Facile synthetic entry into rotationally restricted 9-arylacridines

Article abstract of DOI:10.1515/hc-2013-0106

The treatment of 2-(trifluoromethyl)aniline with 2,6- dimethylphenylmagnesium bromide yields 1-methyl-9-(2,6-dimethylphenyl)acridine by the formal reaction of one equivalent of the aniline and two equivalents of the Grignard reagent. Interestingly, one of the methyl groups is eliminated during the reaction, and the product contains three methyl groups only. In a similar way, the reaction of 2-(trifluoromethyl)aniline with 2-ethylphenylmagnesium bromide furnishes 9-(2-ethylphenyl)acridine devoid of one ethyl group. The mechanism is discussed.

Full text of DOI:10.1515/hc-2013-0106

ꢁꢁꢁꢂ
DOI 10.1515/hc-2013-0106ꢀ
ꢀHeterocycl. Commun. 2013; 19(4): 245–247
Preliminary Communication
a
Jianguo Zhang*, Jarosław Sączewski , Ewa Wolińska and Lucjan Strekowski*
Facile synthetic entry into rotationally restricted
9
-arylacridines
Abstract: The treatment of 2-(trifluoromethyl)aniline with continuation of the chemistry of the anionically activated
,6-dimethylphenylmagnesium bromide yields 1-methyl- trifluoromethyl group in 2-(trifluoromethyl)aniline (1,
-(2,6-dimethylphenyl)acridine by the formal reaction Scheme 1) that has previously resulted in the development
2
9
of one equivalent of the aniline and two equivalents of of numerous new methodologies for the synthesis of many
the Grignard reagent. Interestingly, one of the methyl classes of heterocyclic compounds [10–13]. Briefly, the tri-
groups is eliminated during the reaction, and the product fluoromethyl group is stable in the absence of an anionic
contains three methyl groups only. In a similar way, the center in the molecule but undergoes a facile elimination
reaction of 2-(trifluoromethyl)aniline with 2-ethylphenyl- of fluoride when the anionic center is introduced at the γ
magnesium bromide furnishes 9-(2-ethylphenyl)acridine position. Lithium reagents, for the most part, have been
devoid of one ethyl group. The mechanism is discussed.
used previously to activate the trifluoromethyl group.
Treatment of substrate 1 with aryllithiums, generated
Keywords: acridines; Grignard reagents; 2-(trifluorome- at -70°C by the reaction of 1-bromo-2,6-dimethylbenzene
thyl)aniline.
or 1-bromo-2-ethylbenzene with n-butyllithium, gave a
complicated mixture of products, none of them major. The
outcome was similar for reactions conducted in ether or
tetrahydrofuran (THF), at low temperature or under reflux
conditions. These results can be explained in terms of
secondary lithiation reactions resulting in generation of
benzyllithium reagents, in addition to the expected phe-
nyllithium derivatives.
aPresent address: Department of Organic Chemistry, Medical
University of Gdańsk, Al. Gen. J. Hallera 107, 80-416 Gdańsk,
Poland.
*
Corresponding authors: Jianguo Zhang, Department of
Biochemistry and Molecular Biology, The University of Texas
Medical Branch, 301 University Blvd., Galveston, TX 77555-
0
635, USA, e-mail: jiazhang@utmb.edu; and Lucjan Strekowski,
Department of Chemistry, Georgia State University, Atlanta, GA
0302-4098, USA, e-mail: lucjan@gsu.edu
Different types of products, depending on tempera-
ture, were obtained by treatment of 1 with Grignard rea-
gents generated from the two bromobenzenes mentioned
above. At low temperature in the range of -70°C to 23°C,
each reaction produced an acyclic trimeric product
derived from three units of 1 and another acyclic trim-
eric product containing two fragments derived from 1
and a fragment of the aryllithium reagent (not shown).
