Selective Functionalization of Aminoheterocycles by a Pyrylium Salt

Article abstract of DOI:10.1002/anie.201806271

The functionalization of aminoheterocycles by using a pyrylium tetrafluoroborate reagent (Pyry-BF₄) is presented. This reagent efficiently condenses with a great variety of heterocyclic amines and primes the C?N bond for nucleophilic aromatic substitution. More than 60 examples for the formation of C?O, C?N, C?S, or C?SO₂R bonds are disclosed herein. In contrast to C?N activation through diazotization and polyalkylation, this method is characterized by its mild conditions and impressive functional-group tolerance. In addition to small-molecule derivatization, Pyry-BF₄ allows the introduction of functional groups in a late-stage fashion to furnish highly functionalized structures.

Full text of DOI:10.1002/anie.201806271

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Accepted Article
Title: Selective Functionalization of Aminoheterocycles by a Pyrylium
Salt
Authors: Daniel Moser, Yaya Duan, Feng Wang, Yuanhong Ma,
Matthew J O'Neill, and Josep Cornella
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10.1002/anie.201806271
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COMMUNICATION
Selective Functionalization of Aminoheterocycles by a Pyrylium
Salt
Daniel Moser†, Yaya Duan†, Feng Wang, Yuanhong Ma, Matthew J. O’Neill and Josep Cornella*
Katritzky,[17] we envisaged that activation of C(sp2)‒NH2 bonds could
Abstract: The functionalization of aminoheterocycles via a pyrylium
be achieved by a simple condensation w ith a pyrylium reagent (path
tetrafluoroborate reagent (Pyry-BF4) is presented. This reagent
c, Figure 1B); however, such condensation present several
efficiently condenses with a great variety of heterocyclic amines and
challenges due to the low nucleophilicity of the NH2 group in
primes the C‒N bond for nucleophilic aromatic substitution. More
than 60 examples of C‒O, C‒N, C‒S or C‒SO2R are disclosed
herein. In contrast to C‒N activation via diazotization and
polyalkylation, this method is characterized by its mild conditions and
impressive functional group tolerance. In addition to small molecule
derivatization, Pyry-BF4 allows for the introduction of functional
groups in a late-stage fashion to furnish highly functionalized
structures.
aminoheterocycles as shown by the inefficient reactivity with a
Zincke reagent.[18] Indeed, pyrylium salts have successfully been
utilized in the past for the activation of C(sp3)‒NH2 groups in a
variety of synthetically useful contexts.[19][20] However, exploitation of
this concept for the derivatization of C(sp2)‒NH2 in aminoheterocylic
framew orks still remains an enormous challenge in synthesis.[21] In
this report, we describe a practical synthesis of a pyrylium reagent
(Pyry-BF4, 1) which is capable of selectively activating amino groups
in heterocycles (Scheme 1A), thus priming them for SNAr to obtain
high value compounds through C‒O, C‒N, C‒S and C‒SO2R bond
formation.[22]
The construction of molecular complexity through small fragment
connection constitutes a fundamental pillar in drug discovery. To this
end, robust methodologies have been developed for the formation of
[4]
C‒N,[1] C‒O,[2] C‒S[3] and C‒C bonds to elaborate heterocyclic
framew orks. Indeed, reactions based on transition metal catalysts
such as the Buchwald-Hartw ig amination,[1] Ullmann[2] or Chan-
[5]
Lam couplings immediately come to mind as methods to construct
these linkages. Despite the tremendous power of these protocols,
comprehensive surveys of the literature reveal that nucleophilic
aromatic substitution (SNAr) still dominates in industrial contexts.[6] In
this sense, a large proportion of candidates to undergo SNAr are
highly functionalized heterocycles, since they represent the core of
most contemporary small-molecule therapeutics.[7] Accordingly, the
SNAr persists as
a cornerstone reaction highly coveted by
pharmaceutical and agrochemical industries, as it provides a reliable
and scalable approach to expediently assemble complexity.[8]
Notably, the SNAr reaction is still largely restricted to the use of a
heteroaryl halide as the electrophilic partner, which is in turn
prepared via the Vilsmeier-Haack reaction from an amide (Figure
[9]
1A); this reaction usually requires strong acids, thus leading to
functional group incompatibilities. More importantly, due to their high
electrophilicity, some of these heteroaromatic halides are unstable
and prone to decomposition in the absence of special precautions.[10]
Although several reports have sought to develop more stable
electrophilic partners,[11] they uniformly require prefunctionalization
through the respective amide. Therefore, methods to obviate this
restrictive electrophile scope would greatly expand the synthetic
potential of this method.
