Sequential Ring-Opening and Ring-Closing Reactions for Converting para-Substituted Pyridines into meta-Substituted Anilines

Letter

Sequential Ring-Opening and Ring-Closing Reactions for Converting

para -Substituted Pyridines into meta-Substituted Anilines

Tatsuya Morofuji,* Kota Inagawa, and Naokazu Kano*

Cite This: Org. Lett. 2021, 23, 6126 −6130

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sı Supporting Information

ABSTRACT: Herein we report a method for converting para-

substituted pyridine rings into meta-dialkylamino-substituted ben-

zene rings through sequential ring-opening and ring-closing

reactions. The nitrogen atom in the pyridine rings was replaced

with a methine group, and a dialkylamino substituent was introduced

onto the original unsubstituted carbon atom in the pyridine rings.

This process can be formally regarded as a hybrid of the skeletal

editing and C−H amination of pyridine rings.

he transformation of aromatic compounds is an essential

tool for the synthesis of complex molecules. Most of

them are classiﬁed as peripheral transformations of aromatic

philic aromatic substitutions because of their regioselectivity.

This process can be formally regarded as a hybrid of the

skeletal editing and C−H amination of pyridine rings.

rings, such as functional group transformation and aromatic

Complementary to the meta-selective directed C−H function-

electrophilic substitution (Figure 1a, left). Transition-metal-

alization reactions that provide meta-substituted anilines, the

catalyzed C−H functionalization is considered the state-of-the-

proposed method provides various meta-substituted anilines

from para-substituted pyridines without directing groups.

The ring opening of pyridine was conducted to obtain

art peripheral transformation method. In contrast, skeletal

editing of the aromatic rings by replacing the constituent

6,9,10

streptocyanine by a reported method.

The N-arylation of

atoms is still relatively rare; however, it is an attractive

alternative method for enabling unique synthetic routes for

para-phenylpyridine (1a) with 2,4-dinitrochlorobenzene

yielded the corresponding N-arylpyridinium salt 2a (Scheme

functionalized aromatic compounds (Figure 1a, right).

). Treatment of 2a with piperidine followed by salt exchange

Benzene ring formation reactions using pyryliums are

aﬀorded the desired streptocyanine 3a in good yield.

representative examples (Figure 1b), where the oxygen

Subsequently, we optimized the reaction conditions for the

5 + 1) ring-closing reaction using streptocyanine 3a as the C5

atom is replaced with a carbon atom bearing a substituent

through the reaction. As another example, we reported that

ring-opening reactions of para-substituted pyridines followed

by (5 + 1) ring-closing reactions of the resulting

streptocyanines with enolates yielded para-acyl-substituted

(

source and trimethylsulfonium iodide as the C1 source (Table

). Streptocyanine 3a, trimethylsulfonium iodide, and sodium

tert-butoxide (NaO Bu) were mixed and stirred in tetrahy-

drofuran (THF) at 80 °C for 16 h in a pressure tube to give

the desired meta-substituted aniline 4a in 21% yield (entry 1).

The reaction conducted at 120 °C presented the best yield of

the product compared with that at 140 °C (entries 2 and 3).

benzene derivatives (Figure 1c, top). In this type of reaction,

the substituent is generally introduced together with the

carbon atom and is necessarily bonded to it.

On the basis of this background, we envisaged that a process

combining peripheral functionalization and skeletal editing of

the aromatic rings would be highly challenging; however, it can

provide a novel and unique synthetic strategy. Here we report

sequential reactions for converting para-substituted pyridine

rings to meta-amino-substituted benzene rings (Figure 1c,

bottom). The key to this transformation is the (5 + 1) ring-

closing reaction of streptocyanine with dimethylsulfonium

methylide. Through this process, the nitrogen atom in the

pyridine rings was replaced with a methine group, and a

dialkylamino substituent was introduced onto the original

unsubstituted carbon atom in the pyridine rings. The resulting

meta-substituted anilines are diﬃcult to synthesize by electro-

Increasing the amount of NaO Bu improved the yield (entry

). Reducing the amounts of sulfonium salt decreased the yield

(

entry 5). An examination of the C1 source revealed that the

use of trimethylsulfonium tetraﬂuoroborate gave 4a in almost

quantitative yield (entries 6 and 7).