By contrast, conducting the reaction in THF under reflux
conditions resulted in formation of a single major product
in each case (Schemes 1 and 2). Products 8 and 10 were
3
Jarosław Sączewski: Department of Chemical Technology of Drugs,
Medical University of Gdańsk, 80-416 Gdańsk, Poland
Ewa Wolińska: Department of Chemistry, Siedlce University, 08-110
Siedlce, Poland
Introduction
Biaryl, biheteroaryl and aryl-substituted heterocyclic obtained in the respective yields of 35% and 66% follow-
2
2
2
3
compounds with the central sp -sp or sp -sp bond can ing purification, and their structures are fully consistent
1
13
be severely restricted in rotational freedom when substi- with the analytical data including H NMR, C NMR and
tuted in the vicinity of the central bond joining the two high resolution mass spectra (HRMS). The oily compound
subsystems of the molecule [1]. There is no general syn- 8 was additionally transformed into a solid hydrobromide
thetic approach to the synthesis of such compounds, as salt that was characterized by elemental analysis. It is
exemplified by some selected recent reports [2–9]. In this important to note that compounds 8 and 10 are devoid of
communication, we describe a new method to synthesize an alkyl group of the aryl Grignard reagent. The mecha-
9
-arylacridines with a severe steric hindrance between the nism, that takes this feature into account, is suggested in
acridine system and the aryl substituent. This work is a Scheme 1. In full agreement with the previously published
Brought to you by | University of Queensland - UQ Library
Authenticated | 130.102.42.98
Download Date | 9/29/13 2:58 PM

2
46ꢀꢁꢁꢁꢂꢀJ. Zhang et al.: Facile synthetic entry into rotationally restricted 9-arylacridines
F
F
CF3
CF2
ArMgBr
-MgBrF
F
NH
NH2
NH
MgBr
3
1
2
Ar
Ar
Ar Me
F
F
ArMgBr
-MgBrF
ArMgBr
MgBrF
F
-
NH
NH
MgBr
N
H
Me
4
5
6
MeMe
MeMe
Me
Me
ArMgBr
-MeMgBr
N
N
Me
MgBr
7
8
Me
Me
Ar =
Scheme 1ꢀ
reactivity of substrate 1 in the presence of lithium rea- specifically, the different outcomes of the reactions of
gents, the first step involves ionization of 1 to generate a 1 conducted at 23°C and under reflux conditions can be
magnesium derivative 2. Elimination of MgBrF generates explained in terms of an increased nucleophilicity of the
the aza-ortho-xylene 3 that is recognized as the major Grignard reagents at the elevated temperature. The pre-
intermediate in the anionically activated chemistry of 1. A ferred addition of 2 with aza-ortho-xylene 3 and analogs
subsequent nucleophilic addition of the Grignard reagent takes place at low temperature to produce the acyclic
with 3 is suggested to reinstate aromaticity by formation of products mentioned above. This is due to high concen-
4
. A similar sequence of reactions through the intermedi- tration of 2 and the presence of Grignard reagent in an
ary of 5 leads to the key diaryl-substituted non-aromatic aggregated form. By contrast, the more nucleophilic mon-
intermediate 6 the electrocyclization of which or its mag- omeric Grignard molecules successfully compete with 2 in
nesium derivative results in the formation of an aromatic the addition reaction with 3 at elevated temperature.
ring. Compound 7 is the suggested direct precursor to the
It should be noted that the two compounds described
final product 8 by the formal elimination of methylmag- in this preliminary report are examples taken from a large
nesium bromide. It is important to stress ‘the formal elimi- library of compounds synthesized by using the general
nation’ because this transformation may involve a more procedure. A full account on this chemistry will be pub-
complicated pattern that is consistent with the simple lished in due course.
elimination of MeMgBr. In a similar way, the intermedi-
ate product 9 is the suggested precursor to product 10
(
Scheme 2).
