated by a solvent-separated ion pair, in which
initial complexation of the nitrogen atom to K+
coordinated to DME confers a steric bias at C2 (Scheme
3, right).22,23 Exposure of 4p to KHMDS in THF-d8
Scheme 5. Synthetic Application Profile.
corroborated this notion, showing
a
significant
deshielding of the pyridine H atoms by 1H-NMR
spectroscopy.13 Although preactivated N-oxide azines
offered a solution to enable a C2–silylation (Table 1,
entry 11),19 we wondered whether a site-selectivity switch
could be effected with unfunctionalized azines by a subtle
modulation of the solvent denticity and aggregation.24
Interestingly, solvents lacking a proximal bidentate
coordination mode such as dioxane predominantly
resulted in a C2–silylation (3a-3e),25-27 suggesting the
involvement of contacted ion pairs.22,23 This
interpretation gains credence by the erosion in C2-
In summary, we have developed a mild and site-selective
C2/C4–silylation of (poly)azines that obviates the need
for transition metals, thus complementing existing sp2 C–
H silylation events. The method can be applied for late-
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Pirnot, M. T.; Lin, S.; Dreher, S. D.; DiRocco, D. A.; Davies,
stage silylation of azine drugs, with a site-selectivity that
can be modulated by the nature of the solvent utilized.
Further studies into the mechanism and related processes
are currently ongoing.34
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Demonstrating the Viability of a Radical Pathway. Science
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Jiang, Y.; Ma, D. Selected Copper-Based Reactions for C–N,
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ASSOCIATED CONTENT
Supporting Information. Experimental procedures,
crystallographic data and spectral data. This material is
available free of charge via the Internet at
http://pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Author
Palladium-Catalyzed
Suzuki-Miyaura
Cross-Coupling
Reactions Employing Dialkylbiaryl Phosphone Ligands. Acc.
Chem. Res. 2008, 41, 1461. (g) Liu, J.; Robins, M. J. SNAr
Displacements with 6-(Fluoro, Chloro, Bromo, Iodo and
Alkylsulfonyl)Purine Nucleosides: Synthesis, Kinetics and
Mechanism. J. Am. Chem. Soc. 2007, 129, 5962.
* rmartinromo@iciq.es
Author Contributions
(4) Selected references: (a) Murakami, K.; Yamada, S.; Kaneda,
T.; Itami, K. C–H Functionalization of Azines. Chem. Rev.
2017, 117, 9302. (b) Nakao, Y. Transition Metal-Catalyzed
C–H Functionalization for the Synthesis of Substituted
Pyridines. Synthesis 2011, 20, 3209.
‡ Y. Gu and Y. Shen contributed equally to this work.
Funding Sources
No competing financial interests have been declared.
(5) For selected metal-catalyzed C–heteroatom bond-formations
of azines: (a) Yang, L.; Semba, K.; Nakao, Y. Para-Selective
C–H Borylation of (Hetero)Arenes by Cooperative
Iridium/Aluminum Catalysis. Angew. Chem. Int. Ed. 2017,
56, 4853. (b) Ito, E.; Fukushima, T.; Kawakami, T.;
Murakami, K.; Itami, K. Catalytic Dehydrogenative C-H
Imidation of Arenes Enabled by Photo-generated Hole
Donation to Sulfonimide. Chem 2017, 2, 383. (c) Obligacion,
J. V.; Semproni, S. P.; Chirik, P. J. Cobalt-Catalyzed C–H
Borylation. J. Am. Chem. Soc. 2014, 136, 4133. (d) Foo, K.;
Sella, E.; Thomé, I.; Eastgate, M. D.; Baran, P. S. A Mild,
Ferrocene-Catalyzed C–H Imidication of (Hetero)Arenes. J.
Am. Chem. Soc. 2014, 136, 5279. (e) Allen, L. J.; Cabrera, P.
J.; Lee, M.; Sanford, M. S. N-Acyloxyphthalimides as
Nitrogen Radical Precursors in the Visible Light
Photocatalyzed Room Temperature C-H Amination of
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Boursalian, G. B.; Ngai, M.-Y.; Hojczyk, K. N.; Ritter, T. Pd-
Catalyzed Aryl C−H Imidation with Arene as the Limiting
Reagent. J. Am. Chem. Soc. 2013, 135, 13278. (h) Fier, P. S.;
Hartwig, J. F. Selective C-H Fluorination of Pyridines and
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ACKNOWLEDGMENT
We thank ICIQ and MINECO (CTQ2015-65496-R) for
support and the ICIQ X-Ray Diffraction Unit for the
crystallographic data. Y. S. and Y. G. thank China
Scholarship Council (CSC) and MINECO for predoctoral
fellowships.
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Grubbs, R. H.; Stoltz, B. M.; Krenske, E. H.; Houk K. N.;
Zare, R. N. Ionic and Neutral Mechanisms for C−H Bond
Silylation of Aromatic Heterocycles Catalyzed by Potassium
tert-Butoxide. J. Am. Chem. Soc. 2017, 139, 6880.
(16) It is worth noting that not even traces of 2a/3a were observed
by exposing electron-poor azines to either KOtBu /Et3SiH
(see ref. 15) or KHMDS/Et3SiH, indicating that our silylation
follows a different mechanistic rationale.
(17) The addition of extra KHMDS/Et3SiBPin does not improve
yields. The mass balance accounts for unreacted azine
(18) For a mechanistic rationale, see ref. 13.
(10) (a) Rubio-Pérez, L.; Iglesias, M.; Munárriz, J.; Polo, V.;
Passarelli, V.; Pérez-Torrente, J. J.; Oro, L. A. Chem. Sci.
