Base-catalyzed aryl halide isomerization enables the 4-selective substitution of 3-bromopyridines

Article abstract of DOI:10.1039/d0sc02689a

The base-catalyzed isomerization of simple aryl halides is presented and utilized to achieve the 4-selective etherification, hydroxylation and amination of 3-bromopyridines. Mechanistic studies support isomerization of 3-bromopyridines to 4-bromopyridines proceedsviapyridyne intermediates and that 4-substitution selectivity is driven by a facile aromatic substitution reaction. Useful features of a tandem aryl halide isomerization/selective interception approach to aromatic functionalization are demonstrated. Example benefits include the use of readily available and stable 3-bromopyridines in place of less available and stable 4-halogenated congeners and the ability to converge mixtures of 3- and 5-bromopyridines to a single 4-substituted product.

Full text of DOI:10.1039/d0sc02689a

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ARTICLE
Base-Catalyzed Aryl Halide Isomerization Enables the 4-Selective
Substitution of 3-Bromopyridines
Thomas R. Puleo and Jeffrey S. Bandar*
The base-catalyzed isomerization of simple aryl halides is presented and utilized to achieve the 4-selective etherification,
hydroxylation and amination of 3-bromopyridines. Mechanistic studies support isomerization of 3-bromopyridines to 4-
bromopyridines proceeds via pyridyne intermediates and that 4-substitution selectivity is driven by a facile aromatic
substitution reaction. Useful features of a tandem aryl halide isomerization/selective interception approach to aromatic
functionalization are demonstrated. Example benefits include the use of readily available and stable 3-bromopyridines in
place of less available and stable 4-halogenated congeners and the ability to converge mixtures of 3- and 5-bromopyridines
to a single 4-substituted product.
metalation of haloarenes can lead to rearrangement through
intermolecular metal-halogen transposition.6 In addition to
typically requiring stoichiometric lithium bases under cryogenic
Introduction
The synthetic value of aryl halides derives from their
thoroughly studied reactivity that allows reliable and
predictable access to functionalized aromatic compounds.1 The
utility of these widely available substrates can be significantly
increased as new reactivity modes are discovered and applied.
In this regard, catalytic aryl halide isomerization drew our
attention as a relatively underdeveloped yet potentially useful
process (Scheme 1).2
conditions,
a
synthetically useful dance requires
a
thermodynamic gradient in order to drive
a
selective
rearrangement.3 In this regard, important achievements have
been made in identifying specific classes of metalated
haloarenes that rearrange as a strategy for electrophilic
functionalization.7
We sought to identify more mild and general conditions for
aryl halide isomerization as an entry to developing new arene
functionalization methods. Inspired by sporadic reports of
rearranged aryl halide side products8 in reactions involving
aryne9,10 intermediates, we hypothesized that non-nucleophilic
bases could enable reversible HX elimination/addition as an
additional isomerization pathway (Figure 1a). We further
proposed that pairing isomerization with a tandem substitution
reaction could provide a driving force for nontraditional
selectivity in aromatic substitution reactions (Figure 1b).11 We
herein describe initial studies on a general approach to catalytic
aryl halide isomerization and demonstrate its utility as a new
route to 4-functionalized pyridines.12
Scheme 1. Concept of catalytic aryl halide isomerization.
The rearrangement of halogenated arenes under basic
conditions has been extensively studied in the context of
“halogen dance” chemistry.3 Early studies by Bunnett on the
base-catalyzed isomerization of 1,2,4-tribromobenzene into
1,3,5-tribromobenzene revealed rearrangement occurs via
intermolecular halogen transfer, resulting in regioisomeric
mixtures and disproportionated side products.4 This catalytic
rearrangement requires an acidic arene that can generate
electrophilic
halogen
transfer
intermediates
(e.g.
tetrabromobenzenes); thus, isomerization is observed for
tribromobenzenes but not for simple aryl halides.5 This insight
guided decades of development of modern “halogen dance”
methodology, wherein stoichiometric and irreversible
a. Department of Chemistry
Colorado State University
Fort Collins, Colorado, 80523 (USA)
E-mail: jeff.bandar@colostate.edu
Electronic Supplementary Information (ESI) available: [details of any supplementary
information available should be included here]. See DOI: 10.1039/x0xx00000x
Figure 1. A general approach to aryl halide isomerization and its
application to a new selective substitution reaction.