Received: July 3, 2021

Published: July 27, 2021

2021 American Chemical Society

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Org. Lett. 2021, 23, 6126−6130

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Letter

After the reaction conditions were optimized, the scope of

the conversion of the para-substituted pyridines into meta-

amino-substituted benzenes was investigated (Scheme 2). The

Scheme 2. Conversion of para-Substituted Pyridines 1 into

meta-Substituted Anilines 4

Figure 1. Methods for manipulating substituents or constituent atoms

of aromatics.

Scheme 1. Ring Opening of para-Phenylpyridine (1a)

Table 1. Investigations of the (5 + 1) Ring-Closing

Reactions

Reaction was run on a 4 mmol scale. Results from ref 6. A: 2,4-

NO) C H Cl, acetone, reﬂux. B: Amine, EtOH, reﬂux, 2 h, then

(

−

KPF or NaSbF . C: (CH ) S BF , NaO Bu, THF, 120 °C, 16 h. See

the SI for details. Isolated yields of products are shown.

entry

C1 source

T (°C)

yield (%)

6 6 3 3 4

−

(CH ) S I

120

140

120

(CH ) S I

scope of amines was examined using para-phenylpyridine (1a)

as the starting material. meta-Phenylanilines bearing cyclic

dialkylamino substituents were obtained (4a, 4b). Notably, the

(5 + 1) ring-closing reaction eﬃciently produced 4a on a 4

mmol scale. Acyclic secondary amines, such as dimethylamine

and diethylamine, also yielded the corresponding products (4c,

(CH ) S I

−

(CH ) S =OI

Trace

>99

−

(CH ) S BF

120

Streptocyanine 3a (0.2 mmol), C1 source, NaO Bu, and THF (4

d). Moreover, unsymmetrical secondary amines were also

mL) were stirred at the indicated temperature in a pressure tube for

6 h. Determined by H NMR spectroscopy.

applicable to the present process (4e). Through sequential

ring-opening and ring-closing reactions, the pyridine ring was

converted to a benzene ring, accompanied by the introduction

of a dialkylamino group at the two-position of the pyridine ring

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Org. Lett. 2021, 23, 6126−6130

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Letter

Scheme 3. Conversion of para-Substituted Pyridines into meta-Arylanilines 4 Using Bioactive Amines

−

A: 2,4-(NO) C H Cl, acetone, reﬂux. B: Amine, EtOH, reﬂux, 2 h, then KPF or NaSbF . C: (CH ) S BF , NaO Bu, THF, 120 °C, 16 h. See the

SI for details. Isolated yields of products are shown.

in 1a. The resulting meta-phenylaniline derivatives are

generally diﬃcult to synthesize by the electrophilic substitution

of biphenyl and anilines owing to their ortho−para orientation.

As substituents in the starting pyridine, aryl groups bearing

both electron-donating and electron-withdrawing groups were

compatible with the process (4f−4h). Notably, the bromo-

substituted product 4h was eﬃciently obtained, which can be

further derivatized by transition-metal-catalyzed cross-coupling

reactions. In addition, anilines bearing a π-extended substituent

at the meta position were also produced (4i−4k). For 4f, 4g,

and 4i, the starting para-substituted pyridines were synthesized

from the parent pyridine in a single step without using a

transition-metal catalyst. (See the Supporting Information

SI).) The use of para-(diphenylamino)pyridine aﬀorded

meta-diaminobenzene 4l.

