A facile three-component solid phase synthesis of steroidal A-ring fused pyrimidines under microwave irradiation

Article abstract of DOI:10.1016/j.steroids.2009.03.006

The preparation of ring-A fused pyrimidines at the steroidal 2,3-position is herein described. The novel steroidal pyrimidines were prepared from the solid phase three-component reaction of 2-hydroxymethylene-3-keto steroids, arylaldehydes and ammonium ac

Full text of DOI:10.1016/j.steroids.2009.03.006

Steroids 74 (2009) 730–734
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Steroids
journal homepage: www.elsevier.com/locate/steroids
A facile three-component solid phase synthesis of steroidal A-ring fused
pyrimidines under microwave irradiation
Madan G. Barthakur, Shyamalee Gogoi, Mandakini Dutta, Romesh C. Boruah∗
Medicinal Chemistry Division, North-East Institute of Science and Technology, Jorhat 785006, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 19 July 2008
Received in revised form 4 March 2009
Accepted 17 March 2009
Available online 28 March 2009
The preparation of ring-A fused pyrimidines at the steroidal 2,3-position is herein described. The
novel steroidal pyrimidines were prepared from the solid phase three-component reaction of 2-
hydroxymethylene-3-keto steroids, arylaldehydes and ammonium acetate under microwave irradiation.
© 2009 Elsevier Inc. All rights reserved.
Keywords:
Heterosteroids
Arylaldehyde
Pyrimidine
Microwave
Ammonium acetate
1. Introduction
importance over two-component reactions in several aspects
such as the simplicity of a one-pot procedure, possible struc-
The pyrimidine heterocyclic core is an important subunit
because of its widespread abundance in the basic structure
tural variations, complicated synthesis and a large number of
accessible compounds [17–19]. In view of the therapeutic impor-
tance of pyrimidines, we were interested to prepare pyrimidine
fused steroids from readily available 2-hydroxymethylene-3-
ketosteroids utilizing multi-component reaction [20]. Herein, we
wish to report a microwave promoted convenient preparation of
steroidal[3,2-b]pyrimidines from the three-component reaction
of 2-hydroxymethylene-3-ketosteroids, arylaldehydes and ammo-
nium acetate.
of numerous natural products [1].
A number of synthetic
pharmacophores based upon the pyrimidyl structure exhibit
antibacterial, antimicrobial, anticancer, anti-HIV-1 and antirubella
virus activities [2–4]. On the other hand, A-ring heterosteroids
are pharmaceutically important compounds due to their inher-
ent biological properties [5,6]. A great deal of attention is being
paid to annelate steroidal moiety with pyrazole, pyridine, isoxazole,
pyrrole rings using various synthetic strategies [7–13]. Neverthe-
less, the effort made towards development of newer synthetic
approaches for A-ring annelated steroidal pyrimidines is still lim-
ited. For example, Clinton and his co-workers have described
the preparation of biologically active steroidal[3,2-b]pyrimidines
from condensation of 2-hydroxymethylene-3-ketosteroids with
acetamidine-hydrochloride [14]. Laitonjam et al. utilized 2-
bis(methylthio) methylene-3-ketosteroid and guanidine nitrate for
the synthesis of A-ring fused steroidal pyrimidine [15]. Recently we
forwarded a microwave promoted facile synthesis of A- and D-ring
annelated pyrimidines from steroidal ␤-formyl enamides and urea
catalysed by Lewis acids [16].
2. Experimental
2.1. General remarks
All reactions were performed as per standard procedure using
silica gel (60–120 mesh, Merck chemicals) and monitored on Merck
aluminium thin layer chromatography (TLC, UV254 nm) plates. Col-
umn chromatography was carried out on silica gel (60–120 mesh,
Merck chemicals). Melting points were determined in open cap-
illary tubes on Buchi B-540 apparatus and are uncorrected. IR
spectra were recorded on a Perkin Elmer FT-IR spectrometer using
KBr pellets or on a thin film using chloroform. All the 1H and
13C NMR spectra were recorded on Brucker Avance DPX 300 MHz
spectrometer using tetramethylsilane (TMS) as internal standard.
