A simple synthesis of di(uracilyl)aryl methanes and 1,ω-bis[di(uracilyl)methyl]benzenes

Article abstract of DOI:10.1016/j.tetlet.2006.09.158

Di(uracilyl)aryl methanes and their homologues, 1,ω-bis[di(uracilyl)methyl]benzenes, have been synthesized in good yields through the HBr-acetic acid catalyzed condensation of 1-alkyl-/1,3-dialkyluracil derivatives with readily available aryl aldehydes and dialdehydes.

Full text of DOI:10.1016/j.tetlet.2006.09.158

Tetrahedron Letters 47 (2006) 8483–8487
A simple synthesis of di(uracilyl)aryl methanes
and 1,x-bis[di(uracilyl)methyl]benzenes
*
Subodh Kumar, Vaishalli Malik, Navneet Kaur and Kuljit Kaur
Department of Chemistry, Guru Nanak Dev University, Amritsar 143 005, India
Received 26 July 2006; revised 18 September 2006; accepted 28 September 2006
Abstract—Di(uracilyl)aryl methanes and their homologues, 1,x-bis[di(uracilyl)methyl]benzenes, have been synthesized in good
yields through the HBr–acetic acid catalyzed condensation of 1-alkyl-/1,3-dialkyluracil derivatives with readily available aryl alde-
hydes and dialdehydes.
ꢀ
2006 Elsevier Ltd. All rights reserved.
The chemistry of diaryl and triarylmethane (TAM)
derivatives has witnessed a rapid growth because of
bilize these strands. The metal ion–p interactions of the
heterocyclic rings and charge–electron interactions with
the heteroatoms of nucleic bases lead to the stabilization
of single strands and stimulate their catalytic pro-
1
the interesting properties associated with their deriva-
tives. The classical chemistry of dyes relies mainly on
the triarylmethyl core because of its brilliant colours
and high tinctorial strength, whereas the acid-labile
nature of the trityl group has made it a very useful
1
0,11
cesses.
Advances in X-ray structure resolutions have
provided further an insight into the nucleic base–metal
ion interactions.
2
protecting group for nucleosides, carbohydrates, etc. A
number of TAM derivatives have found medicinal appli-
cations. Phenol derivatives of TAM exhibit antitumour
activity and inhibitory activity towards histidine protein
However, the synthesis of triarylmethanes based on ura-
1
2
cil derivatives has not attracted attention. The avail-
ability of such scaffolds is expected to provide many
new entities for supramolecular interactions. Herein,
we report a general synthetic approach for the synthesis
of di(uracilyl) methanes, di(uracilyl)aryl methanes and
1,x-bis[di(uracilyl)methyl]benzenes. It is noteworthy
that the condensations of electron-rich enamines,
namely indoles and pyrroles with aldehydes to give het-
eroarylmethanes are well documented. In contrast, this
manuscript provides a first general protocol where the
electron-deficient enamine moiety of uracil can be read-
ily used to achieve similar di(uracilyl)aryl methanes and
their homologues.
3
kinase. Malachite Green has long been used to control
fungal and protozoan infections in fish and it shows
4
selective phototoxicity towards tumour cells. The cat-
ion complexing ability of Malachite Green-based crown
ether has found application in the ionic-conductivity
5
switching of composite films.
Tri-heteroaryl or mixed heteroaryl methanes, due to the
presence of heteroatoms like O, S, N or their combina-
tions in the aryl ring provide additional binding sites
6
and chemical pliability, which has been advantageously
7
used for obtaining supramolecular architectures.
1-Benzyluracil (1) on heating with paraformaldehyde
Amongst heterocycles, pyrimidine-2,4(1H,3H)-diones
(0.5 equiv) in HBr–acetic acid (33%) in an oil bath at
are the most versatile for creating supramolecular archi-
tectures both in living systems and synthetic models.