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in Scheme 3. This pathway exploits the inherent pVrieewfeArreticnlecOenflioner
4-bromopyridines to undergo nuDcOleI:o1p0h.1i0li3c9/D0aSCro0m26a8t9iAc
substitution (SNAr) over 3-bromopyridines.18 However, a likely
challenge is avoiding nucleophilic addition to the proposed 3,4-
pyridyne intermediate, as this could decrease the desired
reaction’s yield and regioselectivity.19 Successful development
of this protocol would offer an attractive route to 4-
functionalized pyridines from 3-bromopyridines, which are
more commercially available20 and stable21 than 4-halogenated
congeners. This method would also complement other recently
developed methods for 4-selective nucleophilic pyridine C–H
functionalization, including McNally’s powerful heterocyclic
phosphonium salt approach.22,23
Results and Discussion
We speculated bases that reversibly deprotonate aryl C–H
bonds may create conditions capable of isomerizing aryl
halides.13 This led us to investigate the non-nucleophilic organic
superbase P4-t-Bu (pKBH+ 30.2 in DMSO) as a potential
isomerization catalyst.14 In 1,4-dioxane, we discovered P4-t-Bu
catalyzes the isomerization of 2-bromobenzotrifluoride (1) into
all possible regioisomers (Scheme 2a). Under these conditions,
3-bromobenzotrifluoride (2) and 4-bromobenzotrifluoride (3)
interconvert but do not form 2-bromobenzotrifluoride (Scheme
2b). No protodehalogenated or polyhalogenated side products
are observed, and we note isomerization occurs to a lesser
extent for 4-iodobenzotrifluoride (4).15 A variety of other
bromoarenes (5, 6 and 7) also isomerize, including the
formation of 4-bromopyridine from 3-bromopyridine (8).16
Although further studies on the scope of this process are
ongoing, these observations suggest P4-t-Bu-catalyzed aryl
halide isomerization is a general and reversible process.
Scheme 3. Proposed pathway for the 4-selective substitution of 3-
bromopyridine (B = base, NuH = nucleophile).
As the proposed process requires stoichiometric base, we
first investigated the use of hydroxide bases as more practical
reagents for promoting aryl halide isomerization. Hydroxide
bases are known to generate and be compatible with aryne
intermediates, and we identified that 3-bromopyridines
isomerize in the presence of 18-crown-6-ligated KOH in N,N-
dimethylacetamide (see Supporting Information).24 Using these
conditions, we then employed two separate strategies for
optimizing
bromopyridine (Table 1). When
a
4-selective etherification reaction of 3-
equivalent of 3-
1
bromopyridine (8) reacts with 4 equivalents of alcohol 9, a 2.4:1
ratio of 4:3-substituted product (10:11) is obtained in 54%
overall yield (Entry 1). This ratio is comparable to reported
selectivities for nucleophilic additions to 3,4-pyridyne, which
typically range from 1:1 to 3:1 for 4:3 addition selectivity.25 The
4-selectivity increases as higher ratios of pyridine:alcohol (8:9)
are used, a result perhaps explainable by less alcohol
intercepting a 3,4-pyridyne intermediate (Entries 2-5). Based on
this observation, we hypothesized that added bromide salts
may enable more efficient isomerization and prevent undesired
side reactions.26 When 50% KBr is added to a reaction using a
1.5:1 pyridine:alcohol (8:9) ratio, the yield increases to 76%
with >14:1 4-selectivity compared to 67% yield and 8.6:1 4-
selectivity in the absence of bromide salt (Entries 6-10).
a
Scheme 2. P4-t-Bu-catalyzed aryl halide isomerization. Yields
1
determined by H NMR spectroscopy; the mass balance is less than
100% with no observed haloarene side products; conditions for
Scheme 2b are as shown in Scheme 2a. Reaction performed in
b
cyclohexane for 14 h.
