Catalyst-Free Phosphorylation of Acridine with Secondary Phosphine Chalcogenides: Nucleophilic Addition vs SNHAr Reaction

Article abstract of DOI:10.1021/acs.orglett.8b03061

Acridine adds secondary phosphine chalcogenides HP(X)R₂ (X = O, S, Se; R = Ar, ArAlk) under catalyst-free conditions at 70-75 °C (both in the presence and absence of the electron-deficient acetylenes) to give 9-chalcogenophosphoryl-9,10-dihydro

Full text of DOI:10.1021/acs.orglett.8b03061

Letter
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Catalyst-Free Phosphorylation of Acridine with Secondary
H
Phosphine Chalcogenides: Nucleophilic Addition vs S Ar Reaction
N
Pavel A. Volkov, Kseniya O. Khrapova, Anton A. Telezhkin, Nina I. Ivanova, Alexander I. Albanov,
Nina K. Gusarova, and Boris A. Trofimov*
A.E. Favorsky Irkutsk Institute of Chemistry, Siberian Branch of the Russian Academy of Sciences, 1 Favorsky St., Irkutsk 664033,
Russian Federation
*
S Supporting Information
ABSTRACT: Acridine adds secondary phosphine chalcoge-
nides HP(X)R (X = O, S, Se; R = Ar, ArAlk) under catalyst-
2
free conditions at 70−75 °C (both in the presence and
absence of the electron-deficient acetylenes) to give 9-
chalcogenophosphoryl-9,10-dihydroacridines in 61−94%
yields. This contrasts with pyridines, which under similar conditions undergo an SNHAr reaction, wherein electron-deficient
acetylenes play the role of oxidants. For acridine, the SNHAr step has been accomplished by the oxidation of the intermediate 9-
phosphoryl-9,10-dihydroacridines (X = O) with chloranil.
unctionalized acridines have a great diversity of
Scheme 1
1
2
F
applications including pharmaceutics, catalysis, optoe-
3
4
lectronics, and the development of advanced materials.
However, comparatively few phosphorylated acridines are the
focus of researchers, partially, due to the lack of reliable
methods for their synthesis. Among these is nucleophilic
substitution of the fluorine atom in 4,5-difluoroacridine by
potassium secondary phosphine to produce the corresponding
bis-4,5-phosphinoacridine designed for metal complex cata-
5
lysts. Some other phosphorylated acridines were synthesized
by the reaction of 9-haloacridines with phosphorus-centered
6
nucleophiles as well as Arbuzov-type rearrangements of
7
trialkylphosphites with acridinium salts.
Attempting to make further contributions to the chemistry
of phosphorylated acridines, we have tried to transfer the
recently found cross-coupling of pyridines with secondary
8
H
phosphine chalcogenides, a novel type of SN Ar reaction
triggered and promoted by electron-deficient acetylenes as
oxidants, which are consequently reduced to alkenes (Scheme
1
). However, to our surprise, instead of the expected SNHAr
reaction, which could lead to the corresponding aromatic
phosphorylated derivatives, we have encountered a facile
addition of secondary phosphine chalcogenides 1a−h to the
9
9
provides slightly higher yields. The yields and reaction time
considerably depend on the substituent structure and nature of
chalcogen in phosphine chalcogenides; bulkier substituents,
lower yields, and longer reaction times are observed (Scheme
2, 2d,g), and the reaction efficiency (yields and time) decreases
in the order Se > S > O (Scheme 2, 2b,e,h). Since the acidity
of phosphine chalcogenides 1 decreases in the same order, it
implies that proton renders an accelerating effect on the
addition process. The results obtained provide evidence that
the straightforward stereoselective addition of secondary
phosphine chalcogenides to acridine opens up an easy
expedient access to a novel family of phosphorylated acridines.
,10-positions of acridine to give 9-chalcogenophosphoryl-
,10-dihydroacridines 2a−h, while acetylene, the supposed
oxidant, remained intact (Scheme 1).
The major results and inferences of this study are
summarized in the present letter. As follows from Scheme 2,
the phosphorylation of acridine with diverse secondary
phosphine chalcogenides proceeds as a facile catalyst-free
reaction to form adducts 2a−h in good to excellent yields
(
61−94%).
The reaction is implemented as a solvent-free version or in
MeCN solution (for solid reactants). In the former case, the
Received: September 25, 2018
process requires a shorter time (1−5 h instead of 2−8 h) and
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b03061
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
The target S HAr reaction has been eventually accomplished
Scheme 2. Addition of Secondary Phosphine Chalcogenides
to Acridine: Synthesis of 9-Chalcogenophosphoryl-9,10-
dihydroacridines
N
by oxidation of the corresponding dihydroacridines 2a−d
(which are actually intermediates in the expected SNHAr
reaction) with chloranil to furnish aromatized products, 9-
phosphorylacridines 4a−d in almost quantitative yields
a
(
Scheme 4).