MgBr
Grignard reagents are mostly aggregated in solution,
Et
Et
Et
Et
and the aggregation diminishes their reactivity [14]. An
increased concentration of the more nucleophilic mono-
meric molecules can be achieved by increasing tempera-
ture. This feature is fully consistent with the suggested
intermediary of 6 at an elevated temperature in compari-
-EtMgBr
1
N
MgBr
N
9
10
son to the reaction conducted at low temperature. More Scheme 2ꢀ
Brought to you by | University of Queensland - UQ Library
Authenticated | 130.102.42.98
Download Date | 9/29/13 2:58 PM

J. Zhang et al.: Facile synthetic entry into rotationally restricted 9-arylacridinesꢀꢂꢁꢁꢁꢀ247
with a silica gel-coated rotor, eluting with hexanes/ether (10:1), af-
forded 8 or 10. The hydrobromide salt of 8 was made by treatment
of a solution of 8 (100 mg, 0.33 mmol) in ether (5 mL) with a mixture
of hydrobromic acid (48%, 1 mL) and ether (10 mL). The resultant
precipitate was crystallized from ether/hexanes (2:1).
Experimental
General
THF was distilled from sodium benzophenone ketyl immediately
before use, and all reactions were conducted under an atmosphere
of nitrogen. Flasks were fitted with rubber septa and Teflon-coated
magnetic stirring bars were used. Crude reaction mixtures were
analyzed and mass spectra of pure components were obtained on
1
-Methyl-9-(2,6-dimethylphenyl)acridine (8)ꢀAn oil; yield 35%;
+
+
+
GC-MS: m/z 267 (M -2Me, 30), 282 M -Me, 50), 297 (M , 100); HRMS
for C H N: calcd m/z 297.1596, found m/z 297.1605.
22 19
1
a Shimadzu GC instrument coupled with an electron impact mass 8‧HBrꢀYield 90%; mp 277–278°C; H NMR: δ 1.75 (s, 6H), 2.04 (s, 3H),
1
7.27 (d, J ꢀ= ꢀ 8 Hz, 2H), 7.48 (m, 3H), 7.62 (t, J ꢀ= ꢀ 8 Hz, 1H), 7.98 (t, J ꢀ= ꢀ 8
Hz, 1H), 8.08 (t, J ꢀ= ꢀ 8 Hz, 1H), 9.19 (d, J ꢀ= ꢀ 8 Hz, 1H), 9.26 (d, J ꢀ= ꢀ 8 Hz,
spectrometer operating at 70 eV. The H NMR spectra (300 MHz) and
1
3
C NMR spectra (75 MHz) were taken at 23°C in CDCl solution. HRMS
3
1
3
were taken on a VG Analytical 70-SE spectrometer.
1H); C NMR: δ 15.3, 20.2, 120.5, 120.9, 24.6, 125.5, 126.5, 128.2, 128.5,
30.1, 131.2, 135.3, 136.0, 136.3, 136.4, 137.9, 138.9, 141.3. Anal. Calcd for
C H N‧HBr: C, 69.85; H, 5.33; N, 3.70. Found: C, 70.23; H, 5.30; N, 3.75.
1
2
2
19
Synthesis of acridines 8 and 10
1
9
-(2-Ethylphenyl)acridine (10)ꢀAn oil; yield 66%; H NMR: δ 0.84
(
t, J ꢀ= ꢀ 8 Hz, 3H), 2.16 (q, J ꢀ= ꢀ 8 Hz, 2H), 7.18 (d, J ꢀ= ꢀ 7 Hz, 1H), 7.39 (m,
A solution of 2,6-dimethylphenylmagnesium bromide or 2-ethylphe-
nylmagnesium bromide (8.0 mmol) in THF (8 mL) was stirred at -70°C
and treated dropwise with a solution of 2-(trifluoromethyl)aniline (2,
1
3
3
1
H), 7.52 (m, 1H), 7.76 (t, J ꢀ= ꢀ 9 Hz, 2H), 8.28 (d, J ꢀ= ꢀ 9 Hz, 2H); C NMR: δ
5.0, 26.3, 125.5, 125.7, 125.8, 126.8, 128.5, 129.4, 130.2, 130.3, 143.0; GC-
+
+
MS: m/z 282 (M -Me, 50), 297 (M , 100); HRMS for C H N: calcd m/z
2
1
17
4
00 mg, 2.4 mmol) in THF (6 mL). The brown mixture was heated un-
2
83.1361, found m/z 283.1350.