As a broader objective, we questioned if aryl halide
isomerization could be utilized to address current challenges in
aromatic functionalization. As a halogen migrates around an
arene, we reasoned that differing electronic properties of
isomeric C–X bonds could provide a source to differentiate
interconverting isomers and drive an overall selective
transformation.17 A mechanistic outline for the application of
this concept to the 4-substitution of 3-bromopyridines is shown
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Table 1. Optimization of 4-selective etherification of 3-
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DOI: 10.1039/D0SC02689A
bromopyridine.a
effect of pyridine:alcohol ratio effect of bromide salt additive b
Entry
8:9
1:4
1:2
1:1
2:1
4:1
Yield
54%
65%
64%
95%
90%
10:11
2.4
5.5
8.1
12.6
11.9
Entry
6
7
8
9
KBr
0%
10%
20%
50%
100%
1
Yield 10:11
1
2
3
4
5
67%
69%
73%
76%
77%
8.6
8.9
11.1
14.2
14.2
10
a
Yields and selectivities determined by H NMR spectroscopy of
the crude reaction mixtures; yields represent total amount of both
isomeric products 10 and 11. b 2.0 equiv of KOH used with a 1:1 ratio
of 8:9.
A reaction profile with the optimized conditions shows the rapid
formation of
a low concentration of 4-bromopyridine
(approximately 5%) that decreases as the reaction reaches
completion (Scheme 4a). Subjection of the 3-substituted ether
product (11) to the reaction conditions does not result in mass
balance loss, indicating the high 4-selectivity is not a result of
selective decomposition or product rearrangement.27 To test
for the generation of 3,4-pyridyne under these conditions,
when the alcohol is replaced with an excess of furan (12) the
corresponding cycloadduct 13 forms in 42% yield (Scheme 4b).28
We also subjected 3-iodopyridine (14) to the reaction
conditions in the absence of alcohol; in the presence of furan
(12) cycloadduct 13 forms and in the presence of KBr a mixture
of 3- and 4-bromopyridine form (8 and 15, Scheme 4c). The
observed mixture of 3- and 4-bromopyridine supports the
proposal of bromide addition to 3,4-pyridyne. Overall, these
results are consistent with an isomerization pathway via 3,4-
pyridyne and 4-substitution selectivity driven by a facile SNAr
reaction.
Scheme 4. Mechanistic studies on the 4-selective etherification of 3-
bromopyridine. a Conditions as shown in Table 1 using 1.5:1 ratio of
8:9 with 50 mol% KBr additive; see Supporting Information for
details.
A substrate scope for the 4-selective etherification of 3-
bromopyridines is provided in Table 2.29 A range of primary and
secondary alcohols are first shown using 1.5 equiv of simple
bromopyridines. Sterically hindered alcohols (16) and those
containing amino groups (17, 23, and 24), a terminal alkene (18)
and a protected sugar (22) are suitable nucleophiles. Pyridines
methylated in all positions react in high yield and selectivity (19,
20, 21 and 24), indicating that steric hindrance and acidic C–H
bonds are tolerated on the arene. Pyridine biaryl substrates also
selectively couple in the 4-position (25 and 26). Both 2-alkoxy
(23) and 2-amino (28) substituents on the pyridine are
tolerated, although we note the high selectivity observed for
these substrates could originate from alcohol addition to a
distorted 3,4-pyridyne intermediate.19 Pyridine substrates with
more electron-withdrawing groups undergo direct 3-
substitution under the current reaction conditions (e.g. 3-
bromo-2-(trifluoromethyl)pyridine).30
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Table 2. Scope of the 4-etherification of 3-bromopyridines.a
bromination in the 3- and 5-positions (35a and 35bV).ieAwpArptilcilceaOtniloinne
of conditions from Table 2 provides access to the 4-ether 36
DOI: 10.1039/D0SC02689A
through convergence of the regioisomeric bromopyridine
mixture, highlighting an additional benefit of this
methodology.31
Scheme 5. 4-selective etherification of a 2,6-disubstituted pyridine.
We next examined if other nucleophiles can participate in
the 4-selective substitution of 3-bromopyridines. We found that
indolines are effective coupling partners and this route provides
straightforward access to 4-aminopyridines from readily
available 3-bromopyridines (37-40, Scheme 6a). The 4-
amination of 3-bromopyridine with indoline proceeds on gram
scale with excellent selectivity (37). A single isomer of the 5-
bromoindoline product 38 is obtained, demonstrating the
chemoselectivity of aryl halide isomerization.
a Yields are of purified 4-ether product; regioselectivities determined
by 1H NMR spectroscopy of the crude reaction mixture; b Selectivity >6:1;
see Supporting Information for details; c P4-t-Bu (1.3 equiv) used as base
in place of KOH.
