Reductive amination of 6-acetylpteridine to 6-N-arylaminoethylpteridine

Article abstract of DOI:10.1515/hc-2012-0046

6-Acetyl-7-methylpteridine derivatives 2 and 3 (lumazine and pterin) were converted to 6-[1-(arylamino) ethyl]pteridine derivatives 8 and 7 , respectively, in good to moderate yields by stepwise reactions with p -substituted anilines via imine intermediates using a Lewis acid catalyst followed by treatment with sodium tetrahydroborate. The one-step reductive amination of the starting acetylpteridine also proceeded in the presence of 2-picolineborane complex in satisfactory yield.

Full text of DOI:10.1515/hc-2012-0046

DOI 10.1515/hc-2012-0046ꢀ
ꢀHeterocycl. Commun. 2012; 18(3): 117–122
Yasuhiro Kuroda, Kazuhiro Isarai and Shizuaki Murata*
Reductive amination of 6-acetylpteridine
to 6-N-arylaminoethylpteridine
Abstract: 6-Acetyl-7-methylpteridine derivatives 2 and 3 Because methane in nature is considered to be not only
(lumazine and pterin) were converted to 6-[1-(arylamino) an energy resource but also a powerful greenhouse
ethyl]pteridine derivatives 8 and 7, respectively, in good to gas, compound 1 and related derivatives are interest-
moderate yields by stepwise reactions with p-substituted ing in a variety of scientific fields from microbiology
anilines via imine intermediates using a Lewis acid cata- to environmental chemistry. Compound 1 is one of the
lyst followed by treatment with sodium tetrahydroborate. most attractive targets in modern nitrogen heterocyclic
The one-step reductive amination of the starting acetylp- chemistry.
teridine also proceeded in the presence of 2-picoline-
borane complex in satisfactory yield.
The structure of 1 is a combination of the follow-
ing building blocks: pteridine, p-substituted arylamine,
sugar, and glutaric acid (Figure 1). The conjunction of
Keywords: amination; imine; lumazine; pteridine; pterin; the first two units, pteridine and amine, in a stereo-con-
reduction.
trolled manner is considered as a key step in chemical
synthesis of 1. Although there have been several methods
reported to partially solve this challenging problem (Tada
and Wada, 2003; Pfleiderer and Gerhard, 2007), the
development of a general procedure for various arylami-
nated pteridine derivatives which are intermediates of 1
and the related compounds has not been reported. In this
paper, we describe a convenient method for preparation
of 6-[1-(arylamino)ethyl]pteridines 7 and 8 using reduc-
tive coupling of 6-acetyl-7-methylpteridines 2 and 3 with
p-substituted anilines 4.
*Corresponding author: Shizuaki Murata, Graduate School of
Environmental Studies, Nagoya University, Furo-cho, Chikusa-ku,
Nagoya 464–8601, Japan,
e-mail:murata@urban.env.nagoya-u.ac.jp
Yasuhiro Kuroda: Graduate School of Environmental Studies,
Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464–8601, Japan
Kazuhiro Isarai: Graduate School of Environmental Studies,
Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464–8601, Japan
Introduction
6-Substituted pteridine derivatives with N-arylaminoalkyl
Results and discussion
substituents are of great interest, because some of their Stepwise procedure via imine intermediates
tetrahydro derivatives, such as tetrahydrofolate and tet-
rahydromethanopterin, play important roles in various Owing to poor solubilities of naturally occurring pteri-
metabolic transformations. For example, tetrahydro- dine derivatives in common organic solvents, the rela-
folate works in methyl transfer process of methionine and tively soluble derivatives 2 and 3 (Scheme 1) were used for
thymine biosyntheses, and folic acid is an essential the reactions with arylamines. These compounds can be
nutrition for humans (Murata et al., 2007). Artificial folate handled using common techniques of organic compounds
derivatives have been investigated as antifolate agