Notes
J . Org. Chem., Vol. 65, No. 26, 2000 9263
1-(5-Ben zylp yr im id in -4-yl)-1H-in d ole (5). The use of indole
as heterocycle following the general procedure (elution with 10%
to 20% ethyl acetate/hexanes) afforded 76 mg (61%) of 5 as an
orange oil, Rf ) 0.50 (50% ethyl acetate/hexanes). 1H NMR
(chloroform-d): δ 9.09 (s, 1H, H2); 8.67 (s, 1H, H6); 7.67 (d, 2H,
J ) 8.8, H4′,7′); 7.18-7.33 (m, 6H); 6.96 (d, 2H, J ) 8.0, H2′′);
6.69 (d, 1H, J ) 3.6, H3′); 4.07 (s, 2H, benzyl). 13C NMR
(chloroform-d): δ 161.36 (C6); 157.39 (C4); 157.27 (C2); 137.92;
135.78; 129.68; 129.01 (C3′′); 128.61 (C2′′); 127.06; 126.93; 126.89
(C5); 123.46; 121.82; 121.30; 112.43; 106.17 (C3′); 35.22 (benzyl).
Anal. Calcd for C19H15N3: C, 79.98; H, 5.30; N, 14.73. Found:
C, 79.40; H, 5.40; N, 15.10.
5-Ben zyl-4-p yr r ol-1-ylp yr im id in e (6). The use of pyrrole
as heterocycle following the general procedure (elution with 10%
to 20% ethyl acetate/hexanes) afforded 41 mg (35%) of 6 as a
yellow oil, Rf ) 0.50 (50% ethyl acetate/hexanes). 1H NMR
(chloroform-d): δ 8.98 (s, 1H, H2); 8.53 (s, 1H, H6); 7.25-7.38
(m, 5H, phenyl); 7.10 (br d, 2H, H2′′); 6.34 (t, 2H, J ) 2, H3′);
4.21 (s, 2H, benzyl). 13C NMR (chloroform-d): δ 161.53 (C6);
157.00 (C2); 156.69 (C4); 137.81 (C1′′); 129.06 (C3′′); 128.44 (C2′′);
127.05 (C4′′); 122.82 (C5); 120.85 (C2′); 111.71 (C3′); 35.37 (benzyl).
Anal. Calcd for C15H13N3: C, 76.57; H, 5.57; N, 17.86. Found:
C, 76.35; H, 5.58; N, 17.64.
ring substitution at C2, and in the case of 9, direct
mesylate displacement at the benzylic position. This new
method affords quick access to highly functionalized
pyrimidines in reasonable overall yields. Starting from
commercially available 5-bromopyrimidine, 4,5-disubsti-
tuted pyrimidines can be obtained in only two separate
reactions. The synthesis of these interesting polycyclic
nitrogen heterocycles by existing methods would likely
require a lengthy synthetic sequence. More highly sub-
stituted mesyloxymethylpyrimidines or even pyridine
derivatives may react in a similar fashion. In fact, we
have prepared a tetrasubstituted pyrimidine (albeit in
low yield) by the reaction of the 2,4-dimethoxy derivative
of 115 with an indole derivative.
Exp er im en ta l Section
Gen er a l. Melting points are uncorrected. 1H and 13C NMR
spectra were recorded at 300 and 75 MHz, respectively, on a
J EOL Eclipse 300 Spectrometer. NMR assignments are based
1
on a combination of the 1H, 13C, H COSY, HMBC, and HMQC
Na p h th a len -2-ylp yr im id in -5-ylm eth a n ol (7). 5-Bromopy-
rimidine (2.00 g, 12.6 mmol) was dissolved in 15 mL of ether
and 25 mL of THF and cooled to -105 °C (internal) with
mechanical stirring.12 A 2.5 M solution of n-butyllithium in
hexanes (6.50 mL, 16.2 mmol) was then added dropwise, over
15 min, at a rate that maintained the temperature between -100
and -105 °C. After 30 min at this temperature, a solution of
2-naphthaldehyde (2.77 g, 17.7 mmol) in 5 mL of THF was then
added via cannula over 15 min, again maintaining the temper-
ature between -100 and -105 °C. The resulting yellow solution
was allowed to warm to 25 °C over 1-2 h and stirred for 18 h at
25 °C. Water and ethyl acetate were added, and the layers were
separated. The organic phase was washed with water, dried
(sodium sulfate), filtered, and concentrated. The crude product
obtained was purified by flash chromatography (elution with
40% to 60% ethyl acetate/hexanes) to give 2.47 g (83%) of 7 as
a white solid, mp 100-102 °C, Rf ) 0.07 (50% ethyl acetate/
hexanes). 1H NMR (chloroform-d): δ 9.14 (s, 1H, H2); 8.79 (s,
2H, H4); 7.83-7.88 (m, 4H); 7.51-7.54 (m, 2H); 7.41 (dd, 1H, J
) 8.5, 1.9, H1′′); 6.07 (d, 1H, J ) 3, CHOH); 2.62 (d, 1H. J ) 3,
OH). Anal. Calcd for C15H12N2O: C, 76.25; H, 5.12; N, 11.86.