8
9
O
N
O
O
N
The H-bonding interactions in the Watson–Crick mod-
HN
NH
HN
(i)
8
el provide the basis of double/multiple strand DNA
+ (CH2O)n
O
N
O
O
and the metal ion interactions of phosphate groups sta-
R
R
R
1
a -1g
2a - 2g
*
Corresponding author. Tel.: +91 183 2258802; fax: +91 183
258820; e-mail: Subodh_gndu@yahoo.co.in
2
Scheme 1. Reagent and condition: (i) HBr–acetic acid (33%), 120 ꢁC.
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.09.158

8484
S. Kumar et al. / Tetrahedron Letters 47 (2006) 8483–8487
Table 1. Synthesis of di(uracilyl)methanes
120 ꢁC provided 2a (75%), mp 260 ꢁC, FAB mass m/z
+
13
1
4
16 (M ) (Scheme 1). In its H NMR spectrum, the
Entry Substrate 1
Product 2 (yield %)
presence of two 2H singlets at d 3.29 and d 7.88, respec-
tively, due to the methylene group and C-6H of uracil
shows the connectivity of the methylene carbon with
two uracil moieties at C-5 and along with other data
O
O
O
HN
HN
NH
O
N
O
N
1
N
O
1
3
(
C NMR, elemental analysis) corroborates structure
a.
2
1
a
2a (75)
Similarly, 1-substituted uracils 1b–g under the identified
reaction conditions gave di(uracilyl)methanes 2b–g
O
N
O
N
O
(
Table 1). The presence of an electron-withdrawing
HN
HN
NH
CH COOEt group at N-1 in 1h restricted its reactivity
2
towards paraformaldhyde and only hydrolyzed uracil
derivative 1i was isolated.
2
O
O
N
2b (68)
O
O
H C
3
CH3
CH3
1
b
In order to extend these reactions towards the synthesis
of diheteroaryl aryl methane derivatives, the reactions
of 1 with various aryl aldehydes were investigated. Stir-
ring a solution of 1a in HBr–acetic acid (33%) with p-
nitrobenzaldehdyde at 120 ꢁC gave 4a as a yellow solid,
O
O
HN
HN
NH
3
O
N
O
N
+
N
O
mp 236 ꢁC, FAB mass m/z 537 (M ) (Scheme 2 and
H C(H C)
(CH ) CH3
Table 2, entry 1). Similarly, ortho- and meta-nitrobenz-
aldehydes and benzaldehdyde underwent condensa-
tion with 1a at 120 ꢁC to provide 4b–d in 70–72%
yields (Table 2). However, 1a on reaction with p-meth-
oxybenzaldehyde at 120 ꢁC gave 4e (65%). The forma-
tion of 4e could be presumed to proceed through either
formation of 4f and subsequent demethylation or
demethylation of 3f and condensation with 1a or
through both. Compound 4e could also be obtained
by condensation of 1a with p-hydroxybenzaldehyde
(
CH ) CH
3
2
6
2 6
2
6
3
2
O
N
c (70)
1
c
O
N
O
HN
HN
NH
4
O
O
N
O
H C(H C)
(CH ) CH3
2 10
3
2
10
(
CH2)10CH3
2
d (72)
1
d
3
e (68%). On reaction of 1a with 3f at 60 ꢁC, 4f
(72%) was isolated. 1,3-Dimethyl-5-formyluracil (3h)
O
N
O
N
O
N
underwent facile condensation with 1a to give unsym-
metrical tris(uracilyl)methane 4l, 70%. However, the
aliphatic aldehydes CH CHO (CH ) CHO and
HN
HN
NH
3
3 2
5
O
O
O
(
CH ) CHO, presumably due to their instability under
3 3
(
CH2)16CH
H
3
C(H
2
C)16
(CH ) CH3
2 16
3
the reaction conditions, failed to provide the respective
derivatives of 4 and unreacted 1a was recovered. Com-
pounds 2 and 4 could be obtained on 5 g scale and did
not require chromatography for purification. Pure
samples were obtained through crystallization.