Bioactive amines were used to demonstrate the utility of the

process (Scheme 3). N-Arylation and the subsequent ring-

opening of para-(4-bromophenyl)pyridine with maprotiline

aﬀorded the corresponding streptocyanine, which was

converted into the meta-phenylaniline derivative 4m (Scheme

a). Bioactive amine derivatives would be synthesized by

combining the present process and the transition-metal-

catalyzed cross-coupling reactions. Fluoxetine and ﬂuorene,

a typical ﬂuorescent molecule, were connected through a meta-

phenylene linker (Scheme 3b). This demonstrates the

connection of a bioactive component and a ﬂuorescent moiety

through a linker, which is often used in biochemistry.

−

We performed the reaction of 3a with (CD ) S BF to gain

mechanistic insights into the (5 + 1) ring-closing reaction

Figure 2a). Deuterated 4a-D was produced, which conﬁrms

that trimethylsulfonium salt is the C1 source of the present

(

Figure 2. Mechanistic studies and plausible reaction mechanism. (a)

Deuterium labeling reaction. (b) Observation of triene intermediate

reaction. In addition, we performed the reaction of 3a with

5a. (c) Plausible reaction mechanism of the (5 + 1) ring-closing

trimethylsulfonium salt in the presence of NaO Bu at room

reaction.

temperature (Figure 2b). The formation of triene intermediate

a was observed by high-resolution mass spectrometry

(

HRMS) and H NMR analyses. This result suggests the

Considering these mechanistic studies, we propose a

mechanism for the (5 + 1) ring-closing reaction, as shown in

intermediacy of 5a in the present reaction.

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Org. Lett. 2021, 23, 6126−6130

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Letter

Figure 2c. Streptocyanine 3 would be thermally converted to

E/Z isomer 3′ due to the single-bond character of the C2−C3

bond. Dimethylsulfonium methylide, the C1 source, attacks

the iminium group in 3′ to give the corresponding sulfonium

the Moritani Scholarship Foundation, The Foundation for the

Promotion of Ion Engineering, the Iketani Science and

Technology Foundation, and Tokuyama Science Foundation.

DFT calculations were performed using the Research Center

for Computational Science, Okazaki, Japan.

The deprotonation of 6 with base gives triene 5,

accompanied by the elimination of dimethyl sulﬁde, which is

critically diﬀerent from the mechanism of our previou₆s

synthesis of para-acyl-substituted benzenes (Figure 1c, top).

Subsequently, the 6π electrocyclization of 5 gives cyclo-

hexadiene 7, and the following elimination of one of the

amines produces the desired meta-substituted anilines 4. To

support this idea, density functional (DFT) calculations were

carried out, which indicated that the electrocyclic reaction of

REFERENCES

■

(1) (a) Taylor, R. Electrophilic Aromatic Substitution; Wiley: New

York, 1990. (b) Arene Chemistry: Reaction Mechanisms and Methods for

Aromatic Compounds; Wiley, 2015.

Functionalization. J. Org. Chem. 2016 , 81 , 343 −350. (b) Leitch, J. A.;

2) (a) Davies, H. M. L.; Morton, D. Recent Advances in C −H

Frost, C. G. Ruthenium-catalysed σ -activation for remote meta -

selective C −H functionalisation. Chem. Soc. Rev. 2017, 46, 7145 −

7153. (c) Dutta, U.; Maiti, S.; Bhattacharya, T.; Maiti, D. Arene

a has a reasonable activation energy (+25.0 kcal/mol; see the

SI ).

In summary, we have developed a method for converting

diversification through distal C(sp )−H functionalization. Science

021 , 372 , No. eabd5992. (d) Lam, N. Y. S.; Wu, K.; Yu, J.-Q.

Advancing the Logic of Chemical Synthesis: C −H Activation as

Strategic and Tactical Disconnections for C −C Bond Construction.