An advantage of this functionalization strategy is
demonstrated with substrates 29-33 in Table 2, where the
bromopyridine substrate is obtained from commercial pyridines
while a 4-halogenated isomer is either not available or
significantly more expensive (see Supporting Information for a
discussion). Using 1-1.2 equiv of these bromopyridines, 4-
substituted products featuring a carbamate (29), an acidic
amide (30), a 2,6-disubstituted pyridine (31), a nicotine isomer
(32) and a ketal (33) can be rapidly accessed.
Scheme 6. The 4-substitution of 3-bromopyridines with additional
a
nucleophiles. Isolated yield of purified 4-substituted products;
1
selectivities determined by H NMR spectroscopy of crude reaction
mixtures; b 1.5 equiv of 3-bromopyridine used; c Selectivity 9:1.
It is interesting to note that 4-hydroxypyridine side products
are not typically observed for the reactions in Table 2 even
though KOH is used as a base.32 To develop a 4-hydroxylation
This strategy can also utilize an arene’s innate halogenation
position as an entry to functionalizing more difficult to access
C–H bonds. This is demonstrated in Scheme 5, where the 2,6-
disubstituted pyridine 34 undergoes facile but unselective
protocol,
we
instead
hypothesized
tandem
isomerization/substitution could be further sequenced with a
base-promoted elimination step. This is demonstrated in
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5
6
(a) Bunnett, J. F.; Moyer, C. E. Jr. J. Am. Chem. Soc. 1971, 93,
1183-1190. (b) Bunnett, J. F.; KearleyD, OF.I:J1.0J.1r0.3J9./DO0rgSC. 0C2h6e8m9A.
1971, 36, 184-186.
For selected applications in target-oriented synthesis, see: (a)
Sammakia, T.; Stangeland, E. L.; Whitcomb, M. C. Org. Lett.
2002, 4, 2385-2388. (b) Guillier, F.; Nivoliers, F.; Godard, A.;
Marsais, F.; Quéguiner, G. Tetrahedron Lett. 1994, 35, 6489-
6492. (c) Contins, D. L.; Saha, J. K. Tetrahedron Lett. 1995, 36,
7995-7998.
Scheme 6b, where the use of -hydroxyamide 42 as a
nucleophile directly delivers the 4-hydroxylated product 43 in
50% yield with >10:1 selectivity. We speculate this reaction
proceeds through the standard 4-substitution pathway
followed by a facile base-promoted acrylamide elimination
reaction.33
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7
8
For examples of the halogen dance on halopyridines, see: (a)
Mallet, M.; Quéguiner, G. Tetrahedron 1985, 41, 3433-3440.
(b) Marzi, E.; Bobbio, C.; Cottet, F.; Schlosser, M. Eur. J. Org.
Chem. 2005, 2005, 2116-2123. (c) Marzi, E.; Bigi, A.; Schlosser,
M. Eur. J. Org. Chem. 2001, 2001, 1371-1376.
For examples of reports that describe a rearranged aryl halide
as a side product potentially derived from an aryne
intermediate, see: (a) Dalman, G. W.; Neumann, F. W. J. Am.
Chem. Soc. 1968, 90, 1601-1605. (b) Zoratti, M.; Bunnett, J. F.
J. Org. Chem. 1980, 45, 1769-1776. (c) Blanchard, S.;
Rodriguez, I.; Kuehm-Caubère, C.; Renard, P.; Pfeiffer, B.;
Guillaumet, G.; Caubère, P. Tetrahedron 2002, 58, 3513-3524.
For reviews of aryne reactivity, see: (a) Pellissier, H.; Santelli,
H. Tetrahedron 2003, 59, 701-730. (b) Reinecke, M. G.
Tetrahedron 1982, 38, 427-498. (c) Goetz, A. E.; Garg, N. K. J.
Org. Chem. 2014, 79, 846-851. (d) Tadross, P. M.; Stoltz, B. M.
Chem. Rev. 2012, 112, 3550-3577.
Conclusions
This work demonstrates base-catalyzed aryl halide
isomerization can be paired with SNAr reactivity to achieve
unconventional substitution selectivity. In contrast, established
“halogen dance” methodology relies on the controlled
rearrangement of specific classes of stoichiometrically
metalated haloarenes prior to treatment with electrophiles.3
Thus, tandem isomerization/selective interception may be a
complementary and general strategy for achieving
nontraditional selectivities in aryl halide functionalization
chemistry.
9
Conflicts of interest
There are no conflicts to declare.