der reflux for 2 h, af er which time the GC-MS analysis showed the ab-
sence of 2. The mixture was quenched with water (5 mL) and concen-
trated on a rotary evaporator. The residue was extracted with ether
(
3 ꢀ× ꢀ 20 mL), dried and concentrated. Purification on a chromatotron Received July 5, 2013; accepted July 8, 2013
References
[
1] Eliel, E. L.; Wilen, S. A. Streochemistry of Organic Compounds;
John Wiley & Sons, Inc.: New York, 1994.
of bromination and nitration of bis-pyrazolo[3,4-b;4′,3′-e]
pyridines. Heterocycl. Commun. 2011, 17, 191–196.
[2] Ghasemnejad-Bosra, H.; Forouzani, M. A simple and efficient
[8] Wang, W.; Lu, L.; Wang, X.-S. An efficient method for the
synthesis of naphthoquinoline derivatives catalyzed by iodine.
Heterocycl. Commun. 2012, 18, 17–21.
one-pot bis-bromine-1,4-diazabicyclo[2.2.2]octane (Br -DABCO)
2
catalyzed synthesis of 14-aryl-14H-dibenzo[a,jꢀ]xanthenes under
solvent-free conditions. Heterocycl. Commun. 2011, 17, 83–85.
3] Damavandi, S.; Sandaroos, R. Solvent-free one pot synthesis
of indenoquinolinones catalyzed by iron(III) triflate. Heterocycl.
Commun. 2011, 17, 121–124.
[9] Reddy, N. B.; Uma, K.; Rao, M.; Sundar, C. S.; Nayak, S. K.;
[
[
[
Reddy, C. S. An efficient KHSO catalyzed synthesis of
4
xanthenes. Heterocycl. Commun. 2012, 18, 53–56.
[10] Strekowski, L.; Kiselyov, A. S. Fluorine chemistry in heterocyclic
synthesis. Trends Heterocycl. Chem. 1993, 3, 73–89.
4] Motamedi, R. Synthesis of novel chromeno[4′,3′-b]
pyrano[6,5-b]quinolone derivatives. Heterocycl. Commun. 2011,
[11] Kiselyov, A. S.; Strekowski, L. The trifluoromethyl group in
organic synthesis. Org. Prep. Proc. Int. 1966, 28, 289–318.
[12] Strekowski, L.; Zhang, J.; Paliakov, E.; Say, M. Chemistry of the
anionically activated perfluoroalkyl group in organic synthesis.
Recent Res. Dev. Org. Chem. 2004, 8, 1–11.
[13] Strekowski, L; Wolinska, E.; Mojzych, M. DNA triple helix
stabilizing agents. In Synthetic and Biophysical Studies of DNA
Binding Compounds. Strekowski, L., Ed. Transworld Research
Network: Kerala, 2007; pp. 263–278.
1
7, 169–172.
5] Quan, Z.-J.; Wei, Y.; Wang, X.-C. Synthesis of novel
thiazolo[2,3-b]quinazolines by cyclization reaction of octahy-
droquinazoline-2-thiones with α-bromoketones. Heterocycl.
Commun. 2011, 17, 181–185.
[
[
6] Damavandi, S.; Sandaroos, R. Novel multicomponent synthesis
of pyrido[2,3-b]indoles. Heterocycl. Commun. 2011, 17,
1
87–189.
7] Marcinkowska, M.; Rasala, D.; Puchala, A.; Galuszka, A.
A comparison of green chemistry metrics for two methods
[14] Richey, H. G., Jr., Ed. Grignard Reagents, New Developments;
John Wiley & Sons, Ltd.: Chichester, 2000.
Brought to you by | University of Queensland - UQ Library
Authenticated | 130.102.42.98
Download Date | 9/29/13 2:58 PM