Novel 5-dimethylamino-1- and 2-indanyl uracil derivatives

Article abstract of DOI:10.1021/jo0609881

5-Dimethylamino-1-aminoindan undergoes thermal decomposition and reacts with 6-chlorouracil to give 5-indanyl-6-chlorouracil derivative 9. The formation of 9 may be rationalized by a putative mechanism based on the intermediacy of the imminium methide species 8a.

Full text of DOI:10.1021/jo0609881

Novel 5-Dimethylamino-1- and 2-Indanyl Uracil
Derivatives
†
†
‡
Konstantin Ulanenko, Eliezer Falb, Hugo E. Gottlieb, and
,
†
Yaacov Herzig*
Global InnoVatiVe R & D, TeVa Pharmaceutical Industries Ltd.,
Netanya 42504, Israel, and Chemistry Department, Bar Ilan
UniVersity, Ramat Gan 52900, Israel
yaacoV.herzig@teVa.co.il
ReceiVed May 12, 2006
FIGURE 1. General structure of novel indanylaminouracils.
6
derivatives such as rasagiline has been reported. In this context,
we synthesized a series of indanylaminouracils I (Figure 1)
designed to combine the neuroprotective activity of 1-amino-
indans with the antioxidant activity of uracils. These compounds
were found to be moderately active in several MS and irritable
bowel syndrome (IBD) models and were therefore deemed as
potential treatments of autoimmune diseases, specifically MS.7
Herein, we wish to report on a novel reaction between
5
6
-(dimethylamino)-1-aminoindan 8 and 6-chlorouracil to yield
-chloro-5-(5-(dimethylamino)-indan-1-yl)-1H-pyrimidine-2,4-
dione 9 in which a C-C bond between the indan and the uracil
systems was formed via a putative novel imminium methide
intermediate 8a (Scheme 1).
In the framework of our ongoing research on novel indanyl-
aminouracils for the treatment of multiple sclerosis, we prepared
5
-Dimethylamino-1-aminoindan undergoes thermal decom-
position and reacts with 6-chlorouracil to give 5-indanyl-6-
chlorouracil derivative 9. The formation of 9 may be
rationalized by a putative mechanism based on the interme-
diacy of the imminium methide species 8a.
4- and 6-(dimethylamino)-indanylaminouracils I (R ) Me N),
2
whereas attempts to prepare the 5-analogue proved unsuccessful,
affording 9 instead of the expected 5-dimethylamino isomer of
I.
The key intermediates 6 and 8 were prepared from 2- and
The connection between neurodegenerative diseases, such as
Parkinson’s (PD), Alzheimer’s (AD), and multiple sclerosis
1
(
MS), and oxidative stress in the brain is well documented.
1-aminoindan, respectively, by a four-step sequence comprising
In this context, it has been postulated that uric acid (UA)
trifluoroacetylation, nitration, reductive alkylation, and hydroly-
may act as an antioxidant and as one of the human defense
damage repair mechanisms. An interesting observation on the
reduced occurrence of idiopathic Parkinson’s disease (IPD) in
nearly 8000 patients suffering from gout (hyperuricaemia)
provided clinical evidence to the remarkable neuroprotection
8
sis. Nitration of 2 occurred exclusively at position 5 to give,
after N-trifluoroacetylation, 3b in an overall yield of 45%.
Nitration of 1, on the other hand, gave a mixture of regioisomers,
from which we isolated by chromatography the 5-isomer in 5%
yield. Reductive alkylation (hydrogenation over Pd/C in the
presence of paraformaldehyde) gave the dimethylamino deriva-
tives 4 and 5, which were then hydrolyzed to afford 6 and 8,
respectively. Reacting 6 and 8 with 6-chlorouracil in DMSO at
2
conferred by UA. In vitro, UA was found as a scavenger of
•
•- 3
active oxygen radicals (e.g., OH , O2 ) , and in vivo, it pre-
vented the symptoms of experimental autoimmune encephalo-
myelitis (EAE), the mouse model of MS. Moreover, MS and
gout are in fact mutually exclusive, strongly suggesting that
1
30-140 °C in the presence of Et3N gave 7 and 9, respectively.