Accordingly, aminoheterocycles occupy a sizeable fraction of
natural chemical space, as well as synthetic pharmaceuticals and
agrochemicals.[7][12] Moreover, the presence of amino groups in a
variety of existing medicinally relevant compounds makes them a
perfect handle for further late-stage modifications. These factors
collectively render aminoheterocycles as perfect candidates to serve
as electrophiles in ipso substitutions. How ever, the conversion of
C(sp2)-NH2 into leaving groups has traditionally been restricted to
the generation of the diazonium salt[13] or the polyalkylation of the
amine[14] (path a and b, Figure 1B). In the former, strong oxidants
and acids are required to generate the diazonium salt which in turn
is unstable at high temperatures, shock sensitive, and explosive.
The use of alkylating agents for the latter example has been
restricted to the activation of simple anilines, since the presence of
Lew is-basic atoms makes this approach unfeasible. Inspired by the
work of Baeyer and Piccard[15] and later by Balaban[16] and
Figure 1. (A) Importance of SNAr reaction for functionalization of
heterocycles; (B) Aminoheterocycles as electrophiles.
The synthesis of the pyrylium tetrafluoroborate 1 (Pyry-BF4) was
achieved by a two-step sequence comprising base-mediated ring
opening/acid-mediated ring closing reactions starting from readily
available and cheap pyridine sulfur trioxide (PST, $14/mol).[23] After
crystallization of the crude mixture, 1 is obtained as an off-white-
beige solid. Pyry-BF4 features a series of attractive characteristics:
(1) non-explosive; (2) readily preparable from PST; (3) scalable
without risk of explosion.[24] At this point, the reactivity of 1 was
benchmarked with the most common and simple pyrylium reagents,
traditionally utilized to activate C‒N bonds.[19][20] As shown in
Scheme 1B, 4-aminopyridinium salt derivative of 2,4,6-
triphenylpyrylium (3) remained unaltered in SNAr upon heating w ith
toluidine. Notably, sterically less encumbered 2,4,6-trimethylpyrylium
was not suitable for condensation with 2. However, when salt 4 was
used instead, smooth C‒N bond w as obtained in mild conditions
(80 °C); the robustness and simplicity of this protocol is highlighted
by the tolerance of a variety of solvents. The difference in reactivity
between pyridinium salts is attributed to the interruption of the co-
planarity: when 2,4,6-trisubstituted pyridiniums are used, steric
protection of the ipso carbon prevents an optimal angle for the
incoming nucleophile.[25]
[a]
[†]
D. Moser,[†] Y. Duan, [†] F. Wang, Y. Ma, M. J. O’Neill, J. Cornella
Max-Planck-Institut für Kohlenforschung, Kaiser-Wilhelm-Platz 1,
Mülheim an der Ruhr, 45470, Germany.
E-mail: cornella@kofo.mpg.de (J.C.)
These authors contributed equally to this work.
Supporting information for this article is given via a link at the end of
the document.
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S bond. As exemplified in Table 2, the reaction could successfully be
performed from the pyridinium salt or from the in situ generated
pyridinium salt, w ithout isolation. Coupling of pyridinium salts 7, 13
and 19 w as carried out by a simple solvent exchange subsequent to
condensation w ith Pyry-BF4, thus enabling a simple, practical and
economical one-pot procedure.
Scheme 1. (A) Synthesis of pyrylium tetrafluoroborate (Py ry -BF4); (B)
Comparison between Pyry -BF4 and commonly employed pyryliums.
aCondensation could not be achieved with 2,4,6-trimethylpyrylium BF4.
As shown in Table 1, Pyry-BF4 reacted smoothly with pyridines
bearing electron-donating (5, 7, 9, 12) and electron-withdrawing
groups (10, 16, 17, 19). Pyridines substituted at the 2-position w ith
Me (6) and Ph (8) could also be accommodated. Substitution next to
the amino center posed no problem for the synthesis of the
pyridinium salt as exemplified by the fluorine-containing pyridinium
salt 13. The method could also be applied to other aminoheterocyclic
framew orks such as 4-aminopyrimidines (11), 2-aminopyrimidines
(14), 2-aminobenzothiazole (15) or the 5-membered 2-
aminothiadiazole 18. In all cases, the pyridinium salt can be carried
on further without the need of isolation if desired (in situ).
