New copper(II) 2-(alkylamino)troponates

Article abstract of DOI:10.1007/s11243-014-9830-0

The copper aminotropones Cu[ON(R′)C₇H₄R-4] ₂ [R = H, R′ = Me (13), Et (14), n-Pr (15), n-Bu (16), Bz (17), MenOCH₂CH₂ (20); R = i-Pr, R′ = Me (18), n-Pr (19), MenOCH₂CH₂ (21)] have been prepared from the corresponding aminotropones HN(R′)OC₇H₄R-4 (1-7) by reacting with copper(II) acetate in aqueous ethanol. 20, 21 contain the flavourant, menthol, as part of the ligand. The structures of 5 (R = H, R′ = Bz), a hydrogen-bonded dimer, 14 and 20, both incorporating square-planar, four-coordinate copper centres, have been determined by X-ray crystallography. The antibacterial activities of complexes 13, 17, 20 and 21 have been assayed against Staphylococcus waneri, an in vitro model of plaque inhibition effects, and found to be more active than a commercial toothpaste formulation, but less active than the O,O-chelated copper(II) complex of ethylmaltol.

Full text of DOI:10.1007/s11243-014-9830-0

Transition Met Chem
DOI 10.1007/s11243-014-9830-0
New copper(II) 2-(alkylamino)troponates
•
Marie C. Barret Purvi H. Bhatia
•
•
Gabriele Kociok-Kohn Kieran C. Molloy
¨
Received: 25 March 2014 / Accepted: 15 April 2014
Ó Springer International Publishing Switzerland 2014
Abstract The copper aminotropones Cu[ON(R0)C7H4R-
4]2 [R = H, R0 = Me (13), Et (14), n-Pr (15), n-Bu (16),
Bz (17), MenOCH2CH2 (20); R = i-Pr, R0 = Me (18), n-Pr
(19), MenOCH2CH2 (21)] have been prepared from the
corresponding aminotropones HN(R0)OC7H4R-4 (1–7) by
reacting with copper(II) acetate in aqueous ethanol. 20, 21
contain the flavourant, menthol, as part of the ligand. The
structures of 5 (R = H, R0 = Bz), a hydrogen-bonded
dimer, 14 and 20, both incorporating square-planar, four-
coordinate copper centres, have been determined by X-ray
crystallography. The antibacterial activities of complexes
13, 17, 20 and 21 have been assayed against Staphylo-
coccus waneri, an in vitro model of plaque inhibition
effects, and found to be more active than a commercial
toothpaste formulation, but less active than the O,O-che-
lated copper(II) complex of ethylmaltol.
recently, tropolone has been elaborated to form mesogenic
complexes when coordinated to metals [12, 13]. Our own
work in this area stems from an interest in copper, zinc and tin
complexeswhichcanbeincorporatedintodentalformulations
[14], including complexes of this triad with ligands such as
maltol and ethylmaltol as well as I [15–17]. In this regard, the
ligandmustbeorallyacceptable, beabletodeliverthemetalin
the correct oxidation state and concentration (i.e. soluble
complexes) and have reasonable long-term stability.
As part of this general interest, we have become interested
in the related 2-(alkylamino)tropone ligand system (II),
which offers a complimentary j2-O,N chelation mode to the
j2-O,O mode inherent in I. Relatively few reports have
appeared concerning the chelation of metals such as Cu(II)
[18–20] and Zn(II) [21] with II, to which we now add our own
findings relating to copper. In particular, as well as broad-
ening the scope of simple ML2 complexes, we report on the
incorporation of a flavouring component, menthol, onto the
ligand periphery. As one of the drawbacks of these com-
plexes for oral delivery is their metallic taste even at low
concentrations, this approach may gosomeway to mitigating
this problem.
Introduction
Hinokitiol, a naturally occurring a-hydroxyketone which can
be extracted from wood (Thujapalicata, Taiwan Hinoki)
continues to attract interest as a ligand due to its attractive
biological properties (antimicrobial [1, 2], insecticidal [3],
cytotoxicity on tumour cells [4]) which make it a favourable
chelating agent for metals which might offer biological syn-
ergism. As a result, numerous metal derivatives of both
hinokitiol (I, R = i-Pr) [5], and its parent, tropolone
(I, R = H) [6–11], have been prepared and analysed. More
¨
Experimental
M. C. Barret ꢀ P. H. Bhatia ꢀ G. Kociok-Kohn ꢀ
K. C. Molloy (&)
Department of Chemistry, University of Bath, Claverton Down,
Starting materials: tropolone was obtained commercially
from Avocado, and hinokitiol was provided by Unilever
Bath BA2 7AY, UK
e-mail: kcm68win@outlook.com
123

Transition Met Chem
Research; both were used as received without further
purification. Reactions were carried out in air unless
otherwise specified. Elemental analyses were performed on
a Carlo-Erba Strumentazione E. A. model 1106 micro-
analyser, and the temperature of the furnace was set to
500 °C. The results were duplicated, and the mean of the
magnesium sulphate, and concentrated under vacuum to
obtain a yellow solid (0.76 g, 78 %). Analysis: Found
(calc. for C8H9NO): C 61.0 (60.9); H 4.4 (4.3); N 4.1
1
(4.0) %. H NMR [d(ppm), CDCl3]: 2.95 [3H, s, NCH3];
6.50–7.19 [5H, m, C7H5]. 13C NMR [d(ppm), CDCl3]: 28.5
[CH3]; 107.3, 121.0, 127.3, 135.3, 136.3 [CH];155.5 [C2];
175.6 [C3]. IR: 3,293 t(N–H); 1,629, 1,590 t(C=O); 1,510
t(C=C).