The structure of 9 was unequivocally determined by elemental
4
hyperuricaemia may protect against MS. Long alkyl chain
analysis, HRMS, and NMR. Unexpectedly, the chlorine re-
mained, and the only methine of the 6-chlorouracil moiety was
replaced by a carbon. Because of the lack of hydrogens in the
uracil unit, few long-range CH correlations were observed in
the HMBC spectrum (see Figure 2). In the IR spectrum,
derivatives of UA and aminouracils were shown by Fraisse et
5
al. to be effective free-radical scavengers and antioxidants. The
neuroprotective effect of aminoindans and their N-propargyl
†
Teva Pharmaceutical Industries Ltd.
Bar Ilan University.
-
1
‡
absorptions in the 3000 and 1600 cm region, characteristic
9
(
1) (a) Benzi, G.; Moretti, A. Neurobiol. Aging 1995, 16, 661-674. (b)
Jesberger, J. A.; Richardson, J. S. Int. J. Neurosci. 1991, 57, 1-17.
2) Davis, J. W.; Grandinetti, A.; Waslien, C. I.; Ross, G. W.; White, L.
R.; Morens, D. M. Am. J. Epidemiol. 1996, 144, 480-484.
3) Simic, M. G.; Jovanovic, S. V. J. Am. Chem. Soc. 1989, 111, 5778-
782. And refs cited in ref 5.
4) (a) Hooper, D. C.; Spitsin, S.; Kean, R. B.; Champion, J. M.; Dickson,
G. M.; Chaudhry, I.; Koprowski, H. Proc. Natl. Acad. Sci. U.S.A. 1998,
of hydroxy-pyrimidines, were found.
Hydrogenation of 9 to give 5-(5-(dimethylamino)-indan-1-
yl)-1H-pyrimidine-2,4-dione 10 further substantiates the as-
(
(
5
(6) (a) Abu-Raya, S.; Blaugrund, E.; Trembovler, V.; Shilderman-Bloch,
E.; Shohami, E.; Lazarovici, P. J. Neurosci. Res. 1999, 58, 456-463. (b)
Youdim, M. B.; Wadia, A.; Tatton, W.; Weinstock, M. Ann. N.Y. Acad.
Sci. 2001, 939, 450-458.
(7) Teva Pharmaceutical Industries Ltd. WO 2006/020070 A2, February
23, 2006.
(8) Warner-Lambert Co. WO 01/83425, November 8, 2001.
(9) Bellamy, L. J. The Infra-red Spectra of Complex Molecules; John
Wiley & Sons: New York, 1958.
(
9
5, 675-680. (b) Hooper, D. C.; Bagasra, O.; Marini, J. C.; Zborek, A.;
Ohnishi, S. T.; Kean, R.; Champion, J. M.; Sarker, A. B.; Bobroski, L.;
Farber, J. L.; Akaike, T.; Maeda, H.; Koprowski, H. Proc. Natl. Acad. Sci.
U.S.A. 1997, 94, 2528-2533.
(5) Fraisse, L.; Verlhac, J.-B.; Roche, B.; Rascle, M.-C.; Rabion, A.;
Seris, J.-L. J. Med. Chem. 1993, 36, 1465-1473.
1
0.1021/jo0609881 CCC: $33.50 © 2006 American Chemical Society
Published on Web 08/04/2006
J. Org. Chem. 2006, 71, 7053-7056
7053

SCHEME 1. Preparation of 6-(5-(Dimethylamino)-2-indanylamino) Uracil 7 and 5-(5-Dimethylaminoindanyl)-6-chlorouracil 9a
a
(a) 1. (CF3CO)2O. 2. H2SO4/HNO3. (b) 1. H2SO4/HNO3. 2. (CF3CO)2O. (c) Chromatography. (d)10% Pd/C, (CH2O)n. (e) K2CO3/MeOH/water. (f)
6
-chlorouracil/DMSO/Et3N, 130-140 °C. (g) n-BuOH, 110 °C, 1.5 h. (h) 10% Pd/C, H2 40 psi, 5 h, Et3N, MeOH/water.
accord with the putative mechanism suggested above. In
contrast, 8‚HCl as well as 6-(dimethylamino)-1-aminoindan were
all inert under these conditions. Both 4- and 6-regioisomers and
compound 6 act as nucleophiles, attacking the uracil ring at the
6
-position. Formation of both 9 and 11 is accompanied by full
racemization of the chiral center at the indan C1 carbon (as
indicated by the loss of optical activity), which supports the
planar structure of 8a.