2
e
(70)
1
e
O
O
N
O
N
H C
3
H
3
C
CH3
O
N
N
6
Keeping in mind that the presence of a fluorescent group
on the methylene bridge of di(uracilyl)methane deriva-
tives 4, could provide a simple means for investigating
their interactions, we planned to synthesize fluorescent
derivatives of 4. The reaction of 1a with naphthalene-
O
N
CH3
O
N
CH3
CH
3
1f
2f (70)
2
2
-aldehyde in HBr–acetic acid gave 4g (82%); mp
10 ꢁC.
O
N
O
N
O
N
H
3
C(H
2
C)
6
N
N
(CH2)6CH3
H
3
C(H
2
C)
6
N
7
O
O
(CH ) CH
O
H
3
C(H
2
C)
6
H
3
2 6
C(H C)
2
6
3
X
1
g
2
g (65)
O
H
O
N
O
N
O
HBr - acetic acid (33%)
O
N
NH
O
N
HN
HN
+
20 o
1
C
HN
N
O
HN
O
O
X
8
O
O
3
a-3g
4a-4g
COOCH CH
COOH
1
a
2
3
1
i (95)
1
h
Scheme 2.

S. Kumar et al. / Tetrahedron Letters 47 (2006) 8483–8487
Table 2. Synthesis of di (uracilyl)aryl methanes (4)
8485
Entry Aldehyde
Uracil Product 4 (yield, %)
Entry Aldehyde
Uracil Product 4 (yield, %)
NO2
O
H
O
H
O
N
O
N
O
N
O
N
NH
1
1a
HN
NH
7
1a
HN
O
O
O
O
NO2
3
a
3g
4
a (80)
4g (82)
NO2
O
O
H
O
H
O
N
O
O
HN
NH
O
2
1a
8
1b
HN
NH
O
N
NO2
O
N
N
O
3
b
3
3
3
g
H C
3
CH3
4
b (72)
4h (70)
NO2
O
O
H
O
H
O
N
O
O
NO2
HN
NH
O
3
1a
9
1c
HN
NH
O
N
O
N
N
O
3
c
g
H C(H C)
3
(CH ) CH3
2 6
2
6
4
c (70)
4
i (72)
O
H
O
H
O
N
O
N
O
N
O
HN
NH
4
1a
10
1f
H
3
C
CH
3
N
N
O
O
O
N
O
3
d
g
CH
3
CH
3
4
d (70)
4
j (70)
OH
O
H
O
H
O
N
O
N
O
N
O
N
5
1a
HN
NH
11
1g
H C(H C)
6
N
(CH ) CH
2 6 3
3
2
O
O
OH
3e
O
N
O
3g
H C(H C)
(CH ) CH3
2 6
3
2
6
4k (68)
4e (68)
OCH3
O
Me
N
Me
N
O
H
O
H
O
O
O
N
O
Me
O
O
N
O
HN
NH
NH
6
1a
12
1a
HN
N
Me
O
N
O
N
O
OCH3
O
N
3h
3f
4
f (72)
4l (70 )
The reactions of 1- and 1,3-disubstituted uracils with
naphthalene-2-aldehyde gave the respective di(uracil-
yl)-2-naphthylmethanes 4h–k in 68–72% yields (Table
2, entries 7–11). The reaction of anthracene-9-aldehyde

8486
S. Kumar et al. / Tetrahedron Letters 47 (2006) 8483–8487
R
R
32, 170–180; (c) Duxbury, D. F. Chem. Rev. 1993, 93, 381–
33.
4
O
N
N
O
2
. (a) Abarca, B.; Asensio, G.; Ballesteros, R.; Varea, T. J.
