Ionic liquids as novel and recyclable reaction media for N-alkylation of amino-9,10-anthraquinones by trialkyl phosphites

Article abstract of DOI:10.1016/j.tetlet.2007.03.077

Ionic liquids such as 1,3-dialkylimidazolium bromides make excellent catalysts and solvents for N-alkylation of amino-9,10-anthraquinones in the presence of trialkyl phosphites. For triethyl phosphite, [bpim][Br] gave better results. The ionic liquids are successfully regenerated and reused.

Full text of DOI:10.1016/j.tetlet.2007.03.077

Tetrahedron Letters 48 (2007) 3753–3756
Ionic liquids as novel and recyclable reaction media for
N-alkylation of amino-9,10-anthraquinones by trialkyl phosphites
Issa Yavari* and Elaheh Kowsari
Chemistry Department, Tarbiat Modarres University, PO Box 14115-175, Tehran, Iran
Received 2 January 2007; revised 4 March 2007; accepted 14 March 2007
Available online 19 March 2007
Abstract—Ionic liquids such as 1,3-dialkylimidazolium bromides make excellent catalysts and solvents for N-alkylation of amino-
9,10-anthraquinones in the presence of trialkyl phosphites. For triethyl phosphite, [bpim][Br] gave better results. The ionic liquids
are successfully regenerated and reused.
ꢀ 2007 Published by Elsevier Ltd.
Ionic liquids (ILs) have attracted considerable attention
in recent years due to their unique properties, such as
lack of measurable vapor pressure, non-flammability
and recyclability.1 Their high polarity and ability to dis-
solve both inorganic and organic materials can result in
enhanced rates of chemical processes and can provide
higher/different selectivities compared to conventional
solvents. Thus, as a result of their ‘green’ credentials
and potential to enhance rate and selectivity,2,3 ILs have
been used as solvents in chemical transformations.
However, the ability of ILs to serve as catalysts4 and
reagents5 has not been explored to any great extent.6,7
products and the neutral starting amines are sufficiently
fast such that a mixture of products may be obtained.
For this reason, when monoalkylation of an amine is de-
sired, the reaction is usually best carried out by reductive
amination. The conventional method for the prepara-
tion of alkylaminoanthraquinones involves the reaction
of 1-chloroanthraquinone with DMF under reflux (140–
150 ꢁC) for up to 32 h. This reaction produces a mixture
of products.10
In this Letter, ILs are employed as useful and novel
reaction media for alkylation of amino-9,10-anthraqui-
nones in the presence of trialkyl phosphites, avoiding
the use of base and highly polar organic solvents. The
effects of some important variables, such as reaction
temperature and the type of IL used on the activity
and selectivity of the reaction, are investigated. Thus,
the reaction of 1-amino-9,10-anthraquinone (1-AAQ)
in the presence of triethyl phosphite (TEP) or trimethyl
phosphite (TMP) in different imidazolium-based ILs at
various temperatures led to 1-alkylamino-9,10-anthra-
quinones in high yields11 (Scheme 1 and Table 1).
9,10-Anthraquinone is the parent compound for a large
palette of anthraquinone dyes and so is the most impor-
tant starting material in their production. Furthermore,
anthraquinone is gaining importance as a catalyst in
wood pulping, and it is known to exhibit quite potent
anticancer activities.8 Amino- and hydroxy-substituted
9,10-anthraquinones are important in the dye industry,
biology and pharmaceutical chemistry.8,9
The alkylation of neutral amines by alkyl halides is com-
plicated from a synthetic point of view because of the
possibility of multiple alkylation which can proceed to
give the quaternary ammonium salt in the presence of
excess alkyl halide. Even with a limited amount of the
alkylating agent, the equilibria between protonated
An initial reaction of 1-AAQ and trialkyl phosphites
was carried out under different conditions. The results
indicated that ionic liquids [YY0im][Br] (Y,Y0 = Me,
Et, n-Pr, n-Bu, or Bn) exhibited excellent catalytic activ-
ities. In contrast,ꢀno reaction was observed in the ILs
containing a PF6 anion. When the reactions were car-
ried out in water or CH2Cl2, no product was observed,
except for the reaction of 1-AAQ and TMP (see Table
1). The poor solubility of 1-AAQ in the hydrophobic
IL [bmim][PF6] and in water or CH2Cl2 may be respon-
sible for this behaviour. It is interesting to note that ILs
Keywords: Amino-9,10-anthraquinone; Ionic liquid; N-alkylation;
Trialkyl phosphite.