1
duplicated measurements was the final result. All H and
13C NMR spectra were recorded on a Bruker Avance
(300 MHz) Fourier transform spectrometer. All spectra
were recorded in d-chloroform and are referenced to
residual solvent peaks. Peak positions were recorded in d
ppm with abbreviations s, d, t and m denoting singlet,
doublet, triplet and multiplet, respectively. All coupling
constants (J) are quoted in Hertz. Infrared spectra were
recorded as a thin oil film sandwiched between NaCl plates
in the frequency range 4,000–400 cm-1 on a Nicolet 510P
2-Ethylaminotropone (2)
The methodology described above was employed with
aqueous ethylamine (70 %) (10 mL) and 2-p-toluene-
sulfonyltropolone (2.00 g, 7.24 mmol) in dichloromethane
(30 mL). An orange oil was obtained (0.77 g, 71 %).
Analysis: Found (calc. for C9H11NO): C 71.9 (72.5); H 7.4
(7.4); N 9.3 (9.4) %. 1H NMR [d(ppm), CDCl3]: 1.31 [3H,
t, NCH2CH3]; 3.28 [2H, q, NCH2CH3]; 6.49–7.21 [5H, m,
C7H5]. 13C NMR [d(ppm), CDCl3]: 13.4 [CH3]; 37.2
[CH2]; 108.4, 121.7, 128.0, 136.1, 136.9 [CH]; 155.2 [C2];
176.2 [C3]. IR data g,: 3,301 t(N–H); 1,630, 1,594 t(C=O);
1,515 t(C=C).
FT-IR spectrometer. All absorptions are quoted in cm-1
.
Synthesis of 2-p-toluenesulfonyltropolone
Following a previously reported procedure [22], tropolone
(5.00 g, 41.0 mmol) and p-toluenesulfonyl chloride
(7.81 g, 41.0 mmol) were mixed together in dry pyridine
(20 mL). After 30 min, the mixture was filtered and the
product obtained was then washed with cold water and
dried in vacuo, yielding the product as a white solid
(11.18 g, 98 %). Analysis: Found [calc. for C14H12O4S]: C
61.0 (60.9) %; H 4.4 (4.3) %. M. p.: 156–158 °C (lit:
156.5–157.5 °C) [23].
2-n-Propylaminotropone (3)
To a solution of 2-p-toluenesulfonyltropolone (2.00 g,
7.24 mmol) in dried DMSO (100 mL) was added n-pro-
pylamine (10 mL), and the solution was stirred overnight.
The mixture was poured into water and extracted with
ether; the ether layer was dried with magnesium sulphate;
and the solvent removed in vacuo. A brown oil was
obtained (0.81 g, 68 %). Analysis: Found [calc. for
C10H13NO]: C 72.7 (73.6); H 8.0 (8.0); N 8.65 (8.58) %.
1H NMR [d(ppm), CDCl3]: 0.94 [3H, t, NCH2CH2CH3];
1.64 [2H, m, NCH2CH2CH3]; 3.18 [2H, m, NCH2CH2-
CH3]; 6.49–7.21 [5H, m, C7H5]. 13C NMR [d(ppm),
CDCl3]: 12.1 [CH2CH2CH3]; 22.2 [CH2CH2CH3]; 44.9
[CH2CH2CH3]; 108.8, 122.1, 128.4, 136.5, 137.3 [CH];
155.7 [C2]; 176.5 [C3]. IR: 3,291 t(N–H); 1,637, 1,595
t(C=O); 1,512 t(C=C).
Synthesis of 2-p-toluenesulfonylhinokitiol
The method described above [22] was applied to hinokitiol
(5.00 g, 30.5 mmol). Hinokitiol and p-toluenesulfonyl
chloride (5.81 g, 30.5 mmol) were mixed in dry pyridine
(20 mL); the product was then washed with cold water and
dried in vacuo, to obtain a pale yellow solid (9.31 g, 96 %).
Analysis: Found (calc. for C17H18O4S): C 64.6 (64.2) %; H
6.1 (5.7) %.
The 2-alkylaminotropones and 2-alkylaminohinokitiols
were prepared following literature procedures; [23, 24] the
methodology described by Rasika Dias et al. [23] was used
for (1), (2), (6), (7), and the one from Pietra et al. [24] was
repeated for (3)–(5) and (8)–(10).