Scheme 4. Oxidative Aromatization of 9-
Chalcogenophosphoryl-9,10-dihydroacridines with
a
Chloranil
a
Reagents and conditions: acridine (1.0 mmol), secondary phosphine
b
chalcogenide 1a−h (1.0 mmol), MeCN (3 mL), 70−75 °C. Without
solvent.
a
The scope of the addition step is extendable over dialkyl
phosphonates as exemplified by Scheme 3 (for experimental
details, see the Supporting Information).
Reagents and conditions: 9-chalcogenophosphoryl-9,10-dihydroacri-
dine 2a−d (1.0 mmol), chloranil (1.2 mmol), toluene (4 mL), 80−85
°
C.
Scheme 3. Addition of Dipropyl Phosphonate to Acridine
Only phosphoryl derivatives (X = O) appeared to be
tolerant of this reaction, while sulfur or selenium analogues (X
S, Se) gave, under the same conditions, mixtures of products
=
that were difficult to identify. In any case, completion of the
H
SN Ar reaction for phosphoryl chalcogenides (X = O) can be
considered a novel synthetically and fundamentally useful
result.
Similar to the reaction mechanism, the resistance of acridine
to a one-step SNHAr reaction in the presence of electron-
deficient acetylenes (stopping this reaction at the addition
stage) may be understood in terms of steric hindrance to the
approach of the acetylene molecule to the nitrogen atom of
two neighboring benzene rings. At the same time, a proton, as
a competitive electrophile, can easily attack the electron lone
pair of the acridine nitrogen. Therefore, the addition of
phosphine chalcogenides to acridines is likely initiated by
equilibrium formation of a salt-like intermediate in which the
positive charge on the nitrogen atom is partially translated to
the position 9 in the resonance structure (Scheme 5). The
chalcogenophosphoryl anion, generated by dissociation of this
intermediate, attacks cationic position 9, to form the final
adducts.
Unlike pyridines, which under similar conditions in the
presence of electron-deficient acetylenes undergo catalyst-free
cross-coupling with secondary phosphine chalcogenides, i.e., a
H
SN Ar reaction, wherein acetylene acts as an oxidant that is
8
reduced to the corresponding alkene, acridine is not oxidized
to its aromatic phosphorylated derivatives, even when heated
with benzoylphenylacetylene at 160 °C for 20 h. According to
1
the H NMR spectrum of the reaction mixture, elimination of
bis(2-phenylethyl)phosphine sulfide 1e from dihydroacridine
2
e took place under these conditions to restore acridine and to
form an adduct of phosphine sulfide 1e to benzoylphenyl-
acetylene. An attempt to aromatize dihydroacridines 2a−h by
oxidation with air oxygen (80 °C, toluene, 8 h) led to a
complex mixture of products, among which acridine was
The key role of the proton in this mechanism is evidenced
by the experiments (Scheme 2) showing that the reaction
efficiency (yields and the process duration) improves for more
1
detected ( H NMR).
B
DOI: 10.1021/acs.orglett.8b03061
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 5. Plausible Mechanism of Nucleophilic Addition
Scheme 7. Plausible Mechanism of 2a−d Oxidative
Aromatization
efficiency in both the presence and absence of electron-
deficient acetylene that essentially differs from the pyridine,
which in the presence of the above acetylene as the oxidant
acidic phosphine chalcogenides, as noted above. The carbon
analogue of acridine, anthracene, which is not able to be
protonated under the above conditions, did not add phosphine
sulfide 1e as checked experimentally. The importance of steric
requirements for the attack of secondary phosphine
chalcogenides at the position 9 that follows from the
mechanism proposed (Scheme 5) is also confirmed by the
experimental results. In fact, higher yields and a shorter
reaction time are observed for less voluminous diphenyl
phosphine chalcogenides and otherwise (Scheme 2).
H
under the same conditions affords SNHAr products in a one-pot
procedure. For acridine, the SN Ar reaction has been
accomplished (almost quantitatively) by oxidation of the
intermediate 9-phosphoryl-9,10-dihydroacridines with chlor-
anil instead of electron-deficient acetylenes which prove to be
weaker oxidants in this case. The reactions developed make
two new families of phosphorylated acridines easily accessible:
9
-chalcogenophosphoryl-9,10-dihydroacridines (intermediates
Remarkably, for presumably less sterically demanding and
more electrophilic acetylene carboxylates, the nucleophilic
attack of the acridine nitrogen at the triple bond to generate
carbanionic zwitterions is, in some cases, possible, as it was
mentioned in earlier publications, wherein the three-
component adducts with methanol or nitromethane were
H
of SN Ar reaction) and 9-phosphorylacridines (final products
of SNHAr reaction), which are new prospective ligands for the
design of metal complex catalysts, precursors of pharmaceut-
icals and building blocks for advanced materials.