Found: C, 75.97; H, 5.14; N, 11.93.
1-(5-Naph th alen -2-ylm eth ylpyr im idin -4-yl)-1H-in dole (8).
The use of indole as heterocycle and alcohol 7 (118 mg, 0.50
mmol) following the general procedure (elution with 10% to 20%
ethyl acetate/hexanes) afforded 78 mg (47%) of 8 as a yellow
solid, mp 86.5-87.5 °C, Rf ) 0.50 (50% ethyl acetate/hexanes).
1H NMR (chloroform-d): δ 9.12 (s, 1H, H2); 8.72 (s, 1H, H6);
7.65-7.80 (m, 4H); 7.74 (d, 1H, J ) 8.3, H4′′); 7.41-7.49 (m, 2H);
7.34 (d, 1H, J ) 0.8, H1′′); 7.20-7.34 (m, 3H); 7.09 (dd, 1H, J )
8.4, 1.8, H3′′); 6.66 (d, 1H, J ) 3.6, H3′); 4.22 (s, 2H, benzyl). 13C
NMR (chloroform-d): δ 161.34 (C6); 157.39 (C4); 157.24 (C2);
135.69; 135.31; 133.43, 132.25; 129.62; 128.76; 127.60; 127.53;
127.08; 126.86; 126.58; 126.50 (C5); 126.40; 125.95; 123.40;
121.77; 121.21; 112.40; 106.14 (C3′); 35.29 (benzyl). Anal. Calcd
for C23H17N3: C, 82.36; H, 5.11; N, 12.53. Found: C, 82.12; H,
5.20; N, 12.34.
5-Hyd r oxym eth ylp yr im id in e (9). The published proce-
dure13 to prepare pyrimidine-5-carboxaldehyde was followed,
starting from 5-bromopyrimidine. The 1H NMR spectrum ob-
tained for our sample of pyrimidine-5-carboxaldehyde matches
the reported data.13 The aldehyde was then treated with lithium
aluminum hydride as described previously14 to afford pure 9,
mp 51-52 °C, lit14 mp 58-60 °C. 1H NMR (chloroform-d): δ 9.17
(s, 1H, H2); 8.77 (s, 2H, H4); 4.79 (s, 2H, CH2); 2.11 (br s, 1H,
OH).
1-(5-Meth ylp yr im id in -4-yl)-1H-in d ole (10) a n d 1-P yr i-
m id in -5-ylm eth yl-1H-in d ole (11). The use of indole as het-
erocycle and alcohol 9 (72 mg, 0.65 mmol) following the general
procedure (elution with 30% to 50% ethyl acetate/hexanes)
afforded 36 mg (26%) of 10 as an off-white solid, mp 120-122
°C, Rf ) 0.38 (50% ethyl acetate/hexanes). 1H NMR (chloroform-
d): δ 9.06 (s, 1H, H2); 8.71 (s, 1H, H6); 7.67-7.72 (m, 2H, H4′,7′);
7.42 (d, 1H, J ) 3.3 Hz, H2′); 7.20-7.32 (m, 2H, H5′,6′); 6.75 (d,
spectra. Mass spectra were run at the Department of Chemistry,
Harvard University. Elemental analyses were performed at
Atlantic Microlab. Thin-layer chromatography was carried out
on Baker Si 250F plates. Visualization was accomplished with
ultraviolet exposure or with phosphomolybdic acid. Flash chro-
matography was carried out on ICN SiliTech silica gel (60 µM).