A variety of anilines smoothly reacted with the pyridinium salt in
the presence of 1 equiv of HCl at 80‒110 °C, thus affording the
desired C‒N coupling product. The transamination is characterized
by its functional group tolerance, proceeding in the presence of
nitriles (20), ketones (21), esters (35), fluorides (33), trifluoromethyl
group (29), tertiary amines and amides (31), and ethers (32).
Anilines bearing functional groups susceptible to reactivity under
Ullmann or Buchwald-Hartw ig such as iodides (34) and chlorides
(24) smoothly delivered the corresponding C‒N linkage in good
yields. Unfortunately, more nucleophilic amines such as butylamine
or morpholine afforded ring-opened products in a Zincke-type
reactivity. The reaction is not limited to primary anilines;
methylaniline (24) or 4-chloro-methylaniline (37) could be
accommodated. Substituted pyridines w ith a 2-chloro group (27)
represent a clear example of the orthogonality of this transformation
in the presence of other leaving groups. Amination w as further
accomplished w ith thiadiazole (28) and benzothiazole pyridinium
salts (30); the lower yields in the former are the consequence of
competing ring opening events of the 5-membered ring. This
protocolwas also effective in the area of C‒O bond formation.[26] The
diversity of counterparts span from aromatic phenol derivatives (38-
44) to linear alkyl alcohols (45). The presence of electron-donating
(41), electron-withdraw ing (45) or neutral aminoheterocycles (38-40,
42-44) bode w ellin the coupling.
Table 1. Synthesis of pyridinium salts. Reaction conditions:
aminoheterocycle (1 equiv.), Pyry-BF4 (1 equiv.) in EtOH at 75 °C.
b
aIsolated yields. Yields determined by NMR using mesitylene as
internal standard.
With the importance of late-stage modification in drug discovery,
the mild conditions of our protocol enable the use of C(sp2)‒NH2
groups as points for diversification (Figure 2A). For example, the
oncology therapeutic ibrutinib, could be successfully modified at its
amino group w ith the in situ protocol to forge a new C‒S bond (77,
42%). The highly nitrogenated anti-anxiety pharmaceutical prazosin
smoothly reacted with Pyry-BF4, permitting the substitution with
simple sodium ethoxide (80, 35%). Naturally occurring substances
such as estradiol also reacted chemoselectively with the phenolic C‒
OH bond (78, 58%). (+)-δ-Tocopherol (Vitamin E) smoothly
delivered the coupling product in good yields (76, 55%). Fungicide
fenhexamid w as also functionalized with excellent yield and
chemoselectivity (79, 54%). To explore the limits of functional group
compatibility, w e turned our attention to adenosine. Current
strategies for the modification of this natural riboside rely on pre-
functionalization to the halide or phosphonium reagent, w ith inosine
as the starting material (Figure 2B). This sequence involves the
protection of the sugar moiety, since POCl3 or the respective
alternatives are generally not compatible w ith free alcohols.[29]
Addition of the nucleophile followed by overall deprotection delivers
the substituted adenosine. In contrast to this lengthy route, 1
smoothly reacted with simple adenosine to deliver the pyridinium
salt, w hich was functionalized in situ with a thiol and an alcohol to
obtain compounds 81 and 82 in 71% and 63% isolated yields,
respectively. These examples further highlight the versatility of the
Pyry-BF4 as a reagent and it is envisioned that the protocol could
access chemical space in challenging contexts such as nucleobase
modifications in chemical biology and epigenetics.[30]
The protocol was successfully expanded to sulfur containing
nucleophiles such as thiols and sulfinates.[27][28] The reaction of
sulfinates forged the desired sulfones for an abundance of different
heterocyles; pyridines bearing morpholine (48), nitro (49), ethers (52,
58), chloro (55) and trifluoromethyl (53) substituents smoothly
coupled w ith good to excellent yields (Table 2C). Substituted aryl
sulfinates bearing diverse substituents in the aromatic ring (54, 56,
59), as well as alkyl sulfinates (47) bode well with this protocol. The
formation of C‒S bonds was successfully realized with a wide variety
of thiols bearing bromo (60, 71), chloro (64), fluoro (65), ethers (63)
and nitro (66) groups as well as extended aromatic thiols (69, 70,
72). Ortho-substituted thiols smoothly reacted with excellent yields
thus overriding steric effects (60, 61, 71). Pyridines containing
tertiary amines (72, 73), nitro (74) and fluoro (75) as well as
pyrimidines (68) could also be accommodated in the formation of C‒
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Table 2. Scope of the SNAr mediated by Pyry-BF4 salt. Reaction conditions: (A) pyridinium salt (1 equiv.), amine (1 – 1.5 equiv.), HCl in 1,4-
dioxane (1.5 equiv.), DMSO or EtOH at 80‒110 °C; (B) pyridinium salt (1 equiv.), phenol (1.5 equiv.) at 110‒150 °C; (C) pyridinium salt (1
equiv.), sodium sulfinate (1.5 equiv.), HCl in 1,4-dioxane (1.0 equiv.) in DMSO or EtOH at 25 - 60 °C; (D) pyridinium salt (1 equiv.), thiophenol
(1.5 equiv.) in DMSO or EtOH at 25–60 °C. a NMR yield using mesitylene as internal standard.