*
Corresponding author. Tel.: +98 21 8801 1001; fax: +98 21 8800
6544; e-mail: yavarisa@modares.ac.ir
0040-4039/$ - see front matter ꢀ 2007 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2007.03.077

3754
I. Yavari, E. Kowsari / Tetrahedron Letters 48 (2007) 3753–3756
R
H
H
H
O
N
O
N
Ionic Liquid
(RO)3P
+
(R = Me, Et)
O
O
1-MAAQ
1-EAAQ
(R = Me)
(R = Et)
1-AAQ
O
O
NH2
NR2
Ionic Liquid
(RO)3P
+
(R = Me, Et)
O
O
2-AAQ
2-DMAAQ (R = Me)
2-DEAAQ (R = Et)
Scheme 1. The reaction of 1-AAQ or 2-AAQ with trialkyl phosphites in ILs as solvent and catalyst.
Table 1. Influence of the reaction media on the yield and time of reaction of 1-AAQ (1 mmol) or 2-AAQ (1 mmol) and trialkyl phosphites (1 mmol)
in different ILs (1.0 g) at 120 ꢁC
Entry
Solventa
1-AAQ
2-AAQ
TEP
Yield (%)
TMP
Yield (%)
TEP
Yield (%)
TMP
Yield (%)
Time (h)
Time (h)
Time (h)
Time (h)
1
2
3
4
5
6
7
8
9
10
[eeim][Br]
[bbim][Br]
[emim][Br]
[bmim][Br]
[bpim][Br]
[Bnmim][Br]
[Bnbim][Br]
[pmim][Br]
Water
8
8
8
8
8
12
12
8
24
24
60
85
65
60
85
55
52
82
6
6
6
6
6
11
11
6
12
12
68
84
75
65
95
65
63
87
7
7
7
7
7
7
7
7
24
24
62
95
65
60
85
65
60
85
6
6
6
6
6
6
6
6
6
6
68
98
65
60
87
65
60
85
60
85
No product
No product
No product
No product
No product
No product
CH2Cl2
a [eeim][Br] (e, e = Et, Et); [bbim][Br] (b, b = n-Bu, n-Bu); [emim][Br] (e, m = Et, Me); [bmim][Br] (b, m = n-Bu, Me); [bpim][Br] (b, p = n-Bu, n-Pr);
[Bnmim][Br] (Bn, m = Benzyl, Me); [Bnbim][Br] (Bn, b = Benzyl, n-Bu); [pmim][Br] (p, m = n-Pr, Me).
having longer cationic carbon chains were found to be
more effective for N-alkylation of 1-AAQ. Thus,
[bpim][Br] appeared to be the most suitable IL to per-
form this reaction (see Table 1). No reaction was ob-
served between 1-AAQ and (PhO)3P or Ph3P in the
ILs studied in this work.
by 31P NMR spectroscopy. After 2 h, the 31P signal of
TMP disappeared and a signal at d(P) 4.95 ppm was ob-
served for the H–P(O)(OMe)2 species. Observation of a
sharp doublet at d(H) 6.08 ppm (1JPH = 670 Hz) for the
H–P(O)(OMe)2 in the H NMR of the reaction mixture
confirmed the proposed mechanism (Scheme 2).