Chemical shift values were given as ı (ppm) values. ESI mass
spectra were recorded on a Brucker Daltonic Data Analysis 2.0
spectrometer. Elemental analysis was performed on Perkin Elmer
The multi-component reactions (MCR) attract enormous impor-
tance from the point of combinatorial chemistry and inherit
∗
Corresponding author. Tel.: +91 376 2370121x2355; fax: +91 376 2370011.
E-mail address: rc boruah@yahoo.co.in (R.C. Boruah).
0039-128X/$ – see front matter © 2009 Elsevier Inc. All rights reserved.
doi:10.1016/j.steroids.2009.03.006

M.G. Barthakur et al. / Steroids 74 (2009) 730–734
731
Series II CSNS/O Model 2400 machine calibrated against standard
acetanilide.
113.3, 56.0, 55.1, 54.9, 42.2, 41.1, 39.2, 36.1, 35. 8, 35.5, 34.8, 31.6, 27.7
(2C), 23.9, 23.4, 22.6 (2C), 22.3 (2C), 20.9 (2C), 18.4, 13.3 (2C), 12.5,
11.4. ESI mass m/z = 528 [M+]. Anal calcd for C36H52N2O: C, 81.77;
H, 9.91; N, 5.29. Found: C, 81.59; H, 9.82; N, 5.14.
2.2. Organic synthesis
General procedure for the preparation of 2ꢀ-Aryl-steroidal[3,2-
d]pyrimidine: 2-Hydroxymethylene-3-ketosteroid (1a, 1 mmol),
aromatic aldehyde (2a, 2 mmol) and ammonium acetate (2 mmol)
were intimately mixed with silica gel (60–120 mesh, 2.0 g) in a
mortar and the mixture was irradiated in an open reaction ves-
sel of a Synthwave 402 Prolabo focused microwave reactor for
6 min after setting reaction temperature at 120 ◦C and power at
60% (maximum output 300 W). On completion of reaction (vide
TLC), the reaction mixture was treated with water (50 ml), extracted
with dichloromethane (3 × 30 ml). The organic portion was washed
with water, dried over anhydrous sodium sulfate and the solvent
removed to obtain a crude product. Silica gel column chromatog-
raphy separation using EtOAc/hexane (1:9) as eluant over silica gel
afforded the purified product 3a.
2.2.5. 2ꢀ-Phenyl-(24R)-24-ethyl-5˛-cholest[3,2-d]pyrimidine (3e)
