Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2020 Sep 9;11(38):10517-10522.
doi: 10.1039/d0sc02689a.

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

Thomas R Puleo  1 , Jeffrey S Bandar  1
Affiliations

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

Thomas R Puleo et al. Chem Sci. .

Abstract

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.

PubMed Disclaimer

Conflict of interest statement

There are no conflicts to declare.

Figures

Scheme 1
Scheme 1. Concept of catalytic aryl halide isomerization.
Fig. 1
Fig. 1. A general approach to aryl halide isomerization and its application to a new selective substitution reaction.
Scheme 2
Scheme 2. P4-t-Bu-catalyzed aryl halide isomerization. a Yields determined by 1H NMR spectroscopy; the mass balance is less than 100% with no observed haloarene side products; conditions for (b) are as shown in (a). b Reaction performed in cyclohexane for 14 h.
Scheme 3
Scheme 3. Proposed pathway for the 4-selective substitution of 3-bromopyridine (B = base, NuH = nucleophile).
Scheme 4
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 ESI for details.
Scheme 5
Scheme 5. 4-selective etherification of a 2,6-disubstituted pyridine.
Scheme 6
Scheme 6. The 4-substitution of 3-bromopyridines with additional nucleophiles. a Isolated yield of purified 4-substituted products; selectivities determined by 1H NMR spectroscopy of crude reaction mixtures; b 1.5 equiv. of 3-bromopyridine used; c selectivity 9 : 1.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

References

    1. For selected modes of reactivity, see:

    2. Terrier F., Modern Nucleophilic Aromatic Substitution, Wiley-VCH, Weinheim, 2013
    3. Magano J. Dunetz J. R. Chem. Rev. 2011;111:2177–2250. - PubMed
    4. Zhang N. Samanta S. R. Rosen B. M. Percec V. Chem. Rev. 2014;114:5848–5958. - PubMed
    5. Seyferth D. Organometallics. 2009;28:1598–1605.
    6. Twilton J. Le C. Zhang P. Shaw M. H. Evans R. W. MacMillan D. W. C. Nat. Rev. Chem. 2017;1:0052.
    7. Bunnett J. F. J. Chem. Educ. 1974;51:312–315.

    1. For selected examples of acid-catalyzed rearrangement and disproportionation of haloarenes, see:

    2. Jacobs T. L. Winstein S. Ralls J. W. Robson J. H. J. Org. Chem. 1946;11:27–33. - PubMed
    3. Olah G. A. Tolgyesi W. S. Dear R. E. A. J. Org. Chem. 1962;27:3455–3464.
    4. Olah G. A. Meyer M. W. J. Org. Chem. 1962;27:3464–3469.
    5. Jacquesy J.-C. Jouannetaud M.-P. Tetrahedron Lett. 1982;23:1673–1676.
    1. Schnürch M. Spina M. Khan A. F. Mihovilovic M. D. Stanetty P. Chem. Soc. Rev. 2007;36:1046–1057. - PubMed
    2. Schlosser M. Angew. Chem., Int. Ed. 2005;44:376–393. - PubMed
    3. Erb W. Mongin F. Tetrahedron. 2016;72:4973–4988.
    1. Bunnett J. F. Acc. Chem. Res. 1972;5:139–147.
    2. Moyer Jr. C. E. Bunnett J. F. J. Am. Chem. Soc. 1963;85:1891–1893.
    3. Bunnett J. F. Scorrano G. J. Am. Chem. Soc. 1971;93:1190–1198.
    1. Bunnett J. F. Moyer Jr. C. E. J. Am. Chem. Soc. 1971;93:1183–1190.
    2. Bunnett J. F. Kearley Jr. F. J. J. Org. Chem. 1971;36:184–186.