10 For examples of halide addition to aryne intermediates, see:
(a) Wittig, G.; Hoffmann, R. W. Chem. Ber. 1962, 95, 2729-
2734. (b) Hamura, T.; Chuda, Y.; Nakatsuji, Y.; Suzuki, K.
Angew. Chem. Int. Ed. 2012, 51, 3368-3372. (c) Grushin, V. V.;
Marshall, W. J. Organometallics 2008, 27, 4825-4828. (d)
Bhattacharjee, S.; Guin, A.; Gaykar, R. N.; Biju, A. T. Org. Lett.
2019, 21, 4383-4387.
Acknowledgements
This work was supported by startup funds from Colorado State
University. Acknowledgment is made to the Donors of the
American Chemical Society Petroleum Research Fund for
support of this research (ACS PRF #60171-DNI1). We thank
Professors Andrew McNally (CSU) and Yiming Wang (Pittsburgh)
for input on this manuscript.
11 For reviews of vicarious and cine-substitution reactions, see:
(a) Suwinski, J.; Swuerczek, K. Tetrahedron 2001, 57, 1639-
1662. (b) Ma
̧
104, 2631-2666. (c) Ma
̧
1987, 20, 282-289. (d) Wang, J.; Dong, G. Chem. Rev. 2019,
119, 7478-7528.
12 For examples of cine-substitution reactions on 3-
bromopyridines, see: (a) Vinter-Pasquier, K.; Jamart-Grégoire,
B.; Caubère, P. Heterocycles 1997, 45, 2113-2129. (b) Smith,
K. B.; Huang, Y.; Brown, M. K. Angew. Chem. Int. Ed. 2018, 57,
6146-6149. (c) Dong, Z.; Lu, G.; Wang, J.; Liu, P.; Dong, G. J.
Am. Chem. Soc. 2018, 140, 8551-8562.
13 (a) Popov, I.; Do, H.-Q.; Daugulis, O. J. Org. Chem. 2009, 74,
8309-8313. (b) Imahori, T.; Kondo, Y. J. Am. Chem. Soc. 2003,
125, 8082-8083. (c) Zoltewicz, J. A.; Smith, C. L. J. Am. Chem.
Soc. 1966, 88, 4766-4767.
14 (a) Schwesinger, R.; Schlemper, H. Angew. Chem. Int. Ed.
1987, 26, 1167-1169. (b) Superbases for Organic Synthesis:
Guanidines, Amidines, Phosphazenes and Related
Organocatalysts; Ishikawa, T., Ed.; John Wiley & Sons, Ltd:
Chichester, UK, 2009.
15 (a) This is consistent with known rates of formation of
benzyne and selectivities for benzyne additions although we
cannot rule out other pathways at this time for these
substrates, see reference 9 for reviews. (b) For examples of
classical halogen dance on bromobenzotrifluorides, see:
Mongin, F.; Desponds, O.; Schlosser, M. Tetrahedron Lett.
1996, 37, 2767-2770.
Notes and references
1
For selected modes of reactivity, see: (a) Terrier, F. Modern
Nucleophilic Aromatic Substitution; Wiley-VCH: Weinheim,
2013. (b) Magano, J.; Dunetz, J. R. Chem. Rev. 2011, 111, 2177-
2250. (c) Zhang, N.; Samanta, S. R.; Rosen, B. M.; Percec, V.
Chem. Rev. 2014, 114, 5848-5958. (d) Seyferth, D.
Organometallics 2009, 28, 1598-1605. (e) Twilton, J.; Le, C.;
Zhang, P.; Shaw, M. H.; Evans, R. W.; MacMillan, D. W. C. Nat.
Rev. Chem. 2017, 1, 0052. (f) Bunnett, J. F. J. Chem. Ed. 1974,
51, 312-315.
For selected examples of acid-catalyzed rearrangement and
disproportionation of haloarenes, see: (a) Jacobs, T. L.;
Winstein, S.; Ralls, J. W.; Robson, J. H. J. Org. Chem. 1946, 11,
27-33. (b) Olah, G. A.; Tolgyesi, W. S.; Dear, R. E. A. J. Org.
Chem. 1962, 27, 3455-3465. (c) Olah, G. A.; Meyer, M. W. J.
Org. Chem. 1962, 27, 3464-3469. (d) Jacquesy, J.-C.;
Jouannetaud, M.-P. Tetrahedron Lett. 1982, 23, 1673-1676.