Pyrimidine (3e) was prepared from 1b: White crystals, yield
(426 mg 81%); mp: 170–71 ◦C; IR cm−1: 2957, 1586, 1574, 1546,
1465, 1454, 1424, 759; 1H NMR (CDCl3, 300 MHz) ı 8.41 (s, 1H, aro-
matic proton of pyrimidine), 8.38 (d, 1H, J = 7.20 Hz), 7.57-7.35 (m,
4H, aromatic protons), 2.88-0.88 (m, 42H, alkane protons), 0.85 (s,
3H, 19-CH3), 0.74 (s, 3H, 18-CH3). 13C NMR (CDCl3, 75 MHz): ı 165.0,
161.7, 157.4, 137.7, 129.8, 128.2, 127.6 (2C), 126.9, 125.6, 56.0, 55.9,
53.2, 45.5, 42.1 (2C), 41.1, 39.4 (2C), 36.0, 35.9, 34.7, 33.6, 31.5, 28.8,
28.0 (2C), 25.7, 23.90 23.9, 22.7 (2C), 19.6, 18.8, 18.5, 11.7, 11.4. ESI
mass m/z = 526 [M+]. Anal calcd for C37H54N2: C, 84.35; H, 10.33; N,
5.32. Found: C, 84.52; H, 10.20; N, 5.18.
2.2.6. 2ꢀ-Phenyl-cholest[3,2-d]pyrimidin-4-ene (3f)
Pyrimidine (3f) was prepared from 1c: White crystals, yield
(392 mg 79%); mp: 122–124 ◦C; IR cm−1: 2934, 1586, 1572, 1548,
1492, 1454, 1425, 761; 1H NMR (CDCl3, 300 MHz) ı 8.35 (s, 1H, aro-
matic proton of pyrimidine), 8.17 (d, 1H, J = 6.80), 7.35–7.29 (m, 4H,
aromatic protons), 5.99 (bs, 1H, C4-H), 2.91–0.93 (m, 35H, alkane
protons), 0.85 (s, 3H, 19-CH3), 0.74 (s, 3H, 18-CH3). 13C NMR (CDCl3,
75 MHz): ı 162.3, 157.2, 153.9, 138.0, 128.1, 128.1, 127.97, 127.7, 127.6,
127.5, 126.7, 122.8, 58.0, 56.0, 66.7, 54.3, 42.1 (2C), 39.2 (2C), 38.3,
35.8, 35.5, 34.2, 29.4, 27.7 (2C), 23.6, 22.6 (2C), 22.3 (2C), 18.4, 18.1,
11.7. ESI mass m/z = 496 [M+]. Anal calcd for C35H48N2: C, 84.62; H,
9.74; N, 5.64. Found: C, 84.48; H, 9.90; N, 5.48.
2.2.1. 2ꢀ-Phenyl-5˛-cholest[3,2-d]pyrimidine (3a)
White crystals, yield (398 mg 80%); mp: 169–170 ◦C; IR cm−1
:
2930, 1587, 1575, 1547, 1467, 1454, 1424, 770; 1H NMR (CDCl3,
300 MHz) ı 8.42 (s, 1H, aromatic proton of pyrimidine), 8.37 (d,
1H, J = 6.20 Hz), 7.52–7.14 (m, 4H, aromatic protons), 2.88–0.86 (m,
38H, alkane protons), 0.86 (s, 3H, 19-CH3), 0.75 (s, 3H, 18-CH3).
13C NMR (CDCl3, 75 MHz): ı 165.0, 161.7, 157.4, 137.7, 129.8, 128.2
(2C), 127.6 (2C), 126.9, 56.0, 55.9, 53.2, 42.1, 41.1, 39.4, 39.2, 36.0,
35.5, 35.2, 34.7, 32.3, 28.3, 27.9, 27.7 (2C), 23.9, 23.6, 22.6, 22.3
(2C), 21.0, 18.4, 11.7, 11.4. ESI mass m/z = 498 [M+]. Anal calcd for
C35H50N2: C, 84.28; H, 10.10; N, 5.62. Found: C, 84.48; H, 10.34; N,
5.43.
2.2.7.
2ꢀ-Phenyl-(24R)-24-ethyl-cholest[3,2-d]pyrimidin-4,22-diene
(3g)
2.2.2. 2ꢀ-(p-Tolyl)-5˛-cholest[3,2-d]pyrimidine (3b)
White crystals, yield (435 mg 85%); mp: 174–175 ◦C; IR cm−1
:
Pyrimidine (3g) was prepared from 1d: White crystals, yield
(417 mg 80%); mp: 202–204 ◦C; IR cm−1: 2957, 1586, 1572, 1547,
1492, 1455, 1424, 759; 1H NMR (CDCl3, 300 MHz) ı 8.43 (s, 1H,
aromatic proton of pyrimidine), 8.25 (d, 1H, J = 6.50 Hz), 7.50–7.37
(m, 4H, aromatic protons), 6.07 (bs, 1H, C4-H), 5.18–4.96 (m, 2H,
olefinic protons), 2.99–0.89 (m, 35H, alkane protons), 0.84 (s, 3H,
19-CH3), 0.76 (s, 3H, 18-CH3). 13C NMR (CDCl3, 75 MHz): ı 162.3,
157.2, 153.9, 143.1, 142.7, 138.0, 137.9, 128.1, 128.0, 128.0, 127.7,
127.5, 126.8, 122.8, 58.0, 55.7 (2C), 51.0, 45.4, 42.0 (2C), 41.5, 40.2,
38.3 (2C), 35.5, 34.1, 31.6 (2C), 25.2, 20.9 (2C), 18.7 (2C), 18.1, 12.0,
11.9. ESI mass m/z = 522 [M+]. Anal calcd for C37H50N2: C, 85.00; H,
9.64; N, 5.36. Found: C, 84.88; H, 9.48; N, 5.43.