The N,N-dimethyliminoquinoindene moiety seems to have
FIGURE 2. HMBC correlations for 5-indanyl-6-chlorouracil 9‚HCl
and its reductive displacement product 10.
been reported only when incorporated in either triarylmethane
1
0
11
dyes or fused polycyclic ring systems.
signed structure by providing several more CH correlations in
the HMBC (Figure 2).
The reaction of 6-chlorouracil with p-aminobenzylamine (the
12
ring-opened analogue of 8) was reported to result in a mixture
The formation of 9 may be attributed to the intermediacy of
the reactive imminium methide 8a. The para orientation of the
dimethylamine and the benzylic amine moieties in 8 facilitates
elimination of ammonia to yield the reactive electrophile 8a,
which may then electrophilically attack the uracil ring at the
(10) Guinot, S. G. R.; Hepworth, J. D.; Wainwright, M. J. Chem. Soc.,
Perkin Trans. 2 1998, 297-303.
(11) Guinot, S. G. R.; Hepworth, J. D.; Wainwright, M. Dyes Pigm. 1999,
4
0, 151-156.
12) Brown, N. C.; Gambino, J.; Wright, G. E. J. Med. Chem. 1977, 20,
1186-1189.
5
1
-position. Indeed, refluxing 8 (as a free base) in n-butanol for
.5 h afforded (1-butoxy-indan-5-yl)-dimethyl-amine 11, in good
(
7
054 J. Org. Chem., Vol. 71, No. 18, 2006

and 7-hydroxy aminoindans,24 as well as the documented self-
immolative connector concept in prodrugs, which undergo
spontaneous fragmentation to afford quinine methides and
2
5
enamine methides.
Experimental Section
,2,2-Trifluoro-N-(5-nitro-indan-1-S-yl)-acetamide, 3a. A so-
2
lution of 1-S-aminoindan (33.9 g, 0.255 mol) in toluene (50 mL)
was added dropwise to a mixture of trifluoroacetic anhydride (58.5
g, 39.4 mL, 0.278 mol) and toluene (250 mL) at 0-5 °C. The
reaction mixture was stirred at this temperature for 3.5 h. Potassium
hydroxide (17.1 g, 0.306 mol, 1.2 equiv) in water (150 mL) was
added gradually to the reaction mixture under cooling. The mixture
was stirred at room temperature for 1 h, and the precipitated white
solid was collected by filtration and washed with water. The crude
product (37.3 g, 64%) was used for the next step without
purification. Crude 2,2,2-trifluoro-N-(5-indan-1-S-yl)-acetamide
FIGURE 3. Reactive species proposed by Wright.13
of “unidentifiable products” instead of the expected 6-(p-
aminobenzylamino)uracil, whereas 6-aminouracil gave 6-amino-
5
-(p-aminobenzyl)uracil. Formation of the latter was rationalized
1
3
in a later report by the same author via a thermal [1,3]-
rearrangement of the former to the latter, facilitated by the oxo
groups in the pyrimidine ring and by electron-releasing moieties
in the aromatic ring (stabilizing the reactive benzyl carbocation
species 12) (Figure 3). Although this mechanism is not
applicable in our case (chloro, not amino, at position 6), the
putative 12 supports our proposed imminium methide 8a as the
reactive species.