1
Mechanistically, the reaction may involve the attack of
the phosphorus nucleophile on the electrophilic carbon
atom of the imidazolium cation to form an intermediate
phosphonium salt.12 As amines are found to be more
nucleophilic in ILs than in common organic solvents,13
the AAQ attacks the electrophilic carbon atom of inter-
mediate 1 to form ammonium salt 3 which is converted
to 1-AAQ by loss of HBr. Protonation of intermediate 2
by HBr leads to 4, which dialkyl hydrogen phosphite
eliminates and regenerates the IL (Scheme 2).
The reaction of 2-AAQ with trialkyl phosphites was also
studied in different imidazolium-based ionic liquids at
various temperatures. Although 2-MAAQ is expected
to be less nucleophilic compared to 2-DMAAQ in con-
ventional solvents,13 the reactivity of the former towards
N-alkylation in the ILs used is at least two orders of
magnitude higher than the latter.
Dialkylation of 2-AAQ takes place in the presence of
1 equiv of TMP. In order to obtain information about
the mechanism of this transformation, the reaction mix-
1
These results show that the ILs play a role as a catalyst
as well as a reaction medium during these processes. The
reaction of 1-AAQ and TMP in [bpim][Br] was followed
ture of 2-AAQ and TMP was monitored by H and 31P
NMR spectroscopy. The 31P NMR spectrum of the
reaction mixture of 2-AAQ and TMP in [bpim][Br] after

I. Yavari, E. Kowsari / Tetrahedron Letters 48 (2007) 3753–3756
3755
Br
N
N
N
N
Y
Y
Y'
Y'
ArNH2
+
(RO)3P
+
N
+
+
Br
Y'
O
O
N
O
O
Br
+
ArNH2R
Y
R
P
R
R
P
R
+
O
O
R
3
2
1
- ArNHR
Br
HBr
N
H
+
N
Y
Y'
O
O
R
+
N
R
P
O
O
Br
+
H
N
R
P
R
Y
O
Y'
O
4
Scheme 2. A plausible mechanism for the alkylation of 1-AAQ by trialkyl phosphites in ILs.
2. Ionic Liquids in Synthesis; Wasserscheid, P., Welton, T.,
Eds.; Wiley-VCH: Weinheim, Germany, 1987.
3. Dupont, J.; de Souza, R. F.; Suarez, P. A. Z. Chem. Rev.
2002, 102, 3667.
2 h showed a major signal at 5.0 ppm due to the pres-
ence of H–P(O)(OMe)2. This signal gradually disap-
peared and two new 31P signals appeared at 2.0 and
8.0 ppm, which were attributed to H–P(O)(OMe)(OH)
and H–P(O)(OH)2 as side products of dealkylation of
TMP. The presence of OH groups was confirmed by
1H NMR spectroscopy, which showed a very broad sig-
4. (a) Harjani, J. R.; Nara, S. J.; Salunkhe, M. M. Tetrahe-
dron Lett. 2002, 43, 1127; (b) Namboodiri, V. V.; Varma,
R. S. J. Chem. Soc., Chem. Commun. 2002, 342; (c) Sun,
W.; Xia, C.-G.; Wang, H.-W. Tetrahedron Lett. 2003, 44,
2409; (d) Qiao, K.; Yakoyama, C. Chem. Lett. 2004, 33,
472.
5. (a) Ranu, B. C.; Das, A.; Samanta, S. J. Chem. Soc.,
Perkin Trans. 1 2002, 1520; (b) Ranu, B. C.; Dey, S. S.
Tetrahedron Lett. 2003, 44, 2865; (c) Ranu, B. C.; Dey, S.
S.; Hajra, A. Tetrahedron 2003, 59, 2417; (d) Ranu, B. C.;
Dey, S. S. Tetrahedron 2004, 60, 4183.
6. Ranu, B. C.; Banerjee, S. J. Org. Chem. 2005, 70, 4517.
7. (a) Walborsky, H. M.; Hornyak, F. M. J. Am. Chem. Soc.
1955, 77, 6396; (b) Patro, B.; Ila, H.; Junjappa, H.
Tetrahedron Lett. 1992, 33, 809.