Keywords:pyrylium• amination • C‒N activation • late-stage
functionalization • heterocycles
In conclusion, a method for the nucleophilic aromatic substitution
of amino groups has been developed, which avoids the need for
alkylating agents or the formation of diazonium salts. Pyrylium
tetrafluoroborate serves as activating agent of aminoheterocycles
and primes them for SNAr reactions after simple condensation with
the amino group. The method has proven robust in the synthesis of
References
[1]
For selected reviews on C(sp2)‒N bond formation, see: (a) P. Ruiz-
Castillo; S. L. Buchwald, Chem. Rev. 2016, 116, 12564-12649; (b) A. R.
Muci, S. L. Buchwald, Top. Curr. Chem. 2002, 219, 131-209; (c) J. P.
Wolfe, S. Wagaw, J. ‒F. Marcoux, S. L. Buchwald, Acc. Chem. Res.
1998, 31, 805-818; (d) J. F. Hartwig, Angew. Chem. 1998, 110, 2154-
2177; Angew. Chem. Int. Ed. 1998, 37, 2046-2067; (e) J. F. Hartwig,
Acc. Chem. Res. 1998, 31, 852-860; (f) J. F. Hartwig, Pur. Appl. Chem.
1999, 71, 1417-1423.
C‒O, C‒N, C‒S and C‒SO2R bonds in
a
variety of
aminoheterocycles. The excellent chemoselectivity of Pyry-BF4 to
condense with amino groups has served for the facile modification of
both natural products and synthetic drugs. Importantly 1, could also
be applied in the context of nucleoside synthesis as exemplified by
the simple and practicalmodification of adenosine.
[2]
For recent reviews on C(sp2)‒O bond formation, see: (a) I. P.
Beletskaya, A. V. Cheprakov, Coord. Chem. Rev. 2004, 2337-2364; (b)
C. Sambiagio, S. P. Marsden, A. J. Blacker, P. C. McGowan, Chem.
Soc. Rev. 2014, 43, 3525-3550.
Acknowledgements
Financial support for this work was provided by Max-Planck-
Gesellschaft, Max-Planck-Institut für Kohlenforschung, Dr. Gadient
Engi-Stiftung (D. M.) and the Fulbright Kommission (M. J. O.). We
thank Prof. Dr. A. Fürstner for discussionsand generous support.
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Figure 2. (A) Pharmaceuticals, agrochemicals and naturalproducts; (B) Modification of nucleoside adenosine.
[3]
For recent reviews on C(sp2)‒S bond formation, see: (a) S. V. Ley, A.
W. Thomas, Angew. Chem. 2003, 115, 5558-5607; Angew. Chem. Int.
Ed. 2003, 42, 5400-5449; (b) T. Kondo, T. ‒A. Mitsudo, Chem. Rev.
2000, 100, 3205-3220.
[18] N. Zeghbib, P. Thelliere, M. Rivard, T. Martens, J. Org. Chem. 2016, 81,
3256-3262.
[19] For substitution reactions on alkyl amines via pyridinium reagents, see:
(a) A. R. Katritzky, J. B. Bapat, R. J. Blade, B. P. Leddy, P. –L. Nie, C.
A. Ramsden, S. S. Thind, J. Chem. Soc. Perkin. Trans. 1, 1979, 418-
425 (b) A. R. Katritzky, A. Saba, R. C. Patel, J. Chem. Soc. Perkin.