Org. Chem. 1991, 56, 3224–3229; (b) Nair, V.; Abhilash,
K. G.; Vidya, N. Org. Lett. 2005, 7, 5857–5859; (c) Reese,
C. B.; Yan, H. Tetrahedron Lett. 2001, 42, 5545–5547; (d)
Chakrabarty, M.; Sarkar, S. Tetrahedron Lett. 2002, 43,
HN
NH
O
O
H
H
O
N
O
O
O
O
(
i)
HN
+
1
351–1353; (e) Noack, A.; Schroder, A.; Hartmann, H.
O
HN
NH
Dyes Pigments 2002, 57, 131–147.
R
3. Yamato, M.; Hashigaki, K.; Yasumoto, Y.; Sakai, J.;
Luduena, R. F.; Banerjee, A.; Tsukagoshi, S.; Tashiro, T.;
Tsuruo, T. J. Med. Chem. 1987, 30, 1897–1900.
4. (a) Kandela, I. K.; Bartlett, J. A.; Indig, G. L. Photochem.
Photobiol. Sci. 2002, 1, 309–314; (b) Cho, B. P.; Yang, T.;
Blankenship, L. R.; Moody, J. D.; Churchwell, M.;
Beland, F. A.; Culp, S. J. Chem. Res. Toxicol. 2003, 16,
285–294.
. (a) Kimura, K.; Mizutani, R.; Yokoyama, M.; Arakawa,
R.; Matsubayashi, G.-E.; Okamoto, M.; Doe, H. J. Am.
Chem. Soc. 1997, 119, 2062–2063; (b) Kimura, K.;
Kaneshige, M.; Yokoyama, M. Chem. Mater. 1995, 7,
945–950.
O
N
N
O
1
a, 1c, 1d, 1e
5
O
N
O
H
R
R
6
a, 6c, 6d, 6e
R
N
(
i)
(
i)
O
O
R
9
7
H
R
R
R
5
6
7
O
O
N
N
O
N
HN
O
N
N
R
R
R
R
N
O
O
O
O
O
. (a) Matsumoto, K.; Nakaminami, H.; Sogabe, M.; Kurata,
H.; Oda, M. Tetrahedron Lett. 2002, 43, 3049–3052; (b)
Nair, V.; Thomas, S.; Mathew, S. C. Org. Lett. 2004, 6,
N
O
OO
N
H
HN
NH
N
R
N
R
R
3
513–3515; (c) Nair, V.; Thomas, S.; Mathew, S. C.; Vidya,
O
N
O
O
N
N
O
N.; Rath, N. P. Tetrahedron 2005, 61, 9533–9540.
. (a) Kurata, H.; Nakaminami, H.; Matsumoto, K.;
Kawasa, T.; Oda, M. Chem. Commun. 2001, 529–530;
R
R
8
a, 8c, 8d, 8e
10a, 10c, 10d, 10e
(
b) Rudzevich, Y.; Rudzevich, V.; Sehollmeyer, D.;
Scheme 3. In 6, 8, 10: a, R = C
R = CH (CH CH ; e, R = CH
i) HBr–acetic acid (33%); 120 ꢁC.
6
H
5
; c, R = CH
2 2 5 3
(CH ) CH ; d,
Thondorf, I.; Bohmer, V. Org. Lett. 2005, 7, 613–616.
8. Watson, J. D.; Crick, F. H. Nature 1953, 171, 737.
9. (a) Sessler, J. L.; Jayawickramarajah, J. Chem. Commun.
2
2
)
9
3
2
2
(CH )
15CH . Reagent and condition:
3
(
2
005, 1939–1949; (b) Sherrington, D. C.; Taskinen, K. A.
with 1a in HBr–acetic acid resulted in deformylation of
the aldehyde and the respective di(uracilyl) anthracenyl
methane was not isolated.
Chem. Soc. Rev. 2001, 30, 83; (c) Conn, M. M.; Rebek, J.,
Jr. Chem. Rev. 1997, 97, 1647; (d) Rauter, H.; Hillgeris, E.