Angew. Chem., Int. Ed. 2021, 60, 15767.

para-substituted pyridine rings into meta-amino-substituted

benzene rings through sequential ring-opening and ring-closing

reactions. Mechanistic studies suggest that the (5 + 1) ring-

closing reactions involve the formation of the triene

intermediate followed by electrocyclization. This unique

transformation of the aromatic core can provide various

meta-substituted anilines, which are diﬃcult to synthesize by

electrophilic aromatic substitutions from the easily accessible

para-substituted pyridine. Notably, complex amines can be

used in the present process. The further development of

methods for transforming aromatic cores by sequential ring-

opening and ring-closing reactions is ongoing in our

laboratory.

3) Selected recent examples of skeletal editing: (a) Cao, Z.-C.; Shi,

Z.-J. Deoxygenation of Ethers To Form Carbon −Carbon Bonds via

Nickel Catalysis. J. Am. Chem. Soc. 2017, 139, 6546−6549. (b) Roque,

J. B.; Kuroda, Y.; Göttemann, L. T.; Sarpong, R. Deconstructive

diversification of cyclic amines. Nature 2018, 564, 244−248.

A.; Kwon, O. Hydrodealkenylative C(sp )−C(sp ) bond fragmenta-

tion. Science 2019, 364, 681 −685. (d) Xu, Y.; Qi, X.; Zheng, P.; Berti,

C. C.; Liu, P.; Dong, G. Deacylative transformations of ketones via

aromatization-promoted C −C bond activation. Nature 2019 , 567 ,

73 −378. (e) Fier, P. S.; Kim, S.; Maloney, K. M. Reductive Cleavage

of Secondary Sulfonamides: Converting Terminal Functional Groups

into Versatile Synthetic Handles. J. Am. Chem. Soc. 2019, 141,

8416−18420. (f) Kennedy, S. H.; Dherange, B. D.; Berger, K. J.;

Levin, M. D. Skeletal editing through direct nitrogen deletion of

secondary amines. Nature 2021 , 593 , 223 −227.

4) (a) Boger, D. L. Diels-Alder reactions of heterocyclic azadienes.

Scope and applications. Chem. Rev. 1986 , 86 , 781 −793. (b) Chatto-

padhyay, B.; Gevorgyan, V. Transition-Metal-Catalyzed Denitrogena-

tive Transannulation: Converting Triazoles into Other Heterocyclic

Systems. Angew. Chem., Int. Ed. 2012 , 51 , 862 −872. (c) Prokhorov, A.

M.; Kozhevnikov, D. N. Reactions of triazines and tetrazines with

dienophiles. Chem. Heterocycl. Compd. 2012 , 48 , 1153 −1176.

(d) Anbarasan, P.; Yadagiri, D.; Rajasekar, S. Recent Advances in

Transition-Metal-Catalyzed Denitrogenative Transformations of

,2,3-Triazoles and Related Compounds. Synthesis 2014 , 46 , 3004 −

023. (e) Nogi, K.; Yorimitsu, H. Aromatic metamorphosis:

conversion of an aromatic skeleton into a different ring system.

Chem. Commun. 2017, 53, 4055−4065.

5) (a) Dimroth, K.; Bräuniger, G. Ein Stickstoff-haltiges

ungesattigtes 7-Ring-System mit aromatischen Eigenschaften. Angew.

ASSOCIATED CONTENT

sı Supporting Information

■

The Supporting Information is available free of charge at

https://pubs.acs.org/doi/10.1021/acs.orglett.1c02225.

orcid.org/0000-0001-9146-9290 ;

Experimental procedures, computational studies, and

NMR spectra (PDF)

AUTHOR INFORMATION

Corresponding Authors

■

Tatsuya Morofuji − Department of Chemistry, Faculty of

Science, Gakushuin University, Tokyo 171-8588, Japan;

Email: tatsuya.morofuji@gakushuin.ac.jp

Naokazu Kano − Department of Chemistry, Faculty of Science,

Gakushuin University, Tokyo 171-8588, Japan;

orcid.org/0000-0002-7019-0378 ;

Chem. 1956 , 68 , 519. (b) Li, Y.; Wang, H.; Li, X. Over one century

Email: naokazu.kano@gakushuin.ac.jp

after discovery: pyrylium salt chemistry emerging as a powerful

approach for the construction of complex macrocycles and metallo-

supramolecules. Chem. Sci. 2020, 11, 12249 −12268.