2931, 1582, 1561, 1541, 1466, 1424, 760; 1H NMR (CDCl3, 300 MHz)
ı 8.40 (s, 1H, aromatic proton of pyrimidine), 8.26 (d, 1H, J = 7.94 Hz),
7.48 (d, 1H, J = 7.95 Hz), 7.26 (d, 1H, J = 7.94 Hz), 7.02 (d, 1H,
J = 7.95 Hz), 2.40 (s, 3H, tolyl methyl), 2.86–0.88 (m, 38H, alkane
protons), 0.86 (s, 3H, 19-CH3), 0.76 (s, 3H, 18-CH3). 13C NMR (CDCl3,
75 MHz): ı 164.9, 161.8, 157.3, 139.9, 135.0, 129.0, 128.5, 127.5, 126.6,
125.6, 56.0, 53.2, 42.1, 41.1, 39.2, 35.9, 35.5, 35.2, 34.7, 31.2, 29.0, 27.9,
27.7 (2C), 23.9, 23.6, 22.6 (2C), 22.3 (2C), 21.2, 21.0, 18.4 (2C), 11.7,
11.4. ESI mass m/z = 512 [M+]. Anal calcd for C36H52N2: C, 84.32; H,
10.22; N, 5.46. Found: C, 84.53; H, 10.45; N, 5.64.
2.2.3. 2ꢀ-(p-Chlorophenyl)-5˛-cholest[3,2-d]pyrimidine (3c)
White crystals, yield (416 mg 78%); mp: 155–56 ◦C; IR cm−1
:
2.2.8. 2-(p-Tolyl)-5,6-dihydro-benzo[h]quinazoline (3h)
2928, 1582, 1560, 1543, 1466, 1426, 786; 1H NMR (CDCl3, 300 MHz)
ı 8.42 (s, 1H, aromatic proton of pyrimidine), 8.33 (d, 1H, J = 7.68),
7.38–7.25 (m, 3H), 2.87–0.88 (m, 38H, alkane protons), 0.86 (s, 3H,
19-CH3), 0.77 (s, 3H, 18-CH3). 13C NMR (CDCl3, 75 MHz): ı 165.1,
161.7, 157.4, 135.8, 128.9 (2C), 128.4 (2C), 127.3, 125.6, 55.9 (2C),
53.2, 41.9, 41.1, 39.5, 39.3, 35.9, 35.5, 35.2, 34.8, 31.2, 27.9, 27.7,
23.9, 23.6, 22.5 (2C), 22.3 (2C), 21.0, 21.0, 18.4, 11.7, 11.4. ESI mass
m/z = 532 [M+]. Anal calcd for C35H49N2Cl: C, 78.84; H, 9.26; N, 5.25.
Found: C, 78.59; H, 9.41; N, 5.15.
Pyrimidine (3h) was prepared from 1e: Light yellow crystals,
yield (0.22 g, 80%); mp: 101–103 ◦C; Rf = 0.4 (EtOAc:hexane = 5:95);
IR (CHCl3): ꢀ 2932, 1585, 1565, 1538, 1432, 1419, 1390, 765 cm−1
.
1H NMR (300 MHz, CDCl3): ı 8.59 (s, 1H, aromatic proton of pyrim-
idine), 8.57–8.43 (m, 2H, aromatic protons), 7.45–7.39 (m, 2H,
aromatic protons), 7.33–7.25 (m, 4H), 3.04–2.92 (m, 4H, alkane pro-
tons), 2.43 (s, 3H, –CH3). 13C NMR (75 MHz, CDCl3): ı 162.9, 158.8,
155.5, 140.1, 139.0, 135.1, 132.5, 130.7, 129.0 (2C), 127.8 (2C), 127.7,
127.0, 125.6, 125.4, 27.3, 24.1, 21.2. MS (ESI): m/z = 273 [M+ + 1]. Anal.
calcd for C19 H16 N2: C, 83.79; H, 5.92; N, 10.29. Found: C, 83.96; H,
5.88; N, 10.30.
