Ullmann reactions of 1-amino-4-bromoanthraquinones bearing various 2-substituents furnishing novel dyes

Article abstract of DOI:10.1016/j.dyepig.2016.03.023

Novel 1-amino-4-(ar)alkylaminoanthraquinone derivatives bearing different substituents (Br, CH₂OH, CN, or CH₃) at the 2-position of the anthraquinone scaffold were synthesized by copper-catalyzed Ullmann condensation. The 2-substituted 1-amino-4-bromoanthraquinone derivatives (bromaminic acid analogues) were reacted with a variety of alkyl-, aryl-, and aralkylamines. Different reaction conditions were applied depending on the physical state of the amine and the nature of the substituent at the 2-position of the anthraquinone scaffold. A solvent-free synthetic procedure was developed for reactions with liquid amines. Condensation with solid amines required the addition of a solvent, and reaction conditions had to be optimized for each of the anthraquinone derivatives. Our results emphasize that copper-catalyzed reactions are highly variable depending on the molecules and anions present in the medium, since different reaction mechanisms apply. The synthesized anthraquinone derivatives may be useful as new dyes, or may show biological activity and could be employed as tool compounds in experimental pharmacology.

Full text of DOI:10.1016/j.dyepig.2016.03.023

Accepted Manuscript
Ullmann reactions of 1-amino-4-bromoanthraquinones bearing various 2-substituents
furnishing novel dyes
Enas M. Malik, Mahmoud Rashed, Lukas Wingen, Younis Baqi, Christa E. Müller
PII:
S0143-7208(16)30082-1
10.1016/j.dyepig.2016.03.023
DYPI 5148
DOI:
Reference:
To appear in: Dyes and Pigments
Received Date: 17 January 2016
Accepted Date: 13 March 2016
Please cite this article as: Malik EM, Rashed M, Wingen L, Baqi Y, Müller CE, Ullmann reactions of 1-
amino-4-bromoanthraquinones bearing various 2-substituents furnishing novel dyes, Dyes and Pigments
(2016), doi: 10.1016/j.dyepig.2016.03.023.
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ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
Ullmann reactions of 1-amino-4-bromoanthraquinones bearing various
2-substituents furnishing novel dyes
Enas M. Malika, Mahmoud Rasheda,1, Lukas Wingena,1, Younis Baqib, and Christa E.
Müller*a
Address: aPharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I,
Pharmaceutical Sciences Bonn (PSB), University of Bonn, An der Immenburg 4, D-53121
Bonn, Germany and bDepartment of Chemistry, Faculty of Science, Sultan Qaboos
University, PO Box 36, Postal Code 123, Muscat, Oman.
* Corresponding author
Email: Christa E. Müller - christa.mueller@uni-bonn.de
1These authors contributed equally
1

ACCEPTED MANUSCRIPT
Highlights
• Synthesis of novel 1-amino-4-(ar)alkylaminoanthraquinone derivatives with variable
substituents (Br, CH2OH, CN, or CH3) in the 2-position of the anthraquinone core was
achieved by Ullmann condensation of bromaminic acid analogues with a variety of amines.
• Optimization of the conditions for the different reactions has been conducted.
• Comparison of the different bromaminic acid analogues in terms of chemical reactivity and
reaction conditions is presented.
• The synthesized anthraquinone derivatives may be useful as new dyes or represent
bioactive compounds for experimental pharmacology.
2

ACCEPTED MANUSCRIPT
Abstract
Novel 1-amino-4-(ar)alkylaminoanthraquinone derivatives bearing different substituents (Br,
CH2OH, CN, or CH3) at the 2-position of the anthraquinone scaffold were synthesized by
copper-catalyzed Ullmann condensation. The 2-substituted 1-amino-4-bromoanthraquinone
derivatives (bromaminic acid analogues) were reacted with a variety of alkyl-, aryl-, and
aralkylamines. Different reaction conditions were applied depending on the physical state of
the amine and the nature of the substituent at the 2-position of the anthraquinone scaffold. A
solvent-free synthetic procedure was developed for reactions with liquid amines.
Condensation with solid amines required the addition of a solvent, and reaction conditions
had to be optimized for each of the anthraquinone derivatives. Our results emphasize that
copper-catalyzed reactions are highly variable depending on the molecules and anions present
in the medium, since different reaction mechanisms apply. The synthesized anthraquinone
derivatives may be useful as new dyes, or may show biological activity and could be
employed as tool compounds in experimental pharmacology.
3