(37.0 g, 0.16 mol) was added slowly to 65-67% nitric acid (370
mL), and the suspension was stirred for 20 h. The reaction mixture
was poured onto a water-ice mixture (2000 mL), and the resulting
yellow solid was collected by filtration, washed with water to pH
6
-7, and dried, to give 39.3 g (89%) of a ∼ 30:5:70 (by TLC)
mixture of 2,2,2-trifluoro-N-(4-, 5-, and 6-indan-1-S-yl)-acetamides
3. This crude product was crystallized twice from toluene (15 mL/
g) to give 17 g of a 95:5 mixture of 6- and 5-isomers, from which
The N,N-dimethylamino analogue of 12 was proposed to
result from the irradiation of a solution of N,N-dimethylaniline
in CH2Cl2.14
the latter was isolated by flash column chromatography to give
1
1
.5 g (2%) of 3a: mp 199-200 °C; H NMR (CDCl
3
) δ 8.14 (m,
Although substitutions at position 5 by various electrophiles,
such as phenylselenyl chloride15 and benzenesulfenyl chloride,16
2H), 7.45 (d, 1H, J ) 9 Hz), 6.62 (br d, 1H), 5.61 (q, 1H, J ) 8
Hz), 3.19 (ddd, 1H, J ) 17, 9, 4 Hz), 3.07 (dt, 1H, J ) 17, 8 Hz),
as well as acylation with acid chlorides such as cinnamoyl
chloride17 or hydroximoyl chloride are known, electrophilic
alkylations have, to the best of our knowledge, not been reported.
2
.8 (dddd, 1H, J ) 17, 9, 8, 4 Hz), 2.07 (dq, 1H, J ) 17, 8 Hz);
18
13
C NMR (CDCl
22.6, 120.0, 114.1, 54.5, and 54.4 (for two rotamers of C-1), 32.7,
0.0; HRMS calcd for C11 274.0565, found 274.0605.
2,2,2-Trifluoro-N-(5-nitro-indan-2-yl)-acetamide, 3b. 2-Amino-
indan‚HCl (5.04 g, 0.0294 mol) was dissolved in trifluoroacetic
acid (30 mL), and H SO (3 mL) and HNO (2 mL, 0.03 mol)
were added at 0 °C. After ∼3/4 h, the red solution was allowed to
warm to room temperature and stirred for 6 h. Et O was added
over 30 min, and the resultant suspension was stirred overnight
SO as a white solid
7.37 g, 90%). This solid was dissolved in water (50 mL), and the
3
+ CD
3
OD) δ 156.0, 149.1, 148.3, 145.0, 124.7,
1
3
1
9
5
-Alkyl-6-chlorouracils were reportedly synthesized via 5-alkyl-
9 3 2 3
H F N O
20,21
barbituric acid.
Alternatively, hydroxymethyl at position 5
of 4-chloro-2,6-dimethoxypyrimidine was introduced by meta-
lation of the latter followed by addition of ethyl formate and
2
4
3
22
further reduction. Similarly, nucleoside derivatives containing
a 5-allyl/propyl uracil moiety were prepared via the 5-chloro-
mercury intermediate. Also, the electrophilic substitution of
arylmethyl cations on the C-5 of 2-amino-4,6-dichloropyrimidine
and further nitration resulted in 5-diphenylmethyl-6-chloro-
2
and filtered to give 5-nitro-2-aminoindan‚H
2
4
(
solution was made basic with 25% NH
and then extracted with EtOAc (130 mL). The organic layer was
4
OH (∼15 mL) to pH 10
2
3
uracil.
The relative orientation of the dimethylamino and amino
groups in 5-dimethylamino aminoindans was found to strongly
affect the course of their reaction with 6-chlorouracil. Thus,
compound 6 afforded the expected 7, and 9 was obtained from
separated, dried (MgSO ), and evaporated to give 4.2 g. A toluene
solution of this free base (5.5 mL) was added slowly (over 40 min)
into a stirred and ice-cooled mixture of trifluoroacetic anhydride
4
(3.6 mL, 0.025 mol) in toluene (20 mL). After stirring for 1/2 h at
0
°C, the mixture was allowed to warm to room temperature and
8
. Formation of 9 may be rationalized by the conversion of 8
further stirred for 1/2 h. KOH solution (1.5 g in 10 mL of water)
was added to the mixture at room temperature, and the precipitated
gray solid was collected by filtration, washed with toluene and
to a reactive p-imminium methide intermediate 8a and represents
a novel entry for electrophilic alkylation at the uracil 5-position.