9
10
ASSOCIATED CONTENT
Supporting Information
■
formed in 81% and 1−8% yields, respectively (Scheme 6).
*
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b03061.
Scheme 6. Three-Component Reaction between Acridine,
Acetylene Carboxylates, and Methanol or Nitromethane
Experimental procedures, characterization and NMR
spectral data (PDF)
AUTHOR INFORMATION
Corresponding Author
■
*
E-mail: boris_trofimov@irioch.irk.ru.
ORCID
Apparently, in these reactions, acetylenes become com-
petitive over protons due to the lower acidity of methanol or
Boris A. Trofimov: 0000-0002-0430-3215
Notes
11
nitromethane as compared to phosphine chalcogenides 1
1
2
(
pK 29.9 and 17.2 for MeOH and MeNO , respectively).
a
2
H
The authors declare no competing financial interest.
The completion of the SN Ar step (Scheme 4) likely occurs
as a single electron transfer (SET) from intermediate 9-
phosphoryl-9,10-dihydroacridines 2a−d to the oxidant (chlor-
anil) to give a radical ion pair, which is further transformed to
the final products 4a−d after the proton and hydrogen radical
transfers between the phosphoryl radical cation and chloranil
radical anion moieties (Scheme 7).
ACKNOWLEDGMENTS
This work was supported by the Russian Scientific Foundation
Grant No. 18-73-10080). The main results were obtained
using the equipment of the Baikal Analytical Center of
Collective using SB RAS.
■
(
In an agreement with the proposed mechanism, the most
facile oxidation is observed for dihydroacridine 2d, which has a
stronger electron-donating substituent (compared to other
REFERENCES
■
(
1) For example papers, see: (a) Ramesh, K. B.; Pasha, M. A. Bioorg.
Med. Chem. Lett. 2014, 24, 3907. (b) Schmidt, A.; Liu, M. Adv.
́
Heterocycl. Chem. 2015, 115, 287. (c) Perez, S. A.; de Haro, C.;
Vicente, C.; Donaire, A.; Zamora, A.; Zajac, J.; Kostrhunova, H.;
Brabec, V.; Bautista, D.; Ruiz, J. ACS Chem. Biol. 2017, 12, 1524.
d) Matsheku, A. C.; Chen, M. Y.-H.; Jordaan, S.; Prince, S.; Smith,
G. S.; Makhubela, B. C. E. Appl. Organomet. Chem. 2017, 31, e3852.
(e) Li, Z.; Liu, R.; Tan, Z.; He, L.; Lu, Z.; Gong, B. ACS Sensors 2017,
2, 501. (f) Bragagni, M.; Carta, F.; Osman, S. M.; AlOthman, Z.;
substituents), PhCH(Me)CH , at the phosphorus atom that
2
should facilitate the SET process.
In conclusion, acridine undergoes a facile catalyst-free
phosphorylation with secondary phosphine chalcogenides to
form 9-chalcogenophosphoryl-9,10-dihydroacridines in good
to excellent yields. This nucleophilic addition, which represents
(
H
the first step of the SN Ar reaction, proceeds with the same
C
DOI: 10.1021/acs.orglett.8b03061
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Supuran, C. T. J. J. Enzyme Inhib. Med. Chem. 2017, 32, 701.
(
g) Kusuzaki, K.; Matsubara, T.; Murata, H.; Logozzi, M.; Iessi, E.; Di
Raimo, R.; Carta, F.; Supuran, C. T.; Fais, S. J. J. Enzyme Inhib. Med.
Chem. 2017, 32, 908. (h) Aday, B.; Ulus, R.; Tanc, M.; Kaya, M.;
Supuran, C. T. Bioorg. Chem. 2018, 77, 101.
2) For example papers, see: (a) Gunanathan, C.; Milstein, D.
̧
(
Angew. Chem., Int. Ed. 2008, 47, 8661. (b) Srimani, D.; Diskin-Posner,
Y.; Ben-David, Y.; Milstein, D. Angew. Chem., Int. Ed. 2013, 52, 14131.
(
c) Gigant, N.; Backvall, J.-E. Org. Lett. 2014, 16, 4432. (d) Ye, X.;
̈
Plessow, P. N.; Brinks, M. K.; Schelwies, M.; Schaub, T.; Rominger,
F.; Paciello, R.; Limbach, M.; Hofmann, P. J. Am. Chem. Soc. 2014,
1
36, 5923. (e) Zhu, R.-Y.; He, J.; Wang, X.-C.; Yu, J.-Q. J. Am. Chem.
Soc. 2014, 136, 13194.