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Keywords
Anthraquinones; Bromaminic acid; Dyes; Reactive Blue 2; Synthesis; Ullmann condensation
reaction.
1. Introduction
Anthraquinones (AQs) constitute a large and diverse class of compounds. Besides their
extensive use since decades for the dyeing of natural and synthetic textiles [1,2], AQs are of
importance for various other applications. They are used in imaging devices, and some AQs
are approved for use as colorants in cosmetics, and foods [3–10]. A number of natural and
synthetic AQs have shown a wide range of pharmacological activities including antitumor
[11,12], antiviral [13], antifungal [14], anti-inflammatory [15], laxative [16,17], antiplatelet
[18–20], and neuroprotective effects [21]. Several AQ drugs are on the market; moreover
AQs represent important pharmacological and biochemical tool compounds (Malik E., Müller
CE, submitted).
Starting from the sodium salt of bromaminic acid (1, BAA), our laboratory has previously
synthesized AQ derivatives related to the chlorotriazinyl dye Reactive Blue 2 (2, RB-2), and
its partial structure Acid Blue 25 (3, AB-25) (Figure 1), as potent and selective antagonists of
purine receptors and inhibitors of the ectonucleotidase enzymes [20,22–29]. The synthesized
derivatives represent important pharmacological tools and potential therapeutics.
4

ACCEPTED MANUSCRIPT
Figure 1. Anthraquinone derivatives: Bromaminic acid sodium salt (1), Reactive Blue 2 (2),
and Acid Blue 25 (3)
Access to the target compounds was achieved through copper(0)-catalyzed Ullmann
condensation of BAA (1) with different amines in phosphate buffer solution under microwave
(MW) irradiation (Scheme 1) [22,23]. The compounds typically possess a sulfonate group at
the 2-position of the AQ scaffold, and an (ar)alkylamino residue at the 4-position. The nature
of the 4-substituent was found to be crucial for potency and selectivity for the different
protein targets [20,23–28]. Recently we have become interested in investigating the influence
of the substituent at the 2-position of the AQ scaffold on their biological activities. For this
purpose, we developed a synthetic access to BAA analogues bearing different substituents at
the 2-position as precursors for our target compounds [30].
5

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Scheme 1. General scheme for MW-assisted copper(0)-catalyzed Ullmann amination reaction
of bromaminic acid sodium salt (1).
Here we report on the synthesis of novel 1-amino-4-(ar)alkylamino-AQ derivatives, featuring
Br, CH2OH, CN, or CH3 substitution in the 2-position of the AQ core. The study presents a
comparison of the different BAA analogues in terms of chemical reactivity toward different
amines, and optimization of the conditions required for successful reaction. The synthesized
AQ compounds may be of value for pharmacological applications as well as in textile dye
industry. Indeed, a few of the targeted 2-cyano- and 2-hydroxymethyl-AQ derivatives had
been previously mentioned in patents for use as dyes for polyester fibers with advantageous
dyeing properties, however no synthetic procedures have been provided [31–33].
2. Results and discussion
To obtain the target 2-substituted 1-amino-4-(ar)alkylamino-AQ derivatives, the following 1-
amino-4-bromo-AQ derivatives (BAA analogues) were employed: 1-amino-2,4-dibromo-AQ
(4), 1-amino-4-bromo-2-hydroxymethyl-AQ (5), 1-amino-4-bromo-2-cyano-AQ (6), and 1-
amino-4-bromo-2-methyl-AQ (7) (Scheme 2). Synthesis was achieved by Ullmann
condensation with different amines. The employed amines were either liquid or solid. For
each class of amines, development and optimization of a specific synthetic procedure was
required.
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Scheme 2. General scheme for Ullmann amination reaction of 2-substituted 1-amino-4-
bromoanthraquinone derivatives 4-7.
2.1. Condensation with liquid amines
Starting with the 2-bromo-AQ derivative 4, we first tried the solvent-free method described
by Ukponmwan et al. for condensation with aniline [34]. The reaction was carried out at 140
°C using 25 equivalent (equiv.) of aniline in the presence of potassium acetate and copper(II)
carbonate (27 mol %). It was complete within 1 h, affording 1-amino-2-bromo-4-
phenylaminoanthraquinone (8) in high yield (85 %) (Scheme 2, Table 1). The large excess of
aniline in this reaction served as both, reagent and solvent.
Table 1. Reaction times, HRMS, UV absorption, melting points, yields, and purity of the
synthesized anthraquinone derivatives obtained from liquid aminesa
HRMS (g/mol)b
Cmpd R
R'
Reaction
m.p.
Yield Purity
λmax
7