This proposed mechanism resembles that reported by us for 5-
water, and thoroughly dried to give 3b (3.05 g, 47%) as a grayish
1
solid: mp 102-104 °C; H NMR (DMSO-d
6
) δ 9.75 (br d, 1H, J
(
(
(
13) Wright, G. E. J. Org. Chem. 1980, 45, 3128-3131.
) 6.5 Hz), 8.11 (br s, 1H), 8.07 (dd, 1H, J ) 8, 2 Hz), 7.50 (d,
14) Latowski, T.; Zelent, B. Rocz. Chem. 1977, 51, 1405-1420.
15) Kim, Y. H.; Lee, C. H.; Lee, D. H. Heteroat. Chem. 1993, 4, 463-
1
1
1
3
H, J ) 8 Hz), 4.67 (sextet, 1H, J ) 6.5 Hz), 3.37 (dd, 2H, J )
13
6, 8 Hz), 3.05 (dd, 2H, J ) 16, 6 Hz); C NMR (DMSO-d
6
) δ
4
70.
56.1, 149.4, 146.8, 143.1, 125.5, 122.2, 119.5, 115.8, 50.8, 38.9,
16) Peach, M. E.; Scott, C.; Woo, J. Sulfur Lett. 1986, 5, 23-28.
+
+
8.7; MS TOF ES+ m/z (275, MH ), 257 (MH - H
2
O); HRMS
J.-C. J. Med. Chem. 1985, 28, 497-502.
calcd for C11
H F N
9 3 2
O
3
+ H 275.0644, found 275.0674.
(
18) Kim, J. N.; Ryu, E. K. J. Org. Chem. 1992, 57, 1088-1092.
N-(5-(Dimethylamino)-indan-2-yl)-2,2,2,-trifluoro-acet-
amide, 4. A mixture of 3b (7.0 g, 0.0255 mol) and paraform-
aldehyde (5.67 g, 0.189 mol, ∼7.5 equiv) in MeOH (136 mL)
(19) Koroniak, H.; Jankowski, A.; Krasnowski, M. Org. Prep. Proced.
Int. 1993, 25, 563-568.
20) Volwiler, E. H. J. Am. Chem. Soc. 1925, 47, 2236-2240.
1
2
5
986, 29, 151-154.
22) Pl e´ , N.; Bardin, T. F.; Queguiner, G. J. Heterocycl. Chem. 1992,
9, 467-470.
23) Whitehead, C. W.; Whitesitt, C. A. J. Org. Chem. 1974, 39, 591-
95.
(24) Herzig, Y.; Lerman, L.; Goldenberg, W.; Lerner, D.; Gottlieb, H.
E.; Nudelman, A. J. Org. Chem. 2006, 71, 4130-4140.
(25) Leenders, R. G. G.; Damen, E. W. P.; Bijsterveld, E. J. A.; Scheeren,
H. W.; Houba, P. H. J.; van der Meulen-Muileman, I. H.; Boven, E.; Haisma,
H. J. Bioorg. Med. Chem. 1999, 7, 1597-1610.
(
(
J. Org. Chem, Vol. 71, No. 18, 2006 7055

was hydrogenated, initially at 2 atm, at 30-35 °C for 0.5 h, then
at 4 atm at 50 °C for 1.5 h, over 10% Pd/C (1.4 g, 20 wt % per
nitro compound). The reaction mixture was filtered through Celite,
and the solvent evaporated to leave a white solid (7.5 g), which
was purified by Combi-Flash (hexane/EtOAc, 0-20% EtOAc
2:1 MeOH/water mixture (30 mL) was heated at reflux for 2.5 h.