2.2.4. 2ꢀ-(p-Anisyl)-5˛-cholest[3,2-d]pyrimidine (3d)
White crystals, yield (465 mg 88%); mp: 162–64 ◦C; IR cm−1
:
2933, 1607, 1584, 1564, 1531, 1509, 1465, 1436, 1417, 1249, 801, 760;
1H NMR (CDCl3, 300 MHz) ı 8.44 (s, 1H, aromatic proton of pyrimi-
dine), 7.63 (d, 1H, J = 8.85), 7.16 (d, 1H, J = 8.60), 6.79 (d, 1H, J = 8.66),
6.74 (d, 1H, J = 8.92), 3.79 (s, 3H, –OMe), 2.90–0.88 (m, 38H, alkane
protons), 0.86 (s, 3H, 19-CH3), 0.70 (s, 3H, 18-CH3). 13C NMR (CDCl3,
75 MHz): ı 165.1, 160.9, 158.1, 136.4, 131.7, 129.6 (2C), 129.1, 125.6,
2.2.9. 2-(p-Tolyl)-5,6,7,8-tetrahydro-quinazoline (3i)
Pyrimidine (3i) was prepared from 1f: Light yellow crystals,
yield (0.17 g, 76%); mp: 67–69 ◦C; Rf = 0.5 (EtOAc:hexane = 5:95);
IR (CHCl3): ꢀ 2923, 1582, 1561, 1531, 1417, 772 cm−1 1H NMR
.
(300 MHz, CDCl3): ı 8.43 (s, 1H, aromatic proton of pyrimidine),
8.40 (d, 1H, J = 7.95 Hz), 7.37–7.16 (m, 3H, aromatic protons), 2.72

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M.G. Barthakur et al. / Steroids 74 (2009) 730–734
Table 1
Synthesis of steroidal and non-steroidal pyrimidines (3a–j) from 2-hydroxymethylene-ketones (1a–g) under microwave irradiationa.
aThe reactions were conducted under microwave for 6–9 min.
bAll 2-hydroxymethyleneketones 1a–g were prepared from corresponding 3-oxosteroids and non-steroidal ketones in 88–96% yields.
cIsolated yields based on starting 2-hydroxymethyleneketones 1a–g.
(m, 2H, alkane), 2.60 (m, 2H, alkane), 2.39 (s, 3H, –CH3), 1.79 (m,
4H, alkane). 13C NMR (75 MHz, CDCl3): ı 161.7, 159.2, 157.4, 139.9,
137.2, 130.0, 129.7, 129.0, 127.7, 126.3, 27.4, 26.1, 21.9, 21.3, 21.1. MS
(ESI): m/z = 224 [M+]. Anal. calcd for C15H16 N2: C, 80.32; H, 7.19; N,
12.49. Found: C, 80.09; H, 7.12; N, 12.56.
2.2.10. 5-Ethyl-2,4-diphenyl-pyrimidine (3j)
Pyrimidine (3j) was prepared from 1g: Yellow gum, yield (0.2 g,
75%); Rf = 0.6 (EtOAc:hexane = 5:95); IR (CHCl3): ꢀ 2927, 1585, 1563,
1532, 1493, 1423, 1025, 753 cm−1 1H NMR (300 MHz, CDCl3): ı
.
8.72 (s, 1H, aromatic proton of pyrimidine), 8.50–8.46 (m, 2H, aro-

M.G. Barthakur et al. / Steroids 74 (2009) 730–734
733
Fig. 1. Synthesis of steroidal pyrimidines 3a from 2-hydroxymethylene-3-ketocholestan 1a.
matic protons), 7.66–7.63 (m, 2H, aromatic protons), 7.52–7.45 (m,
6H, aromatic protons), 2.77 (q, 2H, J = 7.53 Hz, –CH2), 1.20 (t, 3H,
J = 7.53 Hz, –CH3). 13C NMR (75 MHz, CDCl3): ı 165.1, 162.2, 158.2,
138.5, 137.8, 131.6, 130.4, 129.2, 128.9 (2C), 128.5 (2C), 128.4 (2C),
128.1 (2C), 23.1, 15.0. MS (ESI): m/z = 260 [M+].
identical conditions and obtained 2ꢀ-(p-tolyl)-5␣-cholest[3,2-d]
pyrimidine (3b), 2ꢀ-(p-chlorophenyl)-5␣-cholest[3,2-d]pyrimidine
(3c) and 2ꢀ-(p-anisyl)-5␣-cholest[3,2-d]pyrimidine (3d) respec-
tively in 78–88% yields. Similarly, 2ꢀ-Phenyl-(24R)-24-ethyl-5␣-
cholest[3,2-d]pyrimidine (3e), 2ꢀ-Phenyl-cholest[3,2-d]pyrimidin-
4-ene (3f) and 2ꢀ-Phenyl-(24R)-24-ethyl-cholest[3,2-d]pyrimidin-
4,22-diene (3g) were prepared from 2-hydroxymethylene-(24R)-
24-ethyl-cholestan-3-one (1b), 2-hydroxymethylene-cholest-4-
en-3-one (1c) and 2-hydroxymethylene-(24R)-24-ethyl-cholestan-
4,22-dien-3-one (1d) respectively in 79–81% yields.