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c
m/z: [M + H]+
(nm)
(oC)
%
(%)d
duration
(h:min)
Calcd
Found
Br
Br
H
05:00
78:30
393.0239 393.0216 580, 612 232–234 84
426.9849 426.9841 574, 602 241-243 63
411.0144 411.0116 576, 606 254–257 93
99
8
2-Cl
100
11
Br
3-F
H
35:00
00:30
96
97
96
97
98
96
97
98
97
98
95
98
99
99
100
95
98
96
98
96
96
97
95
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
CH2OH
CH2OH
CH2OH
CH2OH
CH2OH
CH2OH
CH2OH
CH2OH
CH2OH
CN
345.1234 345.1239 574, 610 219-222
359.1390 359.1386 574, 610 253-254
373.1547 373.1546 578, 608 211-214
373.1547 373.1543 576, 610 224-225
373.1547 373.1553 574, 608 133-135
379.0844 379.0845 570, 606 269-272
379.0844 379.0848 572, 604 249-250
375.1339 375.1316 574, 610 237-240
363.1139 363.1142 572, 606 248-249
88
38
84
78
36
25
50
29
50
45
76
52
55
38
55
57
76
82
74
58
66
21
3-CH3 00:25
3-C2H5 00:25
4-C2H5 00:15
2-C2H5 28:00
3-Cl
2-Cl
01:00
15:00
3-OCH3 01:00
3-F
H
05:00
00:30
340.1086 340.1076 630
354.1237 354.1240 630
368.1399 368.1397 630
368.1399 368.1396 630
368.1399 368.1390 630
374.0691 374.0684 630
374.0691 374.0677 630
329.1290 329.1264 608
357.1603 357.1582 606
357.1603 357.1573 608
357.1603 357.1583 608
363.0900 363.0832 606
363.0900 363.0860 606
227-230
250-251
248-250
216-218
219-222
283-284
258-260
251-253
229-230
230-232
187-188
280-281
230-231
CN
3-CH3 00:10
3-C2H5 00:20
4-C2H5 00:30
2-C2H5 08:30
CN
CN
CN
CN
3-Cl
2-Cl
H
17:00
32:00
01:50
CN
CH3
CH3
3-C2H5 01:50
4-C2H5 00:30
2-C2H5 13:00
CH3
CH3
CH3
3-Cl
2-Cl
18:00
77:00
CH3
8

ACCEPTED MANUSCRIPT
CH3
CH3
3-OCH3 02:40
359.1396 359.1385 570, 608 233–235 70
97
98
95
96
97
96
99
100
97
35
36
37
38
39
40
41
42
43
3-F 15:00
347.1196 347.1183 568, 606 275–277 73
see structure above 00:15
see structure above 00:30
see structure above 01:50
see structure above 02:30
see structure above 00:20
see structure above 00:15
see structure above 01:15
390.1237 390.1235 630
354.1237 354.1215 610, 642 217-218
343.1447 343.1431 610 223-225
270-273
17
8
51
67
50
15
70
439.0457 439.0451 580, 622 186-188
391.1452 391.1455 572, 614 192-193
386.1299 386.1295 610, 640 224-225
375.1509 375.1494 610
219-220
aReaction conditions: AQ, amine (15 equiv.), potassium acetate (2.25 equiv.), copper(I) acetate
(10 mol%), 110 °C, argon. bHRMS recorded on a micrOTOF-Q mass spectrometer (Bruker)
coupled with an HPLC instrument. cIsolated yield. dPurity determined by LC-MS coupled to a
diode array UV detector (220-900 nm).
Next we tried the synthesis of 1-amino-2-bromo-4-phenylaminoanthraquinone (8) based on
the method described by Harris et al. [35], which was previously applied by our group,
however for the condensation of the 2-methyl-substituted AQ analogue (7) with aniline [28].
When compared to the previous method, it requires milder conditions and less of the reagents.
Following this method, the reaction of 2-bromo-AQ 4 was conducted under an argon
atmosphere at 110 °C using 15 equiv. of aniline in the presence of potassium acetate, and
copper(I) acetate (10 mol %), affording product 8 in 84 % yield.
We subsequently tried to optimize the originally published reaction of 2-methyl-AQ 7 with
respect to the concentration of aniline. Accordingly, condensation of the 2-methyl-AQ 7 was
performed using 3, 6, or 10 equiv. of aniline. However, with lower amounts, additional side-
products were formed. Based on liquid chromatography-mass spectroscopy (LC-MS)
9

ACCEPTED MANUSCRIPT
analysis, the AQ dimers (9) and (10) were identified as new side-products (Figure 2).
Therefore, an excess of 15 equiv. of the amine was selected for subsequent condensation
reactions, to avoid reaction of the 1-amino group of the anthraquinone derivative 7, which
was relatively nucleophilic due to the electron-donating effect of the 2-methyl group.
Figure 2. Proposed structures of side-products (anthraquinone dimers) formed at low
concentrations of aniline upon condensation reactions with 1-amino-4-bromo-2-
methylanthraquinone (7).
The solvent-free method under the previously mentioned conditions was subsequently applied
for condensation of AQs 4-7 with different liquid amines (Table 1). Reactions proceeded
smoothly although with variable rates and yields.
After the successful synthesis of 1-amino-2-bromo-4-phenylaminoanthraquinone (8) from 1-
amino-2,4-dibromoanthraquinone (4), the procedure was applied to the condensation of 4
with ortho-chloro- and meta-fluoro-substituted aniline derivatives (11 and 12, respectively,
Table 1). Although the products were obtained in high yields (63 % and 93 %, respectively),
reactions proceeded at a slower rate than in the case of non-substituted aniline, requiring 78
h(11) and 35 h (12) to complete, compared to only 5 h for the synthesis of 8. This is likely due
10