The clear solution was evaporated to dryness. The residue was
dissolved in water (20 mL), and the product was extracted with
ethyl acetate (6 × 80 mL). The organic layers were combined, dried,
and evaporated to dryness to give 8 as slightly brown oil (1 g,
gradient over 35 min) to give 4 as a white solid (4.5 g, 65%): mp
99%): 1H NMR (CDCl
3
) δ 7.22 (d, 1H, J ) 8 Hz), 6.67 (dd, 1H,
1
1
56-157 °C; H NMR (DMSO-d
6
) δ 9.68 (br s, 1H), 7.02 (d, 1H,
J ) 8, 2 Hz), 6.65 (br s, 1H), 4.33 (t, 1H, J ) 7 Hz), 2.95 (m and
s, 7H), 2.79 (dt, 1H, J ) 16, 8 Hz), 2.49 (dddd, 1H, J ) 12.5, 8.5,
J ) 8 Hz), 6.62 (br d, 1H, J ) 1.5 Hz), 6.57 (dd, 1H, J ) 8, 1.5
Hz), 4.52 (quintet, 1H, J ) 7 Hz), 3.13 (two dd, 2H, J ) 14, 8
7.5, 4 Hz), 2.28 (br s, 2H), 1.70 (dtd, 1H, J ) 12.5, 8.5, 7.5 Hz);
Hz), 2.85 (s and two dd, 8H, J ) 14, 8 Hz); 13C NMR (DMSO-d
13
6
)
3
C NMR (CDCl ) δ 150.8, 144.4, 135.4, 123.9, 111.7, 109.0, 56.6,
δ 156.1, 150.1, 141.4, 128.1, 124.6, 115.9, 111.6, 108.8, 51.0, 38.9,
41.2, 37.3, 30.5; HRMS calcd for C11
176.1316.
16 2
H N 176.1313, found
+
3
C
8.6, 37.3; MS TOF ES+ m/z (273, MH ); HRMS calcd for
O 272.1136, found 272.1120.
,2,2-Trifluoro-N-(5-(dimethylamino)-indan-1-S-yl)-acet-
amide, 5. A mixture of 3a (1.5 g, 0.0058 mol), paraformaldehyde
1.75 g, 0.044 mol), and 10% Pd/C (0.3 g, 20%) in MeOH (40
13
H F
15 3
N
2
6-Chloro-5-(5-(dimethylamino)-indan-1-yl)-1H-pyrimidine-
2,4-dione, 9‚HCl Salt. A mixture of 8 (1 g, 0.0055 mol),
6-chlorouracil (0.83 g, 0.0055 mol), and Et N (0.55 g, 0.0055 mol)
3
in DMSO (1 mL) was heated at 130-140 °C for 4 h under nitrogen.
The reaction mixture was cooled to 45-50 °C, and water (50 mL)
was added. The suspension was heated at reflux for 0.5 h and
filtered. The collected solid (free base, 1.3 g, 77%) was dissolved
2
(
mL) was hydrogenated (4 atm) at 50 °C for 2.5 h. The reaction
mixture was filtered (Celite), and the filtrate was evaporated to
dryness, to give 5 as a white solid (1.5 g, 98%), which was used
2
5
in Et O (50 mL), and 4 N ethanolic HCl (1.1 equiv) was added.
without further purification: mp 188-189 °C (dec); [R]
D
-180
) δ 9.67 (br s, 1H), 7.00 (d, 1H,
J ) 8 Hz), 6.58 (s and dd, 2H, J ) 8, 2 Hz), 5.27 (br t, 1H, J )
Hz), 2.93 (ddd, 1H, J ) 15, 9, 5 Hz), 2.86 (s, 6H), 2.76 (dt, 1H,
2
1
The suspension was then further stirred for 0.5 h at room
(
c 1, MeOH); H NMR (DMSO-d
6
temperature, and the solid was collected by filtration to give 1.1 g
(75%): mp 236-238°C (dec). Free base: 1H NMR (DMSO-d
) δ
7
6
J ) 15, 7.5 Hz), 2.39 (dddd, 1H, J ) 12.5, 8, 7, 5 Hz), 1.93 (dtd,
) δ 155.8, 151.0, 144.3,
29.9, 124.2, 116.1, 111.4, 108.3, 54.0, 40.5, 31.9, 30.2; MS TOF
11.24 (br s, 1H), 6.75 (d, 1H, J ) 9 Hz), 6.60 (d, 1 H, J ) 2 Hz),
6.47 (dd, 1H, J ) 9, 2 Hz), 4.42 (br m, 1H), 2.95 (m, 1H), 2.84 (s,
H, J ) 12.5, 8, 7 Hz); 13C NMR (DMSO-d
1
1
6
6H), 2.82 (m, 1H), 2.20 (br m, 2H); 13C NMR (DMSO-d
6
) δ 162.0,
+
149.6, 145.6, 145.2, 142.4, 142.2, 124.1, 118.6, 116.7, 110.3, 45.6,
42.2, 31.4, 29.9. HCl salt: 1H NMR (DMSO-d
) δ 11.89 (bs, 1H),
1.20 (bs, 1H), 7.69 (bs, 1H), 7.53 (bd, 1H, J ) 8 Hz), 7.15 (bd,
H, J ) 8 Hz), 4.50 (bt, 1H, J ) 8 Hz), 3.08 (s, 6H), 3.07 (bddd,
ES+ m/z (273, MH ); HRMS calcd for C13
15 3 2
H F N O 272.1136,
found 272.1130.