C.; Erxleben, A.; Lippert, B. J. Am. Chem. Soc. 1994, 116,
6
16–624; (e) Navarro, J. A. R.; Janik, M. B. L.; Freisinger,
E.; Lippert, B. Inorg. Chem. 1999, 38, 426–432; (f) Lippert,
B. Coord. Chem. Rev. 2000, 200–202, 487–516; (g) Hocek,
M.; Stara, I. G.; Dvorakova, H. Tetrahedron Lett. 2001,
The reactions of 1-alkyluracils with terephthaldehdye
gave 1,4-bis[di(uracilyl)methyl]benzenes 6a and 6c–e.
Similarly, reaction of isophthaldehyde with 1-alkyl-
uracils gave 1,3-bis[di(uracilyl)methyl]benzenes 8a and
4
2, 519–521; (h) Havelkova, M.; Dvorak, D.; Hocek, M.
Tetrahedron 2002, 58, 7431–7435.
8
c–e. The presence of an alkyl substituent at N-3 of ura-
10. Mcfail-Isom, L.; Shui, X.; Williams, L. D. Biochemistry
1998, 37, 17105–17111.
11. Tominaga, M.; Konishi, K.; Aida, T. J. Am. Chem. Soc.
cil did not affect its reactivity towards aryl dialdehydes.
The condensation of 1,3-dialkyluracils (9) with terephth-
aldehyde gave compounds 10a and10c–e (Scheme 3).
1
999, 121, 7704.
1
2. (a) Lam, B. L.; Pridgen, L. N. J. Org. Chem. 1986, 51,
2592–2594; (b) Kinoshita, T.; Konodo, M.; Tanaka, H.;
Furukawa, S. Synthesis 1986, 859–862.
Thus, the condensation of readily available14 1-alkyl-,
and 1,3-dialkyluracil derivatives with aromatic alde-
hydes and dialdehydes provides a versatile approach
for the synthesis of di(uracilyl)aryl methanes and their
homologues Significantly, their synthesis in multigram
quantities, ease of purification through crystallization
and their high yields are advantages.
1
3. General procedure: 1-alkyl- or 1,3-dialkyl uracil derivatives
1
were heated in an oil bath at 120 ꢁC with the aryl
aldehyde (0.5 equiv) (3) or 1,x-dialdehyde (0.25 equiv) (5
or 7) in HBr–acetic acid (33%). On completion, the
reaction mixture was cooled to room temp. and was
poured onto ice. The solid that separated was filtered and
was crystallized from CH
afford pure compounds.
3 3
CN or CH CN–ethanol to
Acknowledgement
Di(uracilyl)methane 2c, white solid; 70%; mp 83 ꢁC
+ + 1
(
CH
(300 MHz, CDCl
.28 (br s, 24H, 12 · CH ), 3.27 (s, 2H, C5-CH ), 3.69 (t,
3
CN); FAB mass M m/z 460 (M ); H NMR
We thank the CSIR and the DST, New Delhi (FIST and
project SR/SI/OC-08/2003), for financial assistance.