2-n-Butylaminotropone (4)
Following the procedure with n-butylamine (10 mL) and
2-p-toluenesulfonyltropolone (2.00 g, 7.24 mmol), 4 was
obtained (0.89 g, 69 %) as a brown-orange oil. Analysis:
Found [calc. for C11H15NO]: C 72.6 (74.6); H 8.6 (8.5); N
7.9 (7.9) %. 1H NMR [d(ppm), CDCl3]: 0.94 [3H, t,
NCH2CH2CH2CH3]; 1.40 [2H, m, NCH2CH2CH2CH3];
1.63 [2H, m, NCH2CH2CH2CH3]; 3.22 [2H, t, NCH2-
CH2CH2CH3]; 6.49–7.21 [5H, m, C7H5]. 13C NMR
[d(ppm), CDCl3]: 13.5 [CH2CH2CH2CH3]; 20.0 [CH2-
Synthesis of 2-methylaminotropone (1)
2-Methylaminotropone was prepared using a solution of
2-p-toluenesulfonyltropolone (2.00 g, 7.24 mmol) in
dichloromethane (30 mL) and aqueous methylamine
(40 %) (10 mL). The mixture was stirred overnight at room
temperature, then the two layers were separated, and the
organic layer was washed with water, dried with
CH2CH2CH3];
30.2
[CH2CH2CH2CH3];
42.3
123

Transition Met Chem
[CH2CH2CH2CH3]; 108.4, 121.7, 127.9, 136.1, 136.9
[CH]; 155.4 [C2]; 176.2 [C3]. IR: 3,307 t(N–H); 1,636,
1,593 t(C=O); 1,516 t(C=C).
salt as a white precipitate. This was dissolved in dilute HCl
and extracted using diethyl ether. The resulting ethereal
solution was washed with water, dried over magnesium
sulphate, filtered, and concentrated under rotary evapora-
tion to produce a yellow oil (2.25 g; 10 %). 1H NMR
(CDCl3): 8.10 [H, br s, OH]; 4.13 [1H, d, Ja-b = 15.0 Hz,
C2Ha]; 4.02 [1H, d, Jb-a = 15.0 Hz, C2Hb]; 3.13 [1H, ddd,
J3-4ax = J3-8 = 9.10, J3-4eq = 3.00 Hz, C3H]; 1.10–2.30
[2H, m, C4H2; 1H, m, C5H; 2H, m, C6H2; 2H, m, C7H2;
1H, m, C8H; 1H, m, C9H]; 0.83, 0.75 [3H, d, J10-9/J11-
2-Benzylaminotropone (5)
Following the same method as for (3), a yellow solid was
obtained using benzylamine (10 mL) and 2-p-toluene-
sulfonyltropolone (2.00 g, 7.24 mmol). Yield 1.34 g,
88 %. Recrystallisation from chloroform/cyclohexane gave
yellow crystals suitable for X-ray analysis. Analysis:
Found [calc. for C14H13NO]: C 79.5 (79.6); H 6.3 (6.2); N
6.7 (6.6) %. 1H NMR [d(ppm), CDCl3]: 4.44 [2H, s, CH2];
6.43–7.52 [10H, m, C6H5 and C7H5]. 13C NMR [d(ppm),
CDCl3]: 46.5 [CH2]; 108.4, 122.2, 127.5, 128.0, 130.1,
131.4, 136.1, 136.9 [CH]; 156.0 [C2]; 175.8 [C3]. IR: 3,304
t(N–H); 1,632, 1,592 t(C=O); 1,512 t(C=C).
= 6.30, 8.40 Hz, C10H3/C11H3]; 0.85 [3H, d, J12-
9
= 8.10 Hz, C12H3]. 13C NMR (CDCl3): 176 [C1]; 66.3
5
[C2]; 80.8 [C3]; 40.2 [C4]; 31.9 [C5]; 34.7 [C6]; 22.6 [C7];
48.3 [C8]; 26.0 [C9]; 21.4, 16.4 [C10/C11]; 23.5 [C12]. IR:
1,720m (C=O); 1,275 m(C–O); 3,120 m(O–H).
Synthesis of 2-menthoxyacetamide (9) [26]
2-Methylamino-4-i-propyltropone (6)
Menthxoyacetyl chloride was produced by dissolving
menthoxyacetic acid (8) (10.0 g, 46.7 mmol) in thionyl
chloride (16.7 mL, 229 mmol) and warming at 50 °C for
3 h. The excess thionyl chloride was removed by warming
in a water bath under reduced pressure, and the acid
chloride (7.30 g; 67 %) was used directly. Ammonia
(19.2 mL) was added directly to the acid chloride, (7.30 g,
31.3 mmol) and stirred at 0 °C for 24 h. The final product
was washed with water, extracted with diethyl ether
(2 9 20 mL), dried over anhydrous magnesium sulphate,
filtered, and dried in vacuo yielding a white solid. Re-
crystallisation from petroleum-ether 60–80 °C gave white
crystals (4.58 g; 46 %; m. p. (°C): 92–94 (Lit: 92–94 [26]).
Analysis for (22): Found [calc. for C12H23O2N]: C 66.4
The method described earlier [23] for (1) was repeated for
(2.00 g,
(6)
using
2-p-toluenesulfonylhinokitiol
6.28 mmol) and the corresponding amine in excess in
solution in dichloromethane (30 mL). Aqueous methyl-
amine (40 %) (10 mL) was used for (6) (0.57 g, 51 %),
aqueous ethylamine (70 %) (10 mL) for (7) (0.92 g, 76 %).
Analysis for (6): Found [calc. for C11H15NO]: C 72.4
(74.6); H 8.3 (8.5); N 7.6 (7.9) %. IR: 3,286 t(N–H);
1,633, 1,595 t(C=O); 1,514 t(C=C).