Anhydrous methylene chloride, tetrahydrofuran, and dimeth-
ylformamide were Aldrich Sure/Seal, and triethylamine was
dried over potassium hydroxide. Other materials were reagent
grade.
Gen er a l P r oced u r e for t h e P r ep a r a t ion of 4,5-Disu b -
stitu ted P yr im id in es. A solution of the alcohol 110,11 (93 mg,
0.50 mmol) was dissolved in methylene chloride (4 mL) and then
cooled to -40 °C. Triethylamine (85 µL, 62 mg, 0.61 mmol) was
added, followed by methanesulfonyl chloride (43 µL, 64 mg, 0.56
mmol). The reaction mixture was stirred for 1 h at -35 to -45
°C. At the same time, the heterocyclic compound (0.75 mmol)
was dissolved in 4 mL of DMF in a separate flask and cooled to
0 °C. Sodium hydride (54 mg of a 60% oil dispersion, 1.35 mmol)
was added, and the resulting suspension was stirred at 5-10
°C for 1 h and then cooled to -40 °C. The mesylate solution was
then added via cannula to the sodium salt of the heterocycle
over 15 min. The reaction mixture was allowed to warm to 25
°C and stirred at that temperature for 18 h. Water and ethyl
acetate were added, and the layers were separated. The organic
phase was dried (sodium sulfate), filtered, and concentrated. The
crude product obtained was purified by flash chromatography
with the indicated eluents to afford the pyrimidine products.
5-Ben zyl-4-im id a zol-1-ylp yr im id in e (2) a n d 5-Ben zyl-2-
im id a zol-1-ylp yr im id in e (3). The use of imidazole as hetero-
cycle following the general procedure (elution with 30% to 60%
ethyl acetate/hexanes) afforded 76 mg (64%) of 2 as a yellow
oil, Rf ) 0.35 (ethyl acetate). 1H NMR (chloroform-d): δ 9.09 (s,
1H, H2); 8.71 (s, 1H, H6); 8.26 (s, 1H, H2′); 7.47 (br s, 1H, H5′);
7.26-7.38 (m, 3H, H3′′, H4′′); 7.23 (br s, 1H, H4′); 7.07 (d, 2H, J
) 7.1, H2′′); 4.19 (s, 2H, benzyl). 13C NMR (chloroform-d):
δ
162.06 (C6); 157.46 (C2); 154.65 (C4); 136.96 (overlapping C1′′ and
C2′); 130.39 (C4′); 129.37 (C3′′); 128.35 (C2′′); 127.50 (C4′′); 124.00
(C5); 118.62 (C5′); 35.10 (benzyl). Exact mass calcd for C14H12N4
m/e 236.1062, found m/e 236.1056. Anal. Calcd for C14H12N4‚0.5
H2O: C, 68.56; H, 5.34; N, 22.84. Found: C, 68.33; H, 5.10; N,
22.84. Also isolated were 20 mg (17%) of 3 as a white solid, mp
1
112-114 °C, Rf ) 0.55 (ethyl acetate). H NMR (chloroform-d):
δ 8.58 (s, 1H, H2′); 8.51 (s, 2H, H4); 7.85 (br s, 1H, H5′); 7.26-
7.36 (m, 3H, H3′′, H4′′); 7.19 (d, 2H, J ) 7.1, H2′′); 7.15 (br s, 1H,
H4′); 3.99 (s, 2H, benzyl). 13C NMR (chloroform-d): δ 158.71 (C4);
153.49 (C2); 138.28 (C1′′); 136.18 (C2′); 131.89 (C5); 130.71 (C4′);
129.12 (C3′′); 128.77 (C2′′); 127.15 (C4′′); 116.57 (C5′); 36.01
(benzyl). Anal. Calcd for C14H12N4: C, 71.17; H, 5.12; N, 23.71.
Found: C, 70.93; H, 5.14; N, 23.49.
(15) Unpublished results.