To extend the scope of the reaction, we employed the three-
component reaction strategy to bicyclic, monocyclic and acyclic
2-hydroxymethylene ketones (1e–g) with 2a–b to afford 2-(p-
tolyl)-5,6-dihydro-benzo[h]quinazoline (3h), 2-(p-tolyl)-5,6,7,8-
tetrahydro-quinazoline (3i), 5-ethyl-2,4-diphenyl-pyrimidine (3j)
in 75–78% yields.
3. Results and discussion
The 2-hydroxymethylene-3-ketosteroids (1a–d) were readily
prepared from 5␣-cholestan-3-one, (24R)-24-ethyl-5␣-cholestan-
3-one, cholest-4-en-3-one and (24R)-24-ethyl-cholest-4,22-dien-
3-one in excellent yields by following a procedure of Weisenborn
et al. [21]. The bicyclic, monocyclic and acyclic 2-hydroxymethylene
derivatives (1e–g) were similarly prepared from 1-tetralone, cyclo-
hexanone and butyrophenone respectively (Table 1).
We carried out the three-component reaction of 2-
hydroxymethylene-3-ketosteroids, using silica gel (60–120 mesh)
as solid phase reaction medium under microwave irradiation and
isolating the product over silica gel by column chromatography.
Under these conditions, 2-hydroxymethylene-cholestan-3-one
(1a) reacted with benzaldehyde (2a) and ammonium acetate
to afford 2ꢀ-Phenyl-5␣-cholest[3,2-d]pyrimidine (3a) in 80%
yield (Fig. 1). The product was characterized by spectral and
analytical analysis. The 1H NMR showed a singlet signal at ı
8.42 due to aromatic proton of pyrimidine ring and absence of
the 2-hydroxymethylene olefinic proton at ı 8.75. The 13C NMR
spectrum of 3a exhibited characteristic aromatic carbon signals at
ı 165.0, 161.7, 157.4, 137.7, 129.8, 128.2, 127.6 and 126.9. The ESI
mass spectrum showed molecular ion peak at m/z 498 (M+).
We examined the feasibility of this synthetic route by carry-
ing three-component reaction of 1a with other aromatic aldehydes
such as p-tolualdehyde (2b), p-chlorobenzaldehyde (2c) and p-
anisaldehyde (2d) in presence of ammonium acetate under
A mechanism is proposed for the formation of pyrimidine
derivatives 3a from three-component reaction of 1a, benzalde-
hyde (2a) and ammonium acetate as shown in Fig. 2. Under the
influence microwave, the 2-hydroxymethylene-3-ketosteroid (1a)
reacted with ammonia, released from decomposition of ammo-
nium acetate, to facilitate amination to afford ␤-aminoketoimine
intermediate A [14]. Condensation of intermediate A with 2a led
to diimine intermediate B which participated in cyclisation reac-
tion by nucleophilic attack of the ketoimine to aldeimine affording
dihydropyrimidine intermediate C with subsequent auto oxidation
to afford 3a.
In conclusion, we have developed an efficient microwave
promoted three-component reaction of 2-hydroxymethylene-3-
ketosteroids, aryldehydes and ammonium acetate for the facile
synthesis of A-ring fused steroidal pyrimidines. The reaction
strategy has been successfully extended to non-steroidal 2-
hydroxymethyleneketone derivatives. The methodology reported
herein represents a new preparation of A-ring fused steroidal
Fig. 2. Proposed mechanism for the formation of pyrimidine derivative 3a.

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M.G. Barthakur et al. / Steroids 74 (2009) 730–734
as well as non-steroidal pyrimidines using easily available 2-
hydroxymethyleneketones as starting materials. The methodology
also provides a facile strategy for A-ring steroidal pyrimidines with
an aryl substitution at 2ꢀ-position.
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Acknowledgements
We thank the Department of Science and Technology, New Delhi
for financial support and CSIR, New Delhi for the award of a fellow-
ship to one of us (MGB). We also thank the Director of this Institute
for his keen interests.
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