2-n-Propylamino-4-i-propyltropone (7)
1
Following the procedure for (3), (7) was obtained using
2-p-toluenesulfonylhinokitiol (2.00 g, 6.28 mmol) and
npropylamine (10 mL). Yields 0.51 g, 39 %. Analysis for
(8): Found [calc. for C13H19NO]: C 74.0 (76.1); H 9.5
(9.3); N 6.2 (6.8). IR: 3,303 t(N–H); 1,632, 1,592 t(C=O);
1,511 t(C=C).
(67.7); H 10.7 (10.7); N 6.2 (6.5) %. H NMR (CDCl3):
5.80, 6.59 [2H, br s, NH2]; 3.98 [1H, d, Ja-b = 15.0 Hz,
C2Ha; 3.78 [1H, d, Jb-a = 15.6 Hz, C2Ha]; 3.10 [1H, ddd,
J3-4ax = J3-8 = 11.4, J3-4eq = 4.50 Hz, C3H]; 1.20–2.20
[2H, m, C4H2; 1H, m C5H; 2H, m, C6H2; 2H, m, C7H2; 1H,
m, C8H; 1H, m, C9H]; 0.84, 0.72 [3H, d, J10-9/J11-9 = 3.90,
6.60 Hz, C10H3/C11H3]; 0.87 [3H, d, J12-5 = 3.30 Hz,
C12H3]. 13C NMR (CDCl3): 174 [C1]; 68.1 [C2]; 80.8 [C3];
40.5 [C4]; 31.8 [C5]; 34.8 [C6]; 22.6 [C7]; 48.4 [C8]; 26.4
[C9]; 21.3, 16.6 [C10/C11]; 23.6 [C12]. IR: 3,189 m(N–H);
1,640 m(C=O).
Synthesis of menthoxyacetic acid (8)
Following a previously reported procedure [25], menthol
(15.6 g, 100 mmol) was dissolved in THF (ca. 50 mL)
under nitrogen. To this solution was added lithium ribbon
(0.80 g, 115 mmol) cut into small pieces, and this mixture
was refluxed under nitrogen for 4 h. This solution was then
filtered to remove the unreacted lithium, and dry mono-
chloroacetic acid (4.25 g, 45.1 mmol) in anhydrous THF
(12.5 mL) was added dropwise to the filtrate. This mixture
was gently refluxed for 20 h. After this time, water (ca.
30 mL) was added. The THF and menthol were fraction-
ally distilled from the yellow suspension, which was then
cooled in an ice bath and filtered to obtain the solid lithium
Synthesis of 2-menthoxyethylamine (10) [26]
In a three-necked round-bottomed flask were placed
2-menthoxyacetamide (9) (4.01 g, 18.9 mmol) and anhy-
drous THF (30 mL). Lithium aluminium hydride (2.15 g,
56.7 mmol) dissolved in anhydrous THF (20 mL) was
added dropwise using a syringe under the flow of nitrogen
to the 2-menthoxyacetamide. During the addition, the
reaction mixture gave off bubbles and became grey. The
123

Transition Met Chem
contents of the flask were stirred vigorously and allowed to
reflux for 8 h, then cooled to room temperature, and stirred
at this temperature overnight. The mixture was cooled to
0 °C by application of an ice bath, and water (5 mL) was
added dropwise. A white precipitate was produced, and
bubbles of gas were given off. The precipitate was removed
by filtration and washed with diethyl ether. The filtrate was
extracted with diethyl ether (2 9 25 mL) and 15 % (w/v)
sodium hydroxide (5 mL). The organic layers were com-
bined, dried over anhydrous magnesium sulphate, filtered,
and concentrated to dryness by rotary evaporation yielding
a colourless liquid (2.87 g; 78 %). Analysis for (23): Found
(calc. for C12H25ON): C 70.1 (72.4); H 12.2 (12.7); N 5.2
26.1 [C16]; 21.3, 16.6 [C17/C18]; 23.7 [C19].IR: 3,300 m(N–
H) and m(O–H); 1,631, 1,595 m(C=O); 1,519 m(C=C).
Synthesis of 2-menthoxyethylamino-4-
isopropylcyclohept-2,4,6-trien-1 one.H2O (12)
2-Menthoxyethylamino-4-isopropylcyclohept-2,4,6-trien-1-
one.H2O (12) was prepared in a similar manner to 11 by
reacting 2-menthoxyethylamine (10) (2.00 g, 10.1 mmol),
two equivalents of triethylamine (1.86 mL, 13.3 mmol) and
2-p-toluenesulfonylhinokitiol (2.12 g, 6.67 mmol) in DMSO
(50 mL) to yield the product as a brown oil (2.54 g; 70 %).