8. Butler, J.; Hoey, B. M. Br. J. Cancer 1987, 55, 53.
9. Remold, M. W.; Kramer, H. E. A. J. Soc. Dyes Colour
1980, 96, 122.
1
nal at 4.0–7.0 ppm. The H NMR spectrum of the reac-
tion mixture also showed the appearance of two
doublets (1JPH = 600 Hz) at 7.4 and 7.7 ppm due to
the P–H protons in H–P(O)(OMe)(OH) and H–
P(O)(OH)2. These observations are consistent with a
second (and perhaps third) dealkylation of TMP in the
presence of 2-AAQ in ILs.
The effect of temperature change on the formation of
1-MAAQ was studied in the temperature range of
25–140 ꢁC. At reaction temperatures above 120 ꢁC,
no change in the yield of the reaction was observed.
Therefore, 120 ꢁC is inferred to be a suitable reaction
temperature. Similar results were obtained for the reac-
tion of 2-AAQ and TMP in [bbim][Br] at various
temperatures.
10. Yoshida, Z.; Takabayashi, F. Tetrahedron 1968, 24,
913.
11. All ILs were prepared and purified in accordance with the
procedure described previously.14 General procedure for
N-alkylation of 1-AAQ or 2-AAQ. The phosphite (1 mmol)
was added to a solution of the AAQ (1 mmol) in
[bpim][Br] (1.0 g) and the solution was heated at 120 ꢁC
for 6–8 h (see Table 1). The reaction mixture was cooled to
ambient temperature before work-up. The products were
extracted with CH2Cl2 (3 · 4 mL) followed by solvent
evaporation. The IL was recovered by the addition of
water (5 mL), then collected and dried under vacuum. The
products were obtained in high yields and purified after
short filtration chromatography through silica gel. These
reactions were performed without any protective atmo-
sphere of inert gas. 1-(Methylamino)-9,10-anthraquinone
(1-MAAQ): Red powder, yield: 0.23 g (95%). Mp 169–
170 ꢁC (reported10 170 ꢁC). IR (KBr) (vmax/cmꢀ1): 1663,
In conclusion, ILs are proved to be useful and novel
reaction media for the N-alkylation of 1-AAQ and
2-AAQ by trialkyl phosphites, avoiding the use of base
and highly polar organic solvents. The effects of reaction
temperature and the type of IL used on the activity and
selectivity were investigated. The IL [bpim][Br] was
found to be the most effective. The use of room-temper-
ature imidazolium ILs significantly enhanced the rate of
N-alkylation of AAQs.
1
References and notes
1623 (2C@O), 3285 (N–H). H NMR (500 MHz, CDCl3):
3.10 (3H, d, 3J = 5.0, Me), 7.09 (1H, dd, 3J = 7.0, 4J = 1.3,
CH), 7.59–7.65 (2H, m, 2CH), 7.73–7.84 (2H, m, 2CH),
8.28 (1H, dd, 3J = 6.5, 4J = 1.2, CH), 8.31 (1H, dd,
1. (a) Welton, T. Chem. Rev. 1999, 99, 2071; (b) Wassersc-
heid, P.; Keim, W. Angew. Chem., Int. Ed. 2000, 39, 3773;
(c) Sheldon, R. J. Chem. Soc., Chem. Commun. 2001, 2399.