ACCEPTED MANUSCRIPT
to the electron-withdrawing effect of the halogen atoms, which deactivates the aromatic ring
and reduces the nucleophilicity of the amine.
For AQ derivatives 5 and 6, bearing a hydroxymethyl or a cyano group at the 2-position,
condensation with aniline was complete within 30 min producing compounds 13 and 22,
respectively (Table 1). Reactions were also fast (10 – 30 min) for methyl- or ethyl-substituted
aniline derivatives (14, 15, 16, 23, 24, 25) with one exception: ortho-ethyl substitution
imposed a negative effect on the rate of the reactions, which were only complete after 28 h
(17), or 8 h (26) for 2-hydroxymethyl-AQ 5, and 2-cyano-AQ 6, respectively (Table 1). This
negative effect can be explained by steric hindrance due to the ortho-ethyl substituent. It is
generally accepted that formation of a copper complex with the nucleophile (e.g. amine)
precedes the activation of the aryl halide (here: the 4-bromo-AQ derivatives) in Ullmann
condensation reactions [36]. In this context, it is highly probable that upon coordination of o-
ethylaniline to the copper catalyst, the presence of the ethyl chain in vicinity to the amino
group would occupy a space near the copper coordination sphere thereby hindering the
subsequent coordination of the 4-bromo-AQ derivative.
In case of a meta-chloro substituted aniline, the reaction with the 2-hydroxymethyl-AQ
derivative 5 was somewhat slower as compared to the non-substituted aniline, producing
product 18 within 60 min. However, the presence of an ortho-chloro substituent slowed down
the reaction much more, and it required 15 h to completion (19). This is likely due to the
electronegativity of the chlorine atom as well as the steric hindrance imposed by the size of
the chlorine atom. The effect of a chloro substituent at the aniline on the rate of its reaction
with 2-cyano-AQ 6 was even more pronounced. It required 17 h to complete the reaction in
case of the meta-chloroaniline product 27, and the time doubled to 32 h when the chlorine
atom was at the ortho-position (product 28) (Table 1).
11

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A meta-methoxy residue on the aniline had a similar effect as a meta-chloro substitution in
the reaction with 2-hydroxymethyl-AQ 5, affording product 20 within 60 min, whereas the
presence of the smaller but more electronegative fluorine atom at the same position delayed
the reaction producing product 21 within 5 hours (Table 1).
1-Naphthylamine and benzylamine reacted as fast as aniline (15-20 min) with 2-cyano-AQ 6,
yielding products 37 and 38, respectively. Reactions of 3-fluorophenethylamine with 2-
hydroxymethyl-AQ 5 and 2-cyano-AQ 6 proceeded equally fast, and products 41 and 42 were
obtained within 20 min and 15 min, respectively.
A similar pattern of reactivity of the previously discussed amines could be observed within
the 2-methyl-AQ series of compounds (products 29-36, 39, and 43, Table 1), although
reactions generally proceeded at a somewhat slower rate.
The applied synthetic procedure afforded the desired products (8-43) in acceptable to
excellent yields (36-93 %), with the exception of the following derivatives: 1-amino-4-(3-
chlorophenylamino)-2-hydroxymethylanthraquinone (18), 1-amino-2-hydroxymethyl-4-(3-
methoxyphenyl)aminoanthraquinone (20), 1-amino-4-(2-chlorophenylamino)-2-
methylanthraquinone (34), 1-amino-2-cyano-4-(naphth-1-ylamino)anthraquinone (37), 1-
amino-4-benzylamino-2-cyanoanthraquinone (38), and 1-amino-2-cyano-4-(2-(3-
fluorophenyl)ethylamino)anthraquinone (42) which were only obtained in low yields (below
30 %). A major side-reaction, which was particularly prominent in the case of the 2-cyano-
AQ derivatives, was reductive debromination of the starting material. The desired products
were, in some cases, difficult to isolate from the debromo-AQ side-products (44-47, Scheme
3) requiring multiple purification runs by column chromatography and therefore resulted in
reduced isolated yields.
12