Trans. 1, 1981, 1492-1494.
[4]
[5]
In Metal-catalyzed Cross-Coupling Reactions; F. Diederich, P. J. Stang,
Eds.; Wiley -VCH: NewYork, 1998.
J. X. Qiao, P. Y. S. Lam in Recent Advances in Chan–Lam Coupling
Reaction: Copper-Promoted C–Heteroatom Bond Cross-Coupling
Reactions with Boronic Acids and Derivatives, (ed D. G. Hall,), Wiley -
VCH, Germany, 2011.
[20] Recently, pyrylium reagents have been utilized to generate alkyl
radicals from alkylamines: (a) C. H. Basch, J. Liao, J. Xu, J. Piane, M. P.
Watson, J. Am. Chem. Soc. 2017, 139, 5313-5316; (b) F. J. R. Klauck,
M. J. James, F. Glorius, Angew. Chem. 2017, 129, 12505-12509;
Angew. Chem. Int. Ed. 2017, 40, 12336-12339; (c) J. Liao, W. Guan, B.
P. Biscoe, J. W. Tucker, J. W. Tomlin, M. R. Garnsey, M. P. Watson,
Org. Lett. 2018, 20, 3030-3033.
[6]
(a) N. Schneider, D. M. Lowe, R. A. Sayle, M. A. Tarselli, G. A.
Landrum, J. Med. Chem. 2016, 59, 4385-4402; (b) D. G. Brown, J.
Boström, J. Med. Chem. 2016, 59, 4443-4458.
[7]
[8]
[9]
E. Vitaku, D. T. Smith, J. T. Njardarson, J. Med. Chem. 2014, 57,
10257-10274.
[21] Substitution to I or H via complex pyridinium reagents has been
accomplished by pyrolytic cleavage at (200-220 °C, 0.5 tor): (a) A. R.
Katritzky, A. Chermprapai, S. Bravo, R. J. Patel, Tetrahedron 1981, 37,
3603-3606; (b) N. F. Eweiss, A. R. Katritzky, P. –L. Nie, C. A. Ramsden,
Synthesis, 1977, 634-635.
F. Terrier in Modern Nucleophilic Aromatic Substitution, Wiley -VCH,
Germany, 2013.
J. A. Joule, K. Mills in Heterocyclic Chemistry 5th ed., John-Wiley
&
Sons Ltd., Chichester, West Sussex, United Kingdom, 2010.
[10] For selected examples of unstable 4-chloroquinazoline derivative en
route to erlotinib, see: (a) R. C. Schnurr, L. D. Arnold, U. S. Patent,
1998, 5747498; (b) P. Knesl, D. Röseling, U. Jordis, Molecules, 2006,
11, 286-297.
[22] Previous synthesis of this compound involved lengthy routes (3-5
steps), see: (a) K. Dimroth, W. Kinzebach, M. Sokya, Chem. Ber. 1966,
99, 2351-2360; (b) J. Strating, J. H. Keijer, E. Molenaar, L. Brandsma,
Angew. Chem. 1962, 74, 465-465; Angew. Chem. Int. Ed. 1962, 1, 399-
399; (c) I. Degani, R. Fochi, C. Vincenzi, Gazz. Chim. Ital. 1964, 94,
203-209; (d) Y. Y. Belosludtsev, B. C. Borer, R. J. K. Taylor, Synthesis
1991, 320-322; (e) T. W. Greulich, C. G. Daniluc, A. Studer, Org. Lett.
2015, 17, 254-257. For an extensive review on the synthesis of various
pyrylium reagents, see: T. S. Balaban, A. T. Balaban, "Pyrylium Salts".
Hetarenes and Related Ring Systems, Six-membered Hetarenes with
one Chalcogen. Science of Synthesis; Thieme-Verlag, Stuttgart ,2003.
[23] Price retrieved from TCI at kg quantities.
[11] For the use of thioethers in place of halogens, see: V. Chandregowda,
G. V. Rao, G. C. Reddy , Synth. Commun. 2007, 37, 3409-3415.
[12] M. Baumann, I. R. Baxendale, Beilstein J. Org. Chem. 2013, 9, 2265-
2319.