6
1
1
1
5
-N,N-(Dimethylamino)-indan-2,5-diamine, 6. Compound 4
1.5 g, 5.5 mmol) was suspended in a mixture of MeOH/water (20:
2 mL), and K CO (1.5 g, 9.48 mmol) was added. The mixture
(
1
1
3
H, 16, 7, 5 Hz), 2.94 (bdt, 1H, J ) 16, 9 Hz), 2.30 (m, 2H);
) δ 161.2, 149.4, 145.1, 145.06, 142.22, 142.18,
23.9, 118.3, 116.4, 110.4, 45.4, 42.0, 31.3, 29.7. Microanal. calcd
for C30
(two molecules of free base + 2 × HCl +
O): C, 51.29; H, 5.17; Cl, 20.19; N, 11.96; O, 11.39. Found:
C
2
3
NMR (DMSO-d
1
6
was heated to 85-90 °C with stirring. The reaction mixture was
cooled to room temperature and evaporated to dryness. The solid
residue was partitioned between EtOAc (5 × 30 mL) and water
H
4 6 5
36Cl N O
H
2
4
(10 mL). The organic phase was separated, dried (MgSO ), and
C, 50.96; H, 5.13; Cl, 20.13; N, 11.82.
5-(5-(Dimethylamino)-indan-1-yl)-1H-pyrimidine-2,4-dione,
evaporated to dryness to give 6 as an oily liquid (0.95 g, 98%):
1
H NMR (DMSO-d
1.5 Hz), 6.53 (dd, 1H, J ) 8, 2 Hz), 3.75 (quintet, 1H, J ) 7
6
) δ 7.00 (d, 1H, J ) 8 Hz), 6.60 (br d, 1H, J
10. Triethylamine (0.1 mL) and 10% Pd/C (20 mg) were added to
)
a solution of 9‚HCl (100 mg, 0.3 mmol) in a 2:1 MeOH/water
Hz), 3.03 (two dd, 2H, J ) 15, 7 Hz), 2.83 (s, 6H), 2.62 (two dd,
H, J ) 15, 6 Hz); 1 C NMR (DMSO-d
3
solution (3 mL). The mixture was reduced under hydrogen (40-
2
1
6
) δ 150.0, 141.9, 128.7,
24.6, 111.46, 109.0, 52.2, 40.8, 40.7; MS TOF ES+ m/z (177,
45 psi) for 5 h and filtered. The catalyst was washed with hot
+
MeOH. The filtrates were combined and evaporated to dryness,
and the residue was washed with water and filtered to give a white
MH ).