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Scheme 3. Production of debromo-AQ derivatives 44-47 as side-products of the Ullmann
amination reaction of 4-bromo-AQ derivatives 4-7.
2.2. Condensation with solid amines
Although the solvent-free method was successfully applied to obtain the target compounds
described above, it was limited to liquid amines and to solid amines with low melting point
(e.g. 1-naphthylamine). Condensation with solid amines with a high melting point
necessitated the use of a solvent as a reaction medium, and optimization of the reaction
conditions had to be performed for each of the 2-substituted BAA analogues.
Optimization of the reaction conditions for 1-amino-2,4-dibromoanthraquinone (4) and 1-
amino-4-bromo-2-cyanoanthraquinone (6)
Initially we tried to reproduce the reaction of 2-bromo-AQ 4 with aniline using ethanol as a
solvent as was described in a patent [37]. The reaction was conducted in a pressure tube at 95
°C in the presence of copper(II) acetate and potassium acetate. However, the method did not
work in our hands. Most of the starting material 4 remained unchanged even after addition of
excess amounts of aniline and catalyst, and after an extended reaction time of 48 h. The same
reaction was subsequently tried under MW irradiation, but again with no success. Systematic
13

ACCEPTED MANUSCRIPT
trials were consequently performed with the goal to optimize the reaction conditions using
MW heating. Different solvents including non-polar (toluene, diglyme), slightly polar
(dichloromethane, 1,4-dioxane, and tetrahydrofuran (THF)), polar aprotic (e.g. acetonitrile,
N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), and N-methyl-2-pyrrolidone
(NMP)) and polar protic (water, ethanol, 2-ethoxyethanol, isopropanol, t-butanol and 1-
pentanol) ones were tried (Figure 3).
40
35
30
25
20
15
10
5
0
Figure 3. Effect of solvent on the yield of 1-amino-2-bromo-4-phenylamino-anthraquinone
(8) obtained in the reaction from 1-amino-2,4-dibromoanthraquinone (4) and aniline. Reaction
conditions: 2-bromo-AQ 4 (0.25 mmol), aniline (0.75 mmol), KOAc (0.35 -1.25 mmol),
Cu(OAc)2 (5 mol%), 5 mL solvent, MW, 95°C. In some cases where no reaction took place,
the temperature was increased during the course of the reaction up to 200 °C. DMF: N,N-
dimethylformamide; DMSO: dimethylsulfoxide; NMP: N-methyl-2-pyrrolidone; THF:
tetrahydrofuran.
14

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Besides acetonitrile and toluene, alcohols were found to be suitable solvents for the reactions,
although yields remained low (12-35 %). Among these solvents, 1-pentanol was superior
resulting in the highest conversion rate (87 %) of 2-bromo-AQ 4, and a yield of 35 % of the
desired product 8. The reaction also yielded the debromo-AQ 44, and 1-amino-2-bromo-4-
pentanoxyanthraquinone as side-products. We subsequently reacted 2-bromo-AQ 4 with the
solid 4-phenylamino-3-sulfoaniline in 1-pentanol in the presence of potassium acetate and
copper(II) acetate. The MW-heated reaction was complete within 5 min affording 40 % of the
desired product 48 (Table 2).
Table 2. Reaction times, HRMS, UV absorption, melting points, yields, and purity of the
synthesized anthraquinone derivatives obtained from solid aminesa
Cmpd R
R'
Reaction HRMS (g/mol)b
m.p.
Yield Purity
λmax
c
m/z: [M + H]+
(oC)
(%)d
%
time
(nm)
(min)
Calcd
Found
Br
3-SO3H-
4-NHC6H5
5
564.0229 564.0220 618
437.0137 437.0107 n.d.
>300
>300
39
98
48
Br
Br
Br
CN
2-CO2H 40
3-CO2H 45
4-CO2H 180
94
50
25
44
96
97
99
96
49
50
51
52
434.9980 434.9990d 580, 616 >300
437.0137 437.0156 584, 616 >300
3-SO3H- 15
4-NHC6H5
511.1071 511.1056 644
384.0984 384.0968 640
>300
>300
CN
2-CO2H 40
97
95
53
15