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Catalyzed Silylation of Aryl C−H Bonds. J. Am. Chem. Soc.
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Electrophilic C-H Silylation of Pyridines Enabled by
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(19) Albini, A.; Pietra, S. Heterocyclic N–Oxides; CRC Press:
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(20) Diederich, F.; de Meijere, A., Eds. Metal-Catalyzed Cross-
Coupling Reactions; Wiley-VCH: Weinheim, 2004.
(21) At present, we do not have a rationale behind the role exerted
by the ketone backbone on site-selectivity en route to 7 and
10.
(11) For an elegant Pd-catalyzed silylation event: (a) Oshima, K.;
(22) For the importance of coordination on the functionalization
of azines: (a) Nagase, M.; Kuninobu, Y.; Kanai M.
Ohmura,
T.;
Suginome
M.
Palladium-Catalyzed
Regioselective Silaboration of Pyridines Leading to the
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C−H
Perfluoroalkylation
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Stereoselective Addition of N-Activated Pyridines. Chem.
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C. –H.; Li, C. –Y.; Ong, T. –G.; Yap, G. P. A. Bimetallic
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Coordinated Alkali Metal Bis(trimethylsilyl)amides. Inorg.
Chem. 1992, 31, 4143.
(28) Clean formation of (Me3Si)2NBPin was detected by GC of
the crude mixtures. This result suggests the activation of
TESBPin by KHMDS, likely via the initial formation of
discrete [(Me3Si)2N(BPin)SiEt3]K species.
(29) The intermediacy of silyl anions was further confirmed by
control experiments with cyclohexene, leading to ring-
opening silylation in the absence of pyridine. For the test of
silyl anions, see: Gilman, H .; Aoki, D.; Wittenberg, D. Some
Reactions of Silyllithium Compounds with Epoxides. J. Am.
Chem. Soc. 1959, 81, 1107. For details, see ref. 13.
(30) See for example: (a) Xu, Z.; Chai, L.; Liu, Z. –Q. Free-
Radical-Promoted Site-Selective C–H Silylation of Arenes
by Using Hydrosilanes. Org. Lett. 2017, 19, 5573. (b) Xu, P.;
Würthwein, E. –V.; Daniliuc, C. G.; Studer, A. Transition-
metal Free Ring-Opening Silylation of Indoles and
Benzofurans with Diphenyl-tert-Butylsilyl Lithium. Angew.
Chem. Int. Ed. 2017, 56, 13872.
1
2
3
4
5
6
7
8
(23) For selected references dealing with the complexation of K+
in DME: (a) Binda, P. I.; Delbridge, E. E.; Dugah, D. T.;
Skelton, B. W.; White, A. H. Synthesis and Structural
Characterization of Some Potassium Complexes of Some
Bis(phenolate) Ligands and Some Novel Heterobimetallic
Binuclear Arrays Formed with Trivalent Lanthanoid Ions. Z.
Anorg. Allg. Chem. 2007, 634, 325. (b) Cole, M. L.; Jones,
C.; Junk, P. C. Ether and crown ether adduct complexes of
9
sodium
methylcyclopentadienide−molecular
[Na(dme)Cp]∞, [K(dme)0.5Cp]∞,
and
potassium
cyclopentadienide
and
of
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
structures
[Na(15-crown-5)Cp],
[Na(18-crown-6)CpMe] and the “naked Cp-” complex [K(15-
crown-5)2][Cp]. J. Chem. Soc., Dalton Trans., 2002, 896. (c)
Jones, C.; Thomas, R. C. The synthesis and structural
characterisation of a diphosphastibolyl potassium complex,
[{[K(DME)][1,4,2-P2SbC2But2]}∞], and a novel hetero-cage
compound. J. Organometallic Chem. 2001, 622, 61.
(31) Careful NMR monitoring under nitrogen atmospheres
revealed the formation of dearomatized N-BPin silylated
azines and the corresponding aromatized congeners. At
present, the exact mechanism by which aromatization occurs
with KHMDS is not fully understood.
(24) (a) Maddock, L. C. H.; Nixon, T.; Kennedy, A. R.; Probert,
M. R.; Clegg, W.; Hevia, E. Utilising Sodium-Mediated
Ferration for Regioselective Functionalisation of
Fluoroarenes via C–H and C–F Bond Activations. Angew.
Chem. Int. Ed. 2018, 57, 187. (b) Algera, R. F.; Ma, Y.;
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(32) For recent defluorinative events of trifluoromethyl groups:
(a) Wang, P.; Pu, X.; Zhao, Y.; Wang, P.; Li, Z.; Zhu, C.; Shi,
Z. Enantioselective Copper-Catalyzed Defluoroalkylation
Using Arylboronate-Activated Alkyl Grignard Reagents. J.
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Chen, K.; Berg, N.; Gschwind, R.; König, B. Selective Single
C(sp3)−F Bond Cleavage in Trifluoromethylarenes: Merging
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(33) (a) von Wolff, N.; Char, J.; Frogneux, X.; Cantat, T.
Synthesis of Aromatic Sulfones from SO2 and Organosilanes
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Aryl(triethyl)silanes for Biaryl and Teraryl Synthesis by
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(25) The higher solubility of KHMDS in DME vs dioxane does
not allow us to completely rule out whether kinetics come
into play for determining C2/C4-selectivity.
(26) The erosion in regioselectivity pattern observed for electron-
rich arenes at C3 (2e, 3e) do not allow us to rule out whether
electronic effects come into play.
(27) Edelmann, F. T.; Pauer, F.; Wedler, M.; Stalke, D.
Preparation and Structural Characterization of Dioxane-
(34) It is worth noting that even unactivated benzene can be
silylated in moderate yield. See ref. 13
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