Analysis for (12): Found [calc. C22H37O3N]: C 73.1 (72.7); H
10.1 (10.2); N 3.2 (3.8) %. 1H NMR (CDCl3): 7.45–6.28 [4H,
m, C3H, C5H, C6H, C7H];3.45[1H, t, NH];3.30–3.95[4H, m,
C8H2, C9H2]; 3.01 [1H. ddd, J10-11ax = J10-15 = 10.5, J10-
1
(5.4) %. H NMR (CDCl3): 2.75 [2H, t, JNH-1 = 3.00 Hz,
NH2]; 3.65 [2H, m, C1H2]; 3.25 [2H, m, C2H2]; 2.97 [1H,
ddd, J3-4ax = J3-8 = 10.5, J3-4eq = 4.50 Hz, C3H];
1.15–2.20 [2H, m, C4H2; 1H, m, C5H; 2H, C6H2; 2H, m,
= 4.50 Hz, C10H]; 1.20–2.20 20 [2H, m, C11H2; 1H, m,
11eq
C7H2; 1H, m, C8H; 1H, m, C9H]; 0.83, 0.71 [3H, d, J10-9
/
C12H; 2H, m, C13H2; 2H, m, C14H2; 1H, m, C15H; 1H, m,
C16H]; 0.83, 0.70 [3H, d, J17-16/J18-16 = 6.00, 7.20 Hz,
C17H3/C18H3]; 0.81 [3H, d, = 9.00 Hz,]; 0.83 [3H, d, J19-
J11-9 = 6.60, 7.20 Hz, C10H3/C11H3]; 0.86 [3H, d, J12-
= 6.00 Hz, C12H3]. 13C NMR (CDCl3): 39.5 [C1]; 69.6
5
[C2]; 78.3 [C3]; 41.3 [C4]; 30.5 [C5]; 33.6 [C6]; 21.4 [C7];
47.3 [C8]; 26.7 [C9]; 19.9, 15.2 [C10/C11]; 22.3 [C12]. IR:
3,205 m(N–H).
= 5.90 Hz, C19H3]; 2.80 [1H, tt, C20H]; 1.15 [3H, d,
12
C21H3/C22H3,]. 13C NMR (CDCl3): 174 [C1]; 158 [C2]; 122
[C3]; 135 [C4]; 127 [C5]; 137 [C6]; 107 [C7]; 68.5 [C8]; 37.8
[C9];78.6[C10];39.5[C11];30.5 [C12];33.5[C13];22.6 [C14];
47.2 [C15]; 24.7 [C16]; 19.9, 15.5 [C17/C18]; 22.9 [C19]; 39.8
[C20]; 24.6, 24.5 [C21/C22]. IR: 3,295 m(N–H); 1,635, 1,593
m(C=O); 1,513 m(C=C).
Synthesis of 2-menthoxyethylamino-cyclohept-2,4,6-
trien-1-one.H2O (11)
2-Menthoxyethylamino-cyclohept-2,4,6-trien-1-one.H2O
(11) was prepared by reacting 2-menthoxyethylamine (10)
(1.00 g, 5.03 mmol), two equivalents of triethylamine
(0.93 mL, 6.67 mmol) and 2-p-toluenesulfonyltropolone
(0.92 g, 3.33 mmol) in DMSO (50 mL). This mixture was
stirred for 1 week at room temperature. After completion
of the reaction, the reaction mixture was dissolved in water
and the two layers were separated using diethyl ether. The
organic layer was washed with water, dried over magne-
sium sulphate, filtered, and rotary evaporated to obtain a
brown oil. Concentrated HCl was added dropwise to this
mixture until the pH reached 1. This was extracted with
diethyl ether and washed with water (2 9 50 mL), dried
over magnesium sulphate, filtered, and rotary evaporated to
yield a brown oil (0.96 g; 60 %). Analysis for (11): Found
[calc. C19H31O3N]: C 71.2 (71.0); H 9.9 (9.7); N 4.4
Synthesis of copper compounds
The method described by us previously [17] was adapted to
prepare (13)–(21). A solution of the appropriate ligand in
water/ethanol mix (1:1) was added to a well-stirred solu-
tion of copper(II) acetate in water/ethanol mix (1:1). After
stirring for 2 h, the solution was refluxed and stirred for
another 2 h and then left at room temperature.
Cu(2-methylaminotroponate)2 (13)
A dark green solid was obtained using (1) (0.81 g,
5.99 mmol) and copper acetate (0.60 g, 2.99 mmol). Yield
99 % (0.98 g). Recrystallisation was from ethanol. Ana-
lysis for (13): Found [calc. for C16H16N2O2Cu]: C 57.9
(57.9); H 4.86 (4.82); N 8.40 (8.44) %. IR: 1,596, 1,569
t(C=O); 1,518 t(C=C).
1
(4.4) %. H NMR (CDCl3): 7.20–6.38 [5H, m, C3H, C4H,
C5H, C6H, C7H]; 3.55 [1H, t, NH]; 3.32–3.90 [4H, m,
C8H2, C9H2]; 3.01 [1H. ddd, J10-11ax = J10-15 = 10.5, J10-
= 4.50 Hz, C10H]; 1.15-2.20 [2H, m, C11H2; 1H, m,
11eq
C12H; 2H, m, C13H2; 2H, m, C14H2; 1H, m, C15H; 1H, m,
C16H]; 0.82, 0.70 [3H, d, J17-16/J18-16 = 6.60, 7.50 Hz,
C17H3/C18H3]; 0.85 [3H, d, J19-12 = 6.30 Hz, C19H3]. 13C
NMR (CDCl3): 177 [C1]; 156 [C2]; 123 [C3]; 137 [C4]; 129
[C5]; 137 [C6]; 108 [C7]; 66.3 [C8]; 40.8 [C9]; 80.3 [C10];
43.5 [C11]; 31.9 [C12]; 34.8 [C13]; 21.8 [C14]; 48.6 [C15];
Cu(2-ethylaminotroponate)2 (14)
Following the same procedure using (2) (0.40 g,
2.68 mmol) and copper acetate (0.27 g, 1.34 mmol), (14)
was obtained. Recrystallisation from chloroform yielded
green crystals (0.46 g, 95 %) suitable for X-ray analysis.