ACCEPTED MANUSCRIPT
CN
CN
CN
3-CO2H 20 + 60e 382.0828 382.0844d 630
>300
27
20
88
98
95
97
54
55
56
4-CO2H 30 + 60f
_
n.d.
630, 658 >300
2-CO2H- 10
4-F
402.0885 402.0883 638
>340
>300
371.1036g
n.d.
CH3
2-CO2H 60
371.1032
616
93
99
57
CH3
CH3
3-CO2H 55
4-CO2H 65
_
608
612
>300
>300
36
40
96
99
58
59
371.1033g
389.0943g
371.1032
CH3
CH3
2-CO2H- 70
4-F
389.0938
612
>300
>300
44
42
95
96
60
61
3-SO3H- 40
4-NHC6H5
500.1280 500.1266 608
CH2OH 2-CO2H 60
CH2OH 3-CO2H 80
CH2OH 4-CO2H 100
389.1132 389.1122 576, 610 >300
387.0986 387.0981g 572, 608 >300
387.0986 387.0981g 574, 608 >320
407.1038 407.1046 576, 610 198-199
98
20
24
81
99
98
97
96
62
63
64
65
CH2OH 2-CO2H- 145
4-F
CH2OH 3-SO3H-4- 35
NHC6H5
514.1078 514.1104f 606
>320
57
97
66
aReaction conditions: AQ, amine (3 equiv.), potassium acetate (5 equiv.), copper(II) acetate (5
mol%), 4 mL of 1-pentanol, methanol, or 2.5 % water/methanol, 95 °C, microwave 80 W.
bHRMS was recorded on a micrOTOF-Q mass spectrometer (Bruker) coupled with an HPLC
instrument. cIsolated yield. dPurity was determined by LC-MS coupled to a diode array UV
detector (220-900 nm), e95 °C for 20 min followed by 120 °C for 60 min, f95 °C for 30 min
followed by 120 °C for 60 min, gm/z: [M – H]–. n.d.: not determined.
We subsequently decided to perform the same reaction using a combination of copper(0) and
copper(II) acetate for catalysis, as described in a patent [38]. However, the addition of
copper(0) (5 min, 32 %) was not advantageous. The reaction was slower when tried in
isopropanol (30 min) affording product 48 in a moderate yield (34 %). When it was
16