(a) Schnürch, M.; Spina, M.; Khan, A. F.; Mihovilovic, M. D.;
Stanetty, P. Chem. Soc. Rev. 2007, 36, 1046-1057. (b)
Schlosser, M. Angew. Chem. Int. Ed. 2005, 44, 376-393. (c) Erb,
W.; Mongin, F. Tetrahedron 2016, 72, 4973-4988.
2
3
4
16 Mallet, M.; Quénguiner, G. Tetrahedron 1982, 38, 3035-3042.
17 (a) Rohrbach, S.; Smith, A. J.; Pang, J. H.; Poole, D. L.; Tuttle,
T.; Chiba, S.; Murphy, J. A. Angew. Chem. Int. Ed. 2019, 58,
16368-16388. (b) Schröter, S.; Stock, C.; Bach, T. Tetrahedron
2005, 61, 2245-2267.
18 Lloung, M.; Loupy, A.; Marque, S.; Petit, A. Heterocycles 2004,
63, 297-308.
(a) Bunnett, J. F. Acc. Chem. Res. 1972, 5, 139-147. (b) Moyer,
C. E. Jr.; Bunnet, J. F. J. Am. Chem. Soc. 1963, 85, 1891-1893.
(c) Bunnett, J. F.; Scorrano, G. J. Am. Chem. Soc. 1971, 93,
1190-1198.
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19 For discussions on 3,4-pyridynes, see: Goetz, A. E.; Garg, N. K.
involvement of aryl halide isomerization; seVeiewSuArpticpleoOrtnilninge
Nat. Chem. 2013, 5, 54-60. (b) Goetz, A. E.; Bronner, S. M.;
Information for details.
DOI: 10.1039/D0SC02689A
Cisneros, J. D.; Melamed, J. M.; Paton, R. S.; Houk, K. N.; Garg, 30 For a similar SNAr reaction, see: Basséne, C. E.; Suzenet, F.;
N. K. Angew. Chem. Int. Ed. 2012, 51, 2758-2762.
Hennuyer, N.; Staels, B.; Caignard, D.-H.; Dacquet, C.; Renard,
P.; Guillaumet, G. Bioorg. Med. Chem. Lett. 2006, 16, 4528-
2532.
20 3-Bromopyridines are substantially more available in chemical
catalogs of various suppliers, including the online database
www.emolecules.com (accessed March 2, 2020); for a 31 See reference 12c for a similar convergence example in a
discussion and examples of the 3-halogenation of pyridines,
see: (a) Joule, J.A. and Mills, K. Heterocyclic Chemistry, 5th ed.
Pd/norbornene co-catalyzed 4-selective amination reaction
using N-hydroxylamine ester electrophiles.
Wiley: West Sussex, 2011. (b) Canibaño, V.; Rodríguez, J. F.; 32 In the reactions reported in Table 2, less than 5% of 4-
Santos, M.; Sanz-Tejedor, M. A.; Carreño, M. C.; Gonzáez, G.;
Garcia-Ruano, J. L. Mild Synthesis 2001, 14, 2175-2179. (c)
Das, B.; Venkateswarlu, K.; Majhi, A.; Siddaiah, V.; Reddy, K. R.
J. Mol. Catal. A. 2007, 267, 30-33.
hydroxypyridine side products are typically observed.
Attempts to perform the reaction in the absence of alcohol
did not significantly increase the yield of hydroxylation
products.
21 (a) Fesat, W. J.; Tsibouklis, J. Polym. Int. 1994, 35, 67-74. (b) 33 N,N-Dibenzyl acrylamide is observed as the major byproduct
Wibaut, J. P.; Broekman, F. W. Recl. Trav. Chim. Pays-Bas
1959, 78, 593-603. (c) Fisher, E. L.; am Ende, C. W.; Humphrey,
J. M. J. Org. Chem. 2019, 84, 4904-4909.
in this reaction. For related hydroxylation strategies, see: (a)
Revuelto, A.; Ruiz-Santaquiteria, M.; de Lucio, H.; Gamo, A.;
Carriles, A. A.; Gutiérrez, K. J.; Sánchez-Murcia, P. A.;
Hermoso, J. A.; Gago, F.; Camarasa, M.-J.; Jiménez-Ruiz, A.;
Velázquez, S. ACS Infect. Dis. 2019, 5, 873-891. (b) Rogers, J.