3) For example papers, see: (a) Zhang, Y.-X.; Zhang, L.; Cui, L.-S.;
Gao, C.-H.; Chen, H.; Li, Q.; Jiang, Z.-Q.; Liao, L.-S. Org. Lett. 2014,
6, 3748. (b) Chen, X.; Zhang, Y.; Chen, Y.; Zhang, J.; Chen, J.; Li,
(
1
M.; Cao, W.; Chen, J. Eur. J. Org. Chem. 2014, 2014, 4170. (c) Cui,
Y.; Liu, J. Tetrahedron Lett. 2017, 58, 1579. (d) Zhao, B.; Miao, Y.;
Wang, Z.; Wang, K.; Wang, H.; Hao, Y.; Xu, B.; Li, W. Nanophotonics
2
017, 6, 1133. (e) Wang, S.; Cheng, Z.; Song, X.; Yan, X.; Ye, K.; Liu,
Y.; Yang, G.; Wang, Y. ACS Appl. Mater. Interfaces 2017, 9, 9892.
4) For example papers, see: (a) Chowdhury, M. A. H.; Rahman, M.
(
S.; Islam, M. R.; Rajbangshi, S.; Ghosh, S.; Hogarth, G.; Tocher, D.
A.; Yang, L.; Richmond, M. G.; Kabir, S. E. J. Organomet. Chem. 2016,
8
05, 34. (b) Manoryk, P. A.; Lampeka, Ya. D.; Ermokhina, N. I.;
Tsymbal, L. V.; Telbiz, G. M.; Gurtovyi, R. I. Theor. Exp. Chem. 2017,
3, 349. (c) Zhang, M.; Wang, G.; Zhao, D.; Huang, C.; Cao, H.;
5
Chen, M. Chem. Sci. 2017, 8, 7807. (d) Cho, A.-N.; Chakravarthi, N.;
Kranthiraja, K.; Reddy, S. S.; Kim, H.-S.; Jin, S.-H.; Park, N.-G. J.
Mater. Chem. A 2017, 5, 7603. (e) Wang, M.; Fan, Q.; Jiang, X. Org.
Lett. 2018, 20, 216.
(
5) Hillebrand, S.; Bartkowska, B.; Bruckmann, J.; Kru
Haenel, M. W. Tetrahedron Lett. 1998, 39, 813.
6) (a) Issleib, K.; Brusehaber, L. Z. Z. Naturforsch., B: J. Chem. Sci.
̈
ger, C.;
(
1
̈
965, 20, 181. (b) Srinivas, V.; Swamy, K. C. K. ARKIVOC 2009, xii,
3
1. (c) Zhang, H.-Y.; Sun, M.; Ma, Y.-N.; Tian, Q.-P.; Yang, S.-D. Org.
Biomol. Chem. 2012, 10, 9627.
7) (a) Ishikawa, K.; Akiba, K.; Inamoto, N. Bull. Chem. Soc. Jpn.
978, 51, 2684. (b) Motoyoshiya, J.; Ikeda, T.; Tsuboi, S.; Kusaura,
(
1
T.; Takeuchi, Y.; Hayashi, S.; Yoshioka, S.; Takaguchi, Y.; Aoyama, H.
J. Org. Chem. 2003, 68, 5950. (c) de Blieck, A.; Masschelein, K. G. R.;
Dhaene, F.; Rozycka-Sokolowska, E.; Marciniak, B.; Drabowicz, J.;
Stevens, C. V. Chem. Commun. 2010, 46, 258.
(8) Trofimov, B. A.; Volkov, P. A.; Khrapova, K. O.; Telezhkin, A.
A.; Ivanova, N. I.; Albanov, A. I.; Gusarova, N. K.; Chupakhin, O. N.
Chem. Commun. 2018, 54, 3371.
(
(
9) Acheson, R. M.; Burstall, M. L. J. Chem. Soc. 1954, 3240.
10) Acheson, R. M.; Woollard, J. J. Chem. Soc., Perkin Trans. 1
1
(
975, 438.
11) Semenzin, D.; Etemad-Moghadam, G.; Albouy, D.; Diallo, O.;
Koenig, M. J. Org. Chem. 1997, 62, 2414.
12) (a) Matthews, W. S.; Bares, J. E.; Bartmess, J. E.; Bordwell, F.
(
G.; Cornforth, F. J.; Drucker, G. E.; Margolin, Z.; McCallum, R. J.;
McCollum, G. J.; Vanier, N. R. J. Am. Chem. Soc. 1975, 97, 7006.
(
1
b) Olmstead, W. N.; Margolin, Z.; Bordwell, F. G. J. Org. Chem.
980, 45, 3295.
D
DOI: 10.1021/acs.orglett.8b03061
Org. Lett. XXXX, XXX, XXX−XXX