ACCEPTED MANUSCRIPT
performed in phosphate buffer in the presence of copper(0), the conditions which had been
optimal for condensation of BAA with 4-phenylamino-3-sulfoaniline [22,23], the yield even
dropped to less than 5 % (Scheme 4). We therefore concluded that 1-pentanol as the solvent
and copper(II) acetate as the catalyst were crucial for the synthesis of compounds 49-51 from
2-bromo-AQ 4 and the corresponding solid amines (Table 2).
Scheme 4. Method optimization for solid aniline derivatives: synthesis of 1-amino-2-bromo-
4-(4-phenylamino-3-sulfophenylamino)anthraquinone (48) under different reaction conditions
using microwave irradiation.
The optimized procedure was subsequently used for the synthesis of products 52-56 (Table 2)
from 2-cyano-AQ 6.
Optimization of the reaction conditions for 1-amino-4-bromo-2-methylanthraquinone (7)
The optimized conditions (1-pentanol, potassium acetate, and copper(II) acetate) were not
successful for reactions of 2-methyl-AQ 7. For example, condensation of 7 with 2-
aminobenzoic acid afforded only 35 % of product 57 (entry 1, Table 3), compared to > 90 %
yield obtained with the corresponding 2-bromo- and the 2-cyano-AQ derivatives (products 49
and 53). Changing the solvent to isopropanol improved the yield to 64 %, but the conversion
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was still incomplete (entry 2, Table 3). Further improvement was observed with ethanol as a
solvent (80 % yield, entry 3, Table 3). Increasing the polarity of the medium by using a
mixture of water and ethanol was not favorable, and the yield decreased with increasing water
concentration, with only 27 % yield in 50 % aq. ethanol (entries 4-6, Table 3). However, an
excellent yield of 90 % was obtained in methanol (entry 7, Table 3), while the yield dropped
to 44 % in ethylene glycol (entry 8, Table 3).
Table 3. Optimization of the reaction of 1-amino-4-bromo-2-methylanthraquinone (7) with
anthranilic acid with regard to the solventa
Isolated Yield (%)
Entry Solvent
Reaction time
(min)
1-pentanol
60
35
64
80
76
71
27
90
43
1
2
3
4
5
6
7
8
isopropanol
130
95
ethanol
water /ethanol (12.5 % v/v)
water /ethanol (25 % v/v)
water /ethanol (50 % v/v)
methanol
130
130
130
110
130
ethylene glycol
aReaction conditions: 2-methyl-AQ 7 (0.1 mmol.), anthranilic acid (3 equiv.), potassium
acetate (5 equiv.), copper(II) acetate (5 mol%), 4 mL of solvent, 95 °C, microwave 80 W.
In the next step, methanol was kept as the solvent, and the effect of varying the catalyst was
studied (Table 4). Replacing copper(II) acetate by copper(II) acetate monohydrate decreased
the yield from 90 % to 40 % indicating that the presence of water in the crystal was
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detrimental for the reaction (entry 2, Table 4). Elemental copper was also not favorable, and
the yield dropped further with increasing the amount of copper(0) (entries 3 and 4, Table 4).
The combination of copper(0) and copper(II) acetate resulted in a slight improvement in the
reaction rate as compared to copper(II) acetate alone (entry 5, Table 4). Quite unexpectedly, a
mixture of copper(0) and copper(II) acetate monohydrate improved both, yield (93 %) and
reaction time (60 min) (entry 6, Table 4) compared to copper(II) acetate monohydrate alone.
Increasing the amount of catalyst to 10 % or 15 % reduced the reaction time to 45 min, and 25
min, respectively, but at the expense of the yield (64 % and 61 %, respectively) (entries 7 and
8, Table 4).
Table 4. Optimization of the reaction of 1-amino-4-bromo-2-methylanthraquinone (7) with
anthranilic acid with regard to the catalysta
Catalyst (5 mol %)b
Time (min)
Isolated Yield (%)
Entry
Cu(OAc)2
110
110
80
90
40
80
63
70
93
64
61
1
2
3
4
5
6
7
8
Cu(OAc)2·H2O
Cu0
Cu0c
80
Cu(OAc)2/Cu0
Cu(OAc)2·H2O/Cu0
Cu(OAc)2·H2O/Cu0d
Cu(OAc)2·H2O/Cu0e
80
60
45
25
aReaction conditions: 2-methyl-AQ 7 (0.1 mmol), anthranilic acid (3 equiv.), potassium
acetate (5 equiv.), 4 mL of methanol, 95 °C, microwave 80 W. bIn case of using a mixture, 5
mol % of each component was employed. c10 mol %, d10 mol % each. e15 mol % each.
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The optimal reaction conditions (methanol, potassium acetate, and a mixture of copper(0),
and copper(II) acetate monohydrate (5 mol % each)) were then successfully used for synthesis
of the 2-methyl-substituted AQ derivatives 58-61 (Table 2)
Optimization of the reaction conditions for 1-amino-4-bromo-2-hydroxymethylanthraquinone
(5)
The conditions applied for 2-methyl-AQ derivative 7 were also employed for the reaction of
the more hydrophilic 2-hydroxymethyl-AQ 5 with 2-amino-5-fluorobenzoic acid, and product
65 could be obtained in 81 % yield (Table 2), although about 10 % of the starting material
was still present at the end of the reaction. When applying the same conditions for the
reaction of 2-hydroxymethyl-AQ 5 with anthranilic acid, only 58 % of the desired product 62
was obtained (entry 1, Table 5), and the reaction was incomplete. Therefore, the effect of the
solvent on the reaction was subsequently tested to improve the yield.
By examining the solvent preference for reactions of BAA (1) and its analogues 4, 6, and 7, a
correlation between the AQ’s 2-substituent and the polarity of the solvent was clearly
observed. An aqueous medium was suitable in case of the polar AQ-2-sulfonate BAA (1) or
its analogue with a carboxylic acid function at position 2 [22,23]. Methanol was preferred in
case of 2-methyl-AQ derivative 7, whereas 1-pentanol was superior for reactions of the 2-
bromo- and the 2-cyano-AQ analogues, 4 and 6. We thus postulated that since derivative 5
has a 2-hydroxymethyl group, which shows intermediate polarity, addition of water to
methanol might be advantageous for the reactions. Therefore, we decided to systematically
investigate the effect of water on the reaction of 2-hydroxymethyl-AQ 5 with anthranilic acid
(Table 5). With 1.25 % water in methanol, product 62 was afforded after 3 h in 69 % yield
(entry 2, Table 5). Increasing the content of water to 2.5 % improved the yield to 88 % and