6
-(5-(Dimethylamino)-indan-2-ylamino)-1H-pyrimidine-2,4-
1
solid (50 mg, 60%): mp 261-262 °C; H NMR (DMSO-d
6
) δ
dione, 7‚HCl Salt. Compound 6 (∼3 g, 0.016 mol) was dissolved
in DMSO (5 mL), and 6-chlorouracil (1.24 g, 8.46 mmol) was added
portionwise over a few min at 70-80 °C. The homogeneous dark
mixture was heated to 135-140 °C. After 3 h, the reaction mixture
was cooled to 100 °C. Ethylene glycol dimethyl ether (40 mL) was
added, and the dark solution was refluxed for ∼1 h, cooled to room
temperature, and filtered. The filtrate was evaporated to dryness,
and the dark residue was boiled in water (∼50 mL) for 0.5 h; the
suspension was filtered, and the collected solid was washed with
1
1.07 (bs, 1H), 10.54 (bs, 1H), 6.89 (d, 1H, J ) 8.5 Hz), 6.65 (s,
H), 6.64 (d, 1H, J ) 2.5 Hz), 6.55 (dd, 1H, J ) 8.5, 2.5 Hz), 4.06
1
(
7
)
dd, 1H, J ) 8, 6.5 Hz), 2.86 (s, 6H), 2.83 (bddd, 1H, J ) 15.5,
.5, 6 Hz), 2.74 (bddd, 1H, J ) 15.5, 8, 6.5 Hz), 2.28 (ddd, 1H, J
12.5, 8, 6 Hz), 1.84 (ddd, 1H, 12.5, 8, 6 Hz); 13C NMR (DMSO-
d
1
2
6
) δ 164.3, 151.2, 150.0, 144.9, 136.9, 131.9, 124.4, 116.0, 111.3,
08.7, 40.8, 40.6, 32.8, 31.1; HRMS calcd for C15H N O
17 3 2
71.1321, found 271.1303.
(1-Butoxy-indan-5-yl)-dimethylamine, 11. A solution of com-
2
Et O to give a brown solid, which after drying under vacuum (2 g)
pound 8 (0.3 g, 1.7 mmol) in n-butanol (3 mL) was heated at 110°C
for 1.5 h under nitrogen. The solvent was evaporated to dryness,
and the residue was purified by column chromatography (hexane/
was suspended in MeOH. Ethanolic HCl (∼3 N, 2-3 mL) was
added, and the resulting solution was evaporated to dryness. The
residue was treated with dichloromethane (DCM) to give a brown
1
EtOAc 95:5) to give 0.15 g (38%) of a clear oil: H NMR (DMSO-
solid which was purified by Combi-Flash (DCM/MeOH) to give
d
3
8
1
1
6
) δ 7.30 (m, 1H), 6.67 (m, 2H), 4.89 (dd, 1H, J ) 7.5, 6.5 Hz),
1
7
‚HCl as a grayish solid (1.1 g, 20%): mp 232-233 °C (dec); H
.11 (bdt, 1H, J ) 16, 8 Hz), 2.98 (s, 6H), 2.80 (ddd, 1H, J ) 16,
.5, 4.5 Hz), 2.34 (ddt, 1H, J ) 13, 8.5, 6.5 Hz), 2.13 (dddd, 1H,
NMR (DMSO-d
7
)
1
6
) δ 10.36 (bs, 1H), 10.14 (bs, 1H), 7.70 (bs, 1H),
.60 (bd, 1H, J ) 8 Hz), 7.42 (d, 1H, J ) 8 Hz), 7.32 (bd, 1H, J
3, 8.5, 4.5, 3.5 Hz); 13C NMR (DMSO-d
6
) δ 151.4, 145.6, 131.6,
5.5 Hz), 4.61 (s, 1H), 4.26 (tq, 1H, 7, 5 Hz), 3.33 (bdt, 2H, J )
25.7, 111.4, 108.8, 82.8, 41.1, 32.8, 32.3; HRMS calcd for
23NO 233.1780, found 233.1730.
6.5, 7 Hz), 3.10 (s, 6H), 2.87 (dd, 1H, J ) 16.5, 4.5 Hz), 2.85
15
C H
13
(
1
3
dd, 1H, J ) 16.5, 4.5); C NMR (DMSO-d
6
) δ 164.3, 154.0, 150.5,
42.9, 142.8, 141.7, 125.9, 119.1, 116.9, 73.1, 52.4, 45.5, 40.0,
Supporting Information Available: 1H and 13C NMR spectra
of reported compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
+
9.5; MS TOF ES+ m/z (287, MH ); HRMS calcd for C15
H 287.1508, found 287.1472.
,N -Dimethyl-indan-1-S, 5-diamine, 8. A mixture of 5 (1.5
g, 0.0055 mol) and potassium carbonate (1.14 g, 0.082 mol) in a
19 4 2
H N O
+
N
5
5
JO0609881
7
056 J. Org. Chem., Vol. 71, No. 18, 2006