123

Transition Met Chem
Analysis for (14): Found [calc. for C18H20N2O2Cu]: C 60.1
(60.0); H 5.7 (5.6); N 7.7 (7.8) %. IR: 1,595, 1,540
t(C=O); 1,513 t(C=C).
C38H56O4N2Cu]: C 68.1 (68.3); H 8.4 (8.4); N 4.1 (4.2) %.
IR: 1,592, 1,572 m(C=O); 1,509 m(C=C).
Synthesis of Cu(2-menthoxyethylamino-4-i-
propyltroponate)2ꢀH2O (21)
Cu(2-n-propylaminotroponate)2 (15)
Using the above methodology with (3) (0.55 g, 2.56 mmol)
added to copper acetate (0.26 g, 1.28 mmol). Following
this, a green solid was obtained (0.55 g, 86 %). Analysis
for (15): Found [calc. for C20H24N2O2Cu]: C 63.1 (63.5); H
4.8 (4.9); N 5.8 (5.7) %. IR: 1,597, 1,570 t(C=O); 1,516
t(C=C).
In a manner similar to that described for (20), (12) (1.00 g,
2.75 mmol) was reacted with copper(II) acetate (0.29 g,
1.45 mmol). A dark green precipitate was produced on
standing. Crystals wereobtained fromhot toluene, but were too
small for crystallographic analysis. Analysis for (21): Found
[calc. C44H70O5N2Cu]: C 68.4 (68.6); H 9.0 (9.1); N 3.4 (3.6).
IR: 3,200 m(O–H); 1,595, 1,570 m(C=O); 1,511 m(C=C).
Cu(2-benzylaminotroponate)2 (16)
Using the above methodology with (4) (0.29 g, 1.37 mmol)
and copper acetate (0.14 g, 0.68 mmol). A green solid was
obtained (0.32 g, 95 %). Analysis for (16): Found [calc. for
C28H24N2O2Cu]: C 68.9 (69.5); H 5.1 (5.0); N 5.8 (5.8) %.
IR: 1,593, 1,570 t(C=O); 1,513 t(C=C).
X-ray crystallography
Experimental details relating to the single-crystal X-ray
crystallographic studies are summarised in Table 1. For all
structures, data were collected on a Nonius Kappa CCD
diffractometer at either 150(2) (5, 20) or 170(2) K (14) using
Cu(2-n-butylaminotroponate)2 (17)
Table 1 Crystallographic data for 5, 14 and 20
A green solid was obtained using (5) (0.46 g. 2.59 mmol)
and copper acetate (0.26 g, 1.29 mmol). Yield 0.46 g,
86 %. Analysis for (17): Found [calc. for C22H28N2O2Cu]:
C 63.2 (63.5); H 6.8 (6.7); N 6.8 (6.7) %. IR: 1,597, 1,569
t(C=O); 1,515 t(C=C).
Compound
reference
5
14
20
Chemical formula
Formula mass
C14H13NO C18H20CuN2O2 C38H56CuN2O4
211.25
359.90
668.38
Crystal system
Monoclinic Monoclinic
Monoclinic
17.9475(9)
5.2632(2)
19.2602(9)
101.034(2)
1,785.71(14)
150(2)
˚
a/A
5.5780(1)
9.3640(2)
9.9188(5)
5.1220(1)
Cu(2-methylamino-4-i-propyltroponate)2 (18)
˚
b/A
˚
c/A
20.8230(3) 17.0174(6)
95.0710(9) 115.424(3)
1,083.38(3) 780.83(5)
A green solid was obtained (0.21 g, 42 %) from (6)
(0.50 g, 2.82 mmol) added to copper acetate (0.28 g,
1.41 mmol). Analysis for (18): Found [calc. for C22H28-
N2O2Cu]: C 63.6 (63.5); H 6.7 (6.7); N 6.5 (6.7) %. IR:
1,606, 1,557 t(C=O); 1,512 t(C=C).
b/°
V/A
3
˚
Temperature/K
Space group
Z
150(2)
P21/c
4
170(2)
P21/c
2
P21
2
No. of reflections
measured
14,213
5,203
17,173
Cu(2-n-propylamino-4-i-propyltroponate)2 (19)
No. of independent 3,152
reflections
2,260
5,971
A green solid was obtained using (7) (0.50 g, 2.44 mmol)
and copper acetate (0.24 g, 1.22 mmol). Yield 0.36 g,
62 %. Analysis for (19): Found [calc. for C26H36N2O2Cu]:
C 66.9 (66.2); H 8.1 (7.6); N 5.7 (5.9). IR,: 1,591, 1,578
t(C=O); 1,512 t(C=C).
Rint
0.0393
0.0534
0.0306
0.0283
0.0961
0.0575
Final R1 values
(I [ 2r(I))
Final wR(F2)
0.1296
0.0795
0.0302
0.0814
1.077
0.1308
0.0736
0.1414
1.060
values (I [ 2r(I))
Final R1 values (all 0.0630
data)
Synthesis of Cu(2-menthoxyethylaminotroponate)2 (20)
Final wR(F2)
values (all data)
0.1342
Using the methodology described earlier for 13–19 [17],
(11) (0.36 g, 1.12 mmol) was reacted with copper(II)
acetate (0.12 g, 0.60 mmol) to produce a dark green pre-
cipitate on standing (0.21 g, 27 %). Recrystallisation from
hot acetone gave pale green crystals suitable for crystal-
lographic analysis. Analysis for (20): Found [calc.