F.; Green, D. M. Tetrahedron Lett. 2002, 43, 3585-3587.
22 For reviews and examples of 4-pyridine C–H functionalization
to C–O and C–N bonds, see: (a) Stephens, D. E.; Larionov, O.
V. Tetrahedron 2015, 71, 8683-8716. (b) Murakami, K.;
Yamada, S.; Kaneda, T.; Itami, K. Chem. Rev. 2017, 117, 9302-
9332. (c) Sundberg, R. J.; Jiang, S. Org. Prep. Proced. Int. 1997,
29, 117-122. (d) Gu, Y.; Shen, Y.; Zarate, C.; Martin, R. J. Am.
Chem. Soc. 2019, 141, 127-132. (e) Cho, J.-Y.; Tse, M. K.;
Holmes, D.; Maleczka, R. E.; Smith, M. R. III. Science 2002, 295,
305-308. (f) Yang, L.; Semba, K.; Nakao, Y. Angew. Chem. Int.
Ed. 2017, 56, 4853-4857.
23 (a) Dolewski, R. D.; Hilton, M. C.; McNally, A. Synlett 2018, 29,
8-14. (b) Hilton, M. C.; Dolewski, R. D.; McNally, A. J. Am.
Chem. Soc. 2016, 138, 13806-13809. (c) Anderson, R. G.; Jett,
B. M.; McNally, A. Angew. Chem. Int. Ed. 2018, 57, 12514-
12518. (d) Patel, C.; Mohnike, M.; Hilton, M. C.; McNally, A.
Org. Lett. 2018, 20, 2607-2610.
24 For examples and discussions of using alkoxide and hydroxide
bases in aryne chemistry, see: (a) Apeloig, Y.; Arad, D.; Halton,
B.; Randall, C. J. J. Am. Chem. Soc. 1986, 108, 4932-4937. (b)
Dong, Y.; Lipschutz, M. I.; Tilley, T. D. Org. Lett. 2016, 18, 1530-
1533. (c) Yuan, Y.; Thomé, I.; Kim, S. H.; Chen, D.; Beyer, A.;
Bonnamour, J.; Zuidema, E.; Chang, S.; Bolm, C. Adv. Synth.
Catal. 2010, 352, 2892-2898. (d) Willoughby, P. H.; Niu, D.;
Wang, T.; Haj, M. K.; Cramer, C. J.; Hoye, T. R. J. Am. Chem.
Soc. 2014, 136, 13657-13665.
25 For examples of low selectivities for addition to unbiased 3,4-
pyridynes, see references 9, 19 and (a) Zoltewicz, J. A.; Nisi, C.
J. Org. Chem. 1969, 34, 765-766. (b) Jamart-Gregoire, B.;
Leger, C.; Caubère, P. Tetrahedron Lett. 1990, 31, 7599-7602.
For changes in selectivities of alcohol addition to arynes
depending on conditions used, see: (c) Bunnet, J. F.; Happer,
D. A. R.; Patsch, M.; Pyun, C.; Takayama, H. J. Am. Chem. Soc.
1966, 88, 5250-5254. (d) Stiles, M.; Miller, R. G.; Burckhardt,
U. J. Am. Chem. Soc. 1963, 85, 1792-1797. It is also possible
that direct 3-substitution of 8 contributes to the low 4:3
substitution regioselectivity.
26 A similar strategy was tested to no effect by Bunnett to rule
out
a
benzyne intermediate in tribromobenzene
isomerization, see reference 5.
27 We note that 3,4-dibromopyridine is not observed during the
course of the reaction, nor does the subjection of the 3-
brominated derivative of 10 to the reaction conditions result
in debromination to give 10. These results suggest an
intermolecular halogen transfer pathway is not involved in
the 4-etherification reaction.
28 Connon, S. J.; Hegarty, A. F. J. Chem. Soc., Perkin Trans. 2000,
1, 1245-1249.
29 A variety of substrates from Table 2 were subjected to the
reaction conditions in the absence of alcohol; 4-
bromopyridines are observed, indicating the likely
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DOI: 10.1039/D0SC02689A
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The base-catalyzed isomerization of simple aryl halides is described, including its application to
the tandem isomerization/4-substitution of 3-bromopyridines as a new strategy for achieving
unconventional selectivity in nucleophilic aromatic substitution reactions.