reduced the reaction time to 2.3 h (entry 3, Table 5). A further increase in water to 5.0 % did
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not lead to improvement of the yield as compared to pure methanol (compare entries 1 and 5,
Table 5). Next, we repeated the reaction in the best solvent mixture, 2.5 % water in methanol,
and modified the catalyst. With a mixture of elemental copper and copper(II) acetate, a
considerable improvement in both, yield (98 %) and reaction time (1 h), was achieved (entry
4, Table 5). These optimized conditions were therefore applied for the synthesis of products
63-66 (Table 2).
Table 5. Optimization of the reaction of 1-amino-4-bromo-2-hydroxymethylanthraquinone
(5) with anthranilic acid
Isolated
Catalyst (5 mol %)
Time (h)
Entry
Solvent
Yield (%)
methanol
Cu(OAc)2
Cu(OAc)2
3.5
3
58
69
1
2
water /methanol
(1.25 % v/v)
water /methanol
(2.5 % v/v)
water /methanol
(2.5 % v/v)
Cu(OAc)2
2.3
1
88
98
53
3
4
5
Cu(OAc)2/Cu0a
Cu(OAc)2
water /methanol
(5 % v/v)
2.5
aReaction conditions: 2-hydroxymethyl-AQ 5 (0.1 mmol), anthranilic acid (3 equiv.),
potassium acetate (5 equiv.), 4 mL of solvent, 95 °C, microwave 80 W. bIn case of using a
mixture 5 mol % of each component was employed.
Discussion of the results
The detailed mechanism of Ullmann-type reactions has not been fully understood yet [39,40].
Copper chemistry is complicated by the fact that many parameters influence the progress or
inhibition of reactions. In our study, the results of the different optimization reactions showed
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a substantial effect of the solvent on the yield and the rate of the reaction. Among the studied
solvents, polar protic ones, namely water and alcohols, were preferred for condensation of the
2-substituted 1-amino-4-bromo-AQ derivatives (1, 4-7) with amines. These solvents possess
free hydroxyl group, and can therefore additionally function as ligands. In a series of
mechanistic investigations conducted by Tuong, Arai and Hida on Ullmann condensations of
haloanthraquinones with amines, the authors demonstrated that the presence of alcohol in the
system enhanced the reactions by forming a complex with the catalyst. The formed copper
complex showed higher catalytic activity than the original copper species (Scheme 5) [40–
48].
Scheme 5. Monomeric and dimeric forms of the alkoxy-CuII species proposed by Arai et al.
[44,45]. X= Cu counter anion e.g. halide, acetate.
The choice between the different alcohols for each of the AQ derivatives is then likely based
on both, polarity of the solvent and solubility of the particular derivative. A correlation could
be observed between the lipophilicity of the AQ derivatives (1,4-7) and the polarity of the
solvent expressed in terms of dielectric constant - the more lipophilic the AQ derivative was,
the less polar the preferred solvent had to be (Table 6). However, 2-methyl-AQ 7, although
more lipophilic than 2-cyano-AQ 6, required a more polar solvent (isopropanol vs. 1-
pentanol). This result emphasizes a role for the solvent as a copper complex ligand.
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Table 6. Log P values of the 4-brominated anthraquinone derivatives and dielectric constant
values for water and alcohols
AQ
R
Log Pa
Dielectric
constant (ε)
Solvent
SO3Na 1.60
CH2OH 1.87
1
5
7
6
4
Water
78.54
32.60
CH3
CN
Br
2.93
2.48
3.27
Methanol
Isopropanol 18.30
1-pentanol 15.14
acalculated using ChemDraw Pro. 12.0© software
The results also confirm how copper catalysts vary in their activity based on molecules
present in the medium. Copper(0) was an optimal catalyst in case of BAA (1) [22], whereas
Cu(II) acetate was preferred for reactions of 2-bromo-AQ 4 and 2-cyano-AQ 6. Regarding 2-
hydroxymethyl-AQ 5 and 2-methyl-AQ 7, addition of Cu0 to CuII was favored. Hence, it is
likely that CuI, generated by comproportionation of Cu0 with CuII, is more catalytically active
than CuII in these cases. However, it might also be possible that CuI with CuII act
cooperatively, and that a dimeric complex of the alcohol with both, CuI and CuII is the active
catalyst.
3. Conclusion
In conclusion, we successfully synthesized 1-amino-4-(ar)alkylamino-AQ derivatives bearing
a bromo-, hydroxymethyl-, cyano-, or methyl-substituent in the 2-position starting from the
corresponding 2-substituted 1-amino-4-bromo-AQ derivatives. Copper-catalyzed solvent-free
Ullmann condensation was used for reactions with liquid amines. For reactions with solid
amines, MW irradiation was applied, and optimization of the conditions in the presence of a
solvent was required. Alcohols were the preferred solvents; they have dual functions in these
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reactions - as solvents and as copper complex ligands. Yields and reaction rates were variable,
dependent on the employed 1-amino-4-bromo-AQ derivative, the amine, the solvent, and the
catalyst. This study extends our knowledge on copper-catalyzed Ullmann condensation
reactions, and provides insights into the structure-reactivity relationships of BAA and its
analogues. A total of 66 AQ derivatives have been synthesized and fully characterized.
Compounds 8, 29, 49, 50, and 61 have previously been reported, whereas compounds 13, 22,
23, 27, 33, and 41 were only mentioned in patents but no synthetic procedures have been
provided. All other synthesized products (55 compounds) represent novel AQ derivatives not
described to date. These AQs are of potential use as dyes e.g. in the textile industry, and
represent potentially bioactive compounds.
Supplementary Material
Material and methods, detailed synthetic procedures, and analytical and spectroscopic data of
all compounds (8, 11 – 43, 48 – 66) are provided.
Acknowledgement
E.M.M is grateful to the Deutscher Akademischer Austauschdienst (DAAD) for a PhD
scholarship. The Cultural Affairs & Mission Sector of the Egyptian Higher Education
Ministry is kindly acknowledged for providing a PhD scholarship to M.R. Y.B. is indebted to
the SQU, Oman, for support (SR/SCI/CHEM/15/01).
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