Goodness of fit on 1.122
F2
Flack parameter
-0.014(13)
CCDC
990207
990208
990209
123

Transition Met Chem
˚
Mo-Ka radiation (k = 0.71073 A). Structure solution fol-
the culture finally re-suspended in PBS (2 ml). The optical
density at 610 nm (OD610) was then adjusted to 1.0 using
PBS.
lowed by full-matrix least squares refinement was performed
using the WinGX-1.70 suite of programmes [27], incorpo-
rating SHELXS and SHELXL within the SHELX-2013 suite
of software [28]. Corrections for absorption (multi-scan)
were made in all cases. Specific details: 14: the asymmetric
is one-half of the molecule, and the remainder generated by
an inversion centre located at the metal.
A known weight of compound was dissolved in DMSO to
make a 10 % solution of the active formulation. 200 lL of
this was then added to the bacterial suspension (190 lL) and
left for 1 min. After decanting, the culture was rinsed 3 times
with water (200 lL) and BHI broth (200 lL) was added
followed by mineral oil (80lL), and the resultant incubated
at 37 °C in a Dynatec plate reader. The absorbance at 610 nm
was monitored every fifteen minutes for 18 h, and the time
taken for culture regrowth to return OD610 to 0.5 noted.
Antibacterial activity
Staphylococcus waneri was cultured in BHI broth (100 ml,
Oxoid, UK) for 24 h at 37 °C (20 % CO2), transferred into
centrifuge tubes and spun at 3,500 rpm for 7 min in a
Mistral 1,000 centrifuge. The supernatant was decanted,
and remaining pellet re-suspended in phosphate-buffered
saline (PBS) (5 ml). This process was repeated twice, and
Results and discussion
A range of 2-alkylaminotropones (1–7) were synthesised
from a straightforward reaction between tosylated tropolone
Scheme 1 Protocols for the synthesis of 2-alkylaminotropone ligands
Scheme 2 Synthetic sequence for the formation of menthol-flavoured 2-alkylaminotropone ligands
123

Transition Met Chem
and the appropriate amine (Scheme 1). For those amines that
are commercially available as aqueous solutions (RNH2,
R = Me, Et), the reactions were carried out in CH2Cl2, as
this facilitates separation of the product into the organic
layer. For the remaining amines (R = C3H7, C4H9,
C6H5CH2), the reactions were carried out in DMSO. In the
cases of 6 and 7, tosylated hinokitiol was prepared as a
mixture of isomers (a, b) in the ratio 9:1 [29], which leads to a
mixture of isomeric 2-alkylamino-4-i-propyltropone pro-
ducts; no attempt to separate these isomers was made, and the
mixture was used without further purification. However, this
complication manifested itself in the purification of the al-
kylaminotropone ligands, which proved more challenging
than for 1–5. In the cases of 6 and 7, while the ligand identity
was confirmed by NMR, purification was effected by the
formation of the copper complexes 18 and 19. Related
2-alkylamino-4-i-propyltropones where R = Et, n-Bu, Bz
were impure as prepared, and while the purity of the resulting
copper complexes was enhanced, satisfactory microanalyt-
ical data could not be obtained.
Fig. 1 The asymmetric unit of 5 showing the labelling scheme used
in the text; thermal ellipsoids are at the 50 % level. Selected
geometric data: O(1)–C(1) 1.2573(18), N(1)–C(2) 1.3457(18), N(1)–
C(8) 1.449(2), C(1)–C(7) 1.432(2), C(1)–C(2) 1.485(2), C(2)–C(3)
1.3982(19), C(3)–C(4) 1.398(2), C(4)–C(5) 1.375(2), C(5)–C(6)
In addition to these unfunctionalised substituents, we
have also prepared analogues containing the flavourant,
menthol (Scheme 2). This follows a sequence in which
menthyoxyacetic acid (8) is converted to the acetyl chlo-
ride and then the amide (9) using aqueous ammonia. 9 was
then reduced to the amine (10), a colourless oil, with excess
LiAlH4 [26] and which was in turn used in the protocols of
Scheme 1 to afford the flavourant-functionalised 2-alkyla-
minotropones (11) and (12).
˚
1.398(2), C(6)–C(7) 1.376(2) A, C(2)–N(1)-C(8) 125.09(12), C(2)–
N(1)–H(1) 115.2(13), C(8)–N(1)–H(1) 119.3(13)°. Hydrogen bond:
˚
H(1)–O(1) 2.9601(16), N(1)_O(1) 2.19(2) A, \N(1)–H(1)_O(1)
145.8(17)°. Symmetry operation: 1 - x, - y, - z
though differingfrom the monomeric R0 = t-Bu[32], the latter
structure presumably dictated by packing of the non-planar R0.
˚
Like the other reported dimers, the C=O [1.2573(18) A] and
NMR data for 1–7 are unexceptional, but show the
presence of the amine R0 along with resonances for the
tropone ring in the correct ratios, while data for 11, 12
confirm the linking of the 2-menthoxyethylamine with the
tropolone. Both these compounds, brown oils, were iso-
lated as monohydrates in analytically pure form after
extraction from the reaction mixture; data for the major
isomer (note: Scheme 1) are given in the Experimental.