3
): d 0.88 (t, J = 6.9 Hz, 6H, 2 · CH ),
3
1
2
2
J = 6.9 Hz, 4H, 2 · N1–CH
2
), 7.43 (s, 2H, C6-H), 8.78 (s,
H, 2 · NH); C NMR (normal/DEPT-135) (75 MHz,
CDCl ): d 14.1 (+ve, CH
1
3
2
3
3
), 22.6 (Àve, CH ), 23.6 (Àve,
2
References and notes
CH ), 26.4 (Àve, CH ), 29.1 (Àve, CH ), 31.7 (Àve, CH ),
2
2
2
2
4
1
8
8.8 (Àve, CH
2
), 110.4 (absent, ArC), 143.3 (+ve, C6-H),
1
. Recent reviews: (a) Nair, V.; Thomas, S.; Mathew, S. C.;
Abhilash, K. G. Tetrahedron 2006, 62, 6731–6747; (b)
Shchepinov, M. S.; Korshun, V. A. Chem. Soc. Rev. 2003,
50.7 (absent, CO), 164.2 (absent, CO). Found C 65.28; H
.70; N 12.10. C H N O requires C 65.19, H 8.75; N
25 40
4
4

S. Kumar et al. / Tetrahedron Letters 47 (2006) 8483–8487
8487
1
7
2.16%. Di(uracilyl) 2-naphthyl methane 4i, white solid; 1,4-bis[di(uracilyl)methyl benzene 6c, white solid; 60%;
+
+
+
+
1
2%; mp 130 ꢁC (CH
3
CN); FAB mass M m/z 586 (M );
mp 245 ꢁC(CH
3
CN); FAB mass M m/z 994 (M ); H
1
H NMR (300 MHz, CDCl ): d 0.85 (t, J = 6.5 Hz, 6H,
NMR (300 MHz, CDCl ): d 0.87 (t, J = 6.9 Hz, 12H,
3
3
2
· CH
3
), 1.23 (br s, 24H, 12 · CH
), 3.51 (s, 1H, C5-CH), 7.13 (s, 2H, C6-
2
), 3.64 (t, J = 6.2 Hz,
4 · CH
8H, 4 · N1–CH ), 5.12 (s, 2H, 2 · C5-CH), 7.15 (s, 4H,
13
3
2
), 1.26 (br s, 48H, 24 · CH ), 3.68 (t, J = 6.9 Hz,
4
H, 2 · N1–CH
2
2
H), 7.44–7.49 (m, 3H, ArH), 7.61 (s, 2H, ArH), 7.79 (d,
C6-H), 7.22 (s, 4H, ArH), 8.71 (s, 4H, 4 · NH); C NMR
(normal/DEPT-135) (75 MHz, CDCl ): d 14.1 (+ve, CH ),
1
3
J = 8.0 Hz, 2H, ArH), 8.80 (s, 2H, 2 · NH); C NMR
normal/DEPT-135) (75 MHz, CDCl ): d 13.9 (+ve, CH ),
2.5 (Àve, CH ), 26.2 (Àve, CH ), 28.9 (Àve, CH ), 29.0
3
3
(
2
3
3
22.5 (Àve, CH
2
), 26.4 (Àve, CH
2
), 29.1 (Àve, CH
2
), 31.6
2
2
2
(Àve, CH
2
), 32.0 (Àve, CH ), 42.5 (+ve, CH), 49.0 (Àve,
2
(
Àve, CH ), 31.6 (Àve, CH ), 41.0 (+ve, CH), 48.9 (Àve,
CH ), 112.9 (absent, ArC), 121.0 (absent, ArC), 128.2
2
2
2
CH
2
), 113.2 (absent, ArC), 126.0 (+ve ArCH), 126.3 (+ve,
(+ve, ArCH), 137.9 (absent, ArC), 144.8 (+ve, C6-H),
150.7 (absent, CO), 163.5 (absent, CO). Found C 67.48; H
ArCH), 126.5 (+ve, ArCH), 127.5 (+ve, ArCH), 127.9
+ve, ArCH), 128.4 (+ve, ArCH), 129.1 (+ve, ArCH),
32.4 (absent, ArC), 133.3 (absent, ArC), 136.6 (absent,
ArC), 144.7 (+ve, C6-H), 150.6 (absent, CO), 163.3
absent, CO). Found 71.68; 7.85; 9.57.
requires C 71.64, H 7.90; N 9.55.
(
1
8.40; N 11.22. C56
11.26.
82 8 8
H N O requires C 67.58, H 8.30; N
14. (a) Malik, V.; Singh, P.; Kumar, S. Tetrahedron 2005, 61,
4009–4014; (b) Malik, V.; Singh, P.; Kumar, S. Tetra-
hedron 2006, 62, 5944–5951.
(
C
H
N
35 46 4 4
C H N O