Author

Kota Inagawa − Department of Chemistry, Faculty of Science,

Gakushuin University, Tokyo 171-8588, Japan

(6) Morofuji, T.; Kinoshita, H.; Kano, N. Connecting a carbonyl and

a π -conjugated group through a p -phenylene linker by (5 + 1)

benzene ring formation. Chem. Commun. 2019, 55, 8575 −8578.

Complete contact information is available at:

https://pubs.acs.org/10.1021/acs.orglett.1c02225

7) (a) Collet, F.; Dodd, R. H.; Dauban, P. Catalytic C −H

amination: recent progress and future directions. Chem. Commun.

2009 , 5061 −5074. (b) Louillat, M.-L.; Patureau, F. W. Oxidative C −

H amination reactions. Chem. Soc. Rev. 2014 , 43 , 901 −910. (c) Park,

Y.; Kim, Y.; Chang, S. Transition Metal-Catalyzed C −H Amination:

Scope, Mechanism, and Applications. Chem. Rev. 2017, 117, 9247−

Notes

The authors declare no competing ﬁnancial interest.

ACKNOWLEDGMENTS

■

9301.

This research was partially supported by the MEXT-supported

program for the Strategic Research Foundation at Private

Universities, Shorai Foundation for Science and Techonology,

(8) (a) Phipps, R. J.; Gaunt, M. J. A Meta-Selective Copper-

Catalyzed C −H Bond Arylation. Science 2009, 323, 1593−1597.

(b) Wang, P.; Li, G.-C.; Jain, P.; Farmer, M. E.; He, J.; Shen, P.-X.;

129

Org. Lett. 2021, 23, 6126−6130

Organic Letters

S.; Falck, J. R. Picolinate-Directed Arene meta -C −H Amination via

Letter

Yu, J.-Q. Ligand-Promoted meta -C −H Amination and Alkynylation. J.

Am. Chem. Soc. 2016 , 138 , 14092 −14099. (c) Anugu, R. R.; Munnuri,

FeCl Catalysis. J. Am. Chem. Soc. 2020, 142, 5266 −5271.

(9) (a) Zincke, T.; Heuser, G.; Möller, W. I. Ueber Dinitrophe-

nylpyridiniumchlorid und dessen Umwandlungsproducte. Justus

Liebigs Ann. Chem. 1904, 333, 296 −345. (b) Steinhardt, S. E.;

Silverston, J. S.; Vanderwal, C. D. Stereocontrolled Synthesis of Z -

Dienes via an Unexpected Pericyclic Cascade Rearrangement of 5-

Amino-2,4-pentadienals. J. Am. Chem. Soc. 2008, 130, 7560−7561.

c) Paton, R. S.; Steinhardt, S. E.; Vanderwal, C. D.; Houk, K. N.

Unraveling the Mechanism of Cascade Reactions of Zincke

Aldehydes. J. Am. Chem. Soc. 2011 , 133 , 3895 −3905.

(10) (a) Köbrich, G. 4-Methyl-pyryliumperchlorat und dessen

Abwandlung zu Pentamethinderivaten. Justus Liebigs Ann. Chem.

961, 648, 114 −123. (b) Jutz, C.; Wagner, R.-M.; Kraatz, A.;

Löbering, H.-G. Umsetzung von vinylogen Formamidiniumsalzen mit

Nucleophilen, II. Polymethiniumsalze aus methylenaktiven Ketonen.