1–7, 11,12 all show m(NH) and m(C=O) in the ranges
3,293–3,307 and 1,629–1,637 cm-1, respectively, in their IR
spectra. The structure of 5 has also been determined (Fig. 1)
and is that of a N–H_O=C hydrogen-bondeddimer, similarto
analogues with R0 = 2,6-i-Pr2C6H3 [30] and 4-F-C6H4 [31],
˚
C(2)-N(1) [1.3457(11) A] in 5 suggest some lengthening with
respect to the monomeric R0 = t-Bu derivative [1.242(4),
˚
1.348(4) A, respectively] as anticipated [32], though the large
esds in these data preclude definitive comment. The C–C
bonds around the ring between C(2)-C(7) [1.375(2)–
˚
1.398(2) A] evidence delocalisation, while the two C–C(1)
bonds are notably longer [C(1)-C(2) 1.485(2), C(1)-C(7)
˚
1.432(2) A]. Thenitrogenatomshowsadegreeofplanarityvia
its bond angles [115.2(13)°–125.09(12)°] implying delocali-
sation of the lone electron pair.
Copper derivatives (13–21) of the aminotropones
described above were prepared by reaction of the above
123

Transition Met Chem
Fig. 4 Antibacterial activity of new copper 2-alkylaminotroponate
complexes 13, 17, 20 and 21 along with bis(ethylmaltolato) copper(II)
[16] and a commercial toothpaste (Signal) for comparison. The plot
shows the time taken for a culture of Staphylococcus waneri to
regrow to half its original size after treatment with the agent
Fig. 2 The asymmetric unit of 14 showing the labelling scheme used
in the text; thermal ellipsoids are at the 50 % level. Selected
geometric data: Cu–O 1.9322(9), Cu–N 1.9366(10), O–C(3)
1.2945(15), NC(1) 1.4623(15), NC(4) 1.3250(15); O–Cu–O0 180,
O–Cu–N 82.35(4), NCu-N0 180, O–Cu–N0 97.65(4)°. Symmetry
operation: 1 - x,1 - y,1 - z
ligands with Cu(II) acetate in aqueous ethanol:
Cu–N bond lengths (Figure captions) are similar to those in
13 reported by others [18]. All three copper aminotropones
˚
show a general lengthening of the C=O by ca. 0.04 A on
The products are green solids, in which the IR m(C=O)
stretch has shifted 30–70 cm-1 to lower wavenumber,
indicating C=O?Cu coordination. Furthermore, m(NH) is
absent in all these complexes, which, in the case of 21, a
combination of microanalysis and a broad m(OH) observed
in the IR at 3,200 cm-1 suggest is a monohydrate.
complexation, while the NC(ring) bond contracts by ca.
˚
0.02 A, though in 20 these two C–N bonds are tending
˚
towards distinction [1.319(8), 1.340(9) A], again reflecting
the lower symmetry of the species; the nitrogen remains
essentially planar in all cases. In the lattice, both 14 and 20
adopt a ‘‘slipped stack’’ arrangement with a p–p separation
˚
The structures of both 14 (Fig. 2) and 20 (Fig. 3) have
been determined. The structures of both compounds adopt
four-coordinate square-planar geometry as seen in the only
other simple analogous copper compound reported to date
(R0 = Me) [18], though examples with R0 = Et along with
further functionalisation of the seven-membered ring [5-
C5H4FeC5H5] also adopt this arrangement [19]. In the case
of 14, the molecule is centrosymmetric about an inversion
centre at the metal, while 20 lacks this symmetry by virtue
of the flexible pendant group on nitrogen. The Cu–O and
of ca. 4.2 A.
The antibacterial activity of 13, 17, 20 and 21, along
with data for the bis(ethylmaltol)copper complex [16] for
comparison, is shown in Fig. 4. This single species biofilm
assay (against Staphylococcus waneri) is an in vitro model
of plaque inhibition effects. The results obtained from this
test reflect the antibacterial activity of the complexes and
are plotted as graphs of absorbance at 610 nm against time,
which shows the delay in biofilm regrowth after treatment.
From this, the time taken to return to an OD610 of 0.5 is
Fig. 3 The asymmetric unit of
20 showing the labelling
scheme used in the text; thermal
ellipsoids are at the 50 % level.
Selected geometric data: Cu–
O(1) 1.931(5), Cu–O(3)
1.923(5), Cu–N(1) 1.926(6),
Cu–N(2) 1.929(6), O(1)-C(1)
1.304(9), O(3)–C(21) 1.297(8),
N(1)–C(7) 1.317(8), N(2)–
C(27) 1.340(9); O(1)–Cu–O(3)
179.7(2), O(1)–Cu–N(1)
82.3(2), O(1)–Cu–N(2) 96.8(2),
O(3)–Cu–N(1) 98.0(2), O(3)–
Cu–N(2) 82.9(2), N(1)–Cu–
N(2) 178.6(3)°
123

Transition Met Chem
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Figure 4 shows that all four 2-alkylaminotropones are more
effective than the formulation in an commercial toothpaste,
though none are as active as the copper derivative of eth-
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Supplementary information
CCDC 990207–990209 contains the supplementary crys-
tallographic data for this paper (Table 1). These data can
be obtained free of charge from The Cambridge Crystal-
lographic Data Centre via www.ccdc.cam.ac.uk/data_
request/cif.
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