4
3J = 6.5, J = 1.2, CH), 9.69 (1H, s, br, NH). 13C NMR

3756
I. Yavari, E. Kowsari / Tetrahedron Letters 48 (2007) 3753–3756
(125.7 MHz, CDCl3): 29.6 (Me), 113.1 (C), 115.3 (CH),
CDCl3): 39.7 (2Me), 108.1 (CH), 116.4 (CH), 122.0 (C),
126.8 (CH), 126.9 (CH), 129.6 (CH), 133.5 (CH), 134.1
(C), 134.4 (CH), 134.7 (C), 135.1 (C), 154.4 (N–C), 180.9,
183.9 (2C@O). 2,2-(Diethylamino)-9,10-anthraquinone (2-
DEAAQ): IL = [bbim][Br], orange powder, yield: 0.26 g
(95%). Mp 195–199 ꢁC. IR (KBr) (vmax/cmꢀ1): 1645, 1618
(2C@O). 1H NMR (500 MHz, CDCl3): 0.83 (6H, t,
3J = 7.2, 2Me), 3.50 (4H, q, 3J = 7.2, 2CH2), 6.94 (1H,
dd, J = 8.9, J = 1.9, CH), 7.46–7.47 (1H, m, CH), 7.71–
7.76 (1H, m, 2CH), 8.17–8.19 (1H, m, CH), 8.26 (1H, dd,
3J = 7.3, 4J = 1.1, CH), 8.30 (1H, dd, 3J = 7.7, 4J = 1.5,
CH). 13C NMR (125.7 MHz, CDCl3): 14.0 (2Me), 38.4
(2CH2), 108.0 (CH), 115.4 (CH), 125.6 (CH), 126.0 (C),
126.9 (CH), 128.1 (CH), 128.2 (CH), 133.7 (C), 133.9
(CH), 134.5 (C), 135.3 (C), 151.7 (N–C), 181.3, 184.4
(2C@O).
118.1 (CH), 126.7 (CH), 126.9 (CH), 133.4 (C), 133.5
(CH), 134.5 (CH), 134.9 (C), 135.8 (C), 153.0 (N–C),
183.4, 184.8 (2C@O). 1-(Ethylamino)-9,10-anthraquinone
(1-EAAQ): Red powder, yield: 0.21 g (85%). Mp 113–
114 ꢁC. IR (KBr) (vmax/cmꢀ1): 1647, 1619 (2C@O), 3268
(N–H). 1H NMR (500 MHz, CDCl3): 1.39 (3H, t, 3J = 7.3,
3
Me), 3.40 (2H, q, J = 7.3, CH2), 7.05–7.06 (1H, m, CH),
3
4
7.52–7.59 (2H, m, 2CH), 7.68–7.71 (1H, m, CH), 7.74–7.77
3
4
(1H, m, CH), 8.24 (1H, dd, J = 6.5, J = 1.0, CH), 8.27
(1H, dd, 3J = 6.5, 4J = 1.1, CH), 9.70 (1H, s, br, NH). 13
C
NMR (125.7 MHz, CDCl3): 14.5 (Me), 37.6 (CH2), 112.8
(C), 115.8 (CH), 118.8 (CH), 127.1 (CH), 127.3 (CH),
133.8 (C), 133.9 (CH), 134.9 (CH), 135.1 (C), 135.4 (C),
135.8 (C), 152.6 (N–C), 183.8, 185.3 (2C@O). 2,2-(Di-
methylamino)-9,10-anthraquinone (2-DMAAQ): IL =
[bbim][Br], orange powder, yield: 0.25 g (98%). Mp 190–
191 ꢁC (reported10 186 ꢁC), IR (KBr) (vmax/cmꢀ1): 1660,
12. Lozinskaya, E. I.; Shaplov, A. S.; Vygodskii, Ya. S. Eur.
Polym. J. 2004, 40, 2065.
1
´
1586 (2C@O). H NMR (500 MHz, CDCl3): 3.22 (6H, s,
13. Crowhurst, L.; Lancaster, N. L.; Perez Arlandis, J. M.;
2Me), 7.14 (1H, dd, 3J = 8.7, 4J = 1.8, CH), 7.42–7.43
(1H, m, CH), 7.68–7.94 (2H, m, 2CH), 8.10–8.12 (1H, m,
CH), 8.22–8.25 (2H, m, 2CH). 13C NMR (125.7 MHz,
Welton, T. J. Am. Chem. Soc. 2004, 126, 11549.
14. Vygodskii, Ya. S.; Lozinskaya, E. I.; Shaplov, A. S.
Macromol. Rapid Commun. 2002, 23, 676.