[13] (a) F. Mo, G. Dong, Y. Zhang, J. Wang, Org. Biomol. Chem. 2013, 11,
1582-1593; (b) L. He, G. Qiu, Y. Gao, J. Wu, Org. Biomol. Chem. 2014,
12, 6965-6971 and references therein.
[14] (a) E. Wenkert, A. ‒L. Han, C. ‒J. Jenny, J. Chem. Soc. Chem.
Commun. 1988, 975-976; (b) S. B. Blakey, D. W. C. MacMillan, J. Am.
Chem. Soc. 2003, 125, 6046-6047; (c) D. ‒Y. Wang, M. Kawahata, Z. ‒
K. Yang, K. Miyamoto, S. Komagawa, K. Yamaguchi, C. Wang, M.
Uchiyama, Nat. Commun. 2016, 7, 12937; (d) J. T. Reeves, D. R.
Fandrick, Z. Tan, J. J. Song, H. Lee, N. K. Yee, C. H. Senanayake, Org.
Lett. 2010, 12, 4388-4391; (e) P. Maity, D. M. Schacklady -McAtee, G. P.
A. Yap, E. R. Sirianni, M. P. Watson, J. Am. Chem. Soc. 2013, 135,
280-285; (f) H. Xiong, A. T. Hoye, K. ‒H. Fan, X. Li, J. Clemens, C. L.
Horchler, N. C. Lim, G. Attardo, Org. Lett. 2015, 17, 3726-3729; (g) D. ‒
Y. Wang, Z. ‒K. Yang, C. Wang, A. Zhang, M. Uchiyama, Angew.
Chem. 2018, 130, 3703-3707; Angew. Chem. Int. Ed. 2018, 57, 3641-
3645.
[24] DSC measurements of 1 conclusively revealed the absence of runaway
exothermal events before 250 °C.
[25] See Supporting Information for a rational design and explanation.
[26] For an elegant direct C‒heteroatom formation in heterocycles through
phosphonium salts, see: (a) M. C. Hilton, R. D. Dolewski, A. McNally , J.
Am. Chem. Soc. 2016, 138, 13806-13809; (b) Dolewski, M. C. Hilton, A.
McNally , Synlett 2018, 29, 8-14.
[27] For early examples of 4-pyridinepyridyl chloride with nucleophiles, see:
(a) H. Fischer, K. Thomas, Chem. Ber. 1956, 89, 2921-2933; (b) D.
Jerchel, L. Jakob, Chem. Ber. 1958, 91, 1266-1273; (c) B. Boduszek, J.
S. Wieczorek, Monatsh. Chem. 1980, 111, 1111-1116; (d) E. Königs, H.
Greiner, Ber. Dtsch. Chem. Ges. 1931, 64, 1049-1056.
[15] (a) A. Baeyer, J. Piccard, Justus Liebigs Ann. Chem. 1911, 384, 208-
224; (b) A. Baeyer, J. Piccard, Justus Liebigs Ann. Chem. 1915, 407,
332-369.
[28] For recent metal-free thioether formation of heterocycles, see: B. Liu,
C.-H. Lim, G. M. Miyake, J. Am. Chem. Soc. 2017, 139, 13616-13619.
[29] For inosine modification, see: (a) F. ‒A. Kang, Z. Sui, W. V. Murray , Eur.
J. Org. Chem. 2009, 461-479; (b) P. Lagisetty, L. M. Russon, M. K.
Lakshman, Angew. Chem. 2006, 118, 3742-3745; Angew. Chem. Int.
Ed. 2006, 45, 3660-3663.
[16] For seminal work, see: A. T. Balaban, C. D. Nenitzescu, Justus Liebigs
Ann. Chem. 1959, 625, 66-73.
[17] For an extensive overview, see: A. R. Katritzky, C. M. Marson, Angew.
Chem. 1984, 96, 403-413; Angew. Chem. Int. Ed. 1984, 23, 420-429
and references therein.
[30] V. Pande, J. Med. Chem. 2016, 59, 1299-1307.
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COMMUNICATION
Daniel Moser†, Yaya Duan†, Feng
Wang, Yuanhong Ma, Matthew J. O’Neill
and Josep Cornella*
Selective Functionalization of
Aminoheterocycles by a Pyrylium
Salt
Pyry-BF4 has been identified as a broadly useful reagentfor the activation of heteroaromatic amines and subsequent
functionalization to forge C‒N, C‒O and C‒Sbonds.The transformation displays remarkable chemoselectivityenabling its
use in late-stage contexts.
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