Justus Liebigs Ann. Chem. 1975 , 1975 , 874 −900. (c) Yamaguchi, I.;

Shingai, S.; Sato, M. Ring-Opening Copolymerization of Pyridinium

Salts with Piperazine To Give Ionic Polymers with Expanded π -

Conjugation System Derived from Through-Space Interaction in a

Piperazinium Ring. Macromolecules 2008, 41, 6292−6298. (d) Co-

lombo, A.; Dragonetti, C.; Righetto, S.; Roberto, D.; Valore, A.;

Benincori, T.; Colombo, F.; Sannicolo, F. Novel highly conjugated

push −pull 4,5-diazafluoren-9-ylidene based efficient NLO chromo-

phores as a springboard for coordination complexes with large

second-order NLO properties. J. Mater. Chem. 2012 , 22 , 19761.

(11) Akiba, K.-y.; Iseki, Y. J.; Wada, M. A Convenient Method for

the Regioselective Synthesis of 4-Alkyl(aryl)pyridines Using Pyr-

idinium Salts. Bull. Chem. Soc. Jpn. 1984, 57, 1994−1999.

(12) Pinder, R. M.; Brogden, R. N.; Speight, T. M.; Avery, G. S.

Maprotiline: A Review of its Pharmacological Properties and

Therapeutic Efficacy in Mental Depressive States. Drugs 1977, 13,

21−352.

13) Rossi, A.; Barraco, A.; Donda, P. Ann. Gen. Hosp. Psychiatry

004, 3, 2.

14) Gonca

Organic Probes. Chem. Rev. 2009, 109, 190−212.

15) (a) Lin, J. J. Name Reactions: A Collection of Detailed Reaction

(

̧ lves, M. S. T. Fluorescent Labeling of Biomolecules with

(

Mechanisms; Springer: Berlin, 2003; pp 88−89. (b) McGarrigle, E. M.;

Myers, E. L.; Illa, O.; Shaw, M. A.; Riches, S. L.; Aggarwal, V. K.

Chalcogenides as Organocatalysts. Chem. Rev. 2007 , 107 , 5841 −5883.

(

c) Pellissier, H. Recent developments in asymmetric aziridination.

Tetrahedron 2010, 66, 1509−1555.

(16) (a) Davies, I. W.; Marcoux, J.-F.; Kuethe, J. T.; Lankshear, M.

D.; Taylor, J. D. O.; Tsou, N.; Dormer, P. G.; Hughes, D. L.; Houk, K.

N.; Guner, V. Demonstrating the Synergy of Synthetic, Mechanistic,

and Computational Studies in a Regioselective Aniline Synthesis. J.

Org. Chem. 2004, 69, 1298−1308. (b) Viteva, L.; Gospodova, T.;

Stefanovsky, Y.; Petrova, K.; Timtcheva, I.; Mazieres, M.-R.; Wolf, J.-

G. Organometallics in Cyanine Chemistry −Synthesis, Reactivity and

Photophysical Properties of some Heptamethine Merocyanine Dyes.

Eur. J. Org. Chem. 2004 , 2004 , 385 −394. (c) Tatton, M. R.; Simpson,

I.; Donohoe, T. J. De Novo Synthesis of Multisubstituted Aryl Amines

Using Alkene Cross Metathesis. Org. Lett. 2014 , 16 , 1920 −1923.

d) Tatton, M. R.; Simpson, I.; Donohoe, T. J. New methods for the

synthesis of naphthyl amines; application to the synthesis of

dihydrosanguinarine, sanguinarine, oxysanguinarine and (±)-macle-

karpines B and C. Chem. Commun. 2014 , 50 , 11314 −11316. (e) Li,

X.; Yu, H.; Huang, Y. Amine-Triggered 6 π -Electrocyclization-

Aromatization Cascade of Ynedienamines. Adv. Synth. Catal. 2017,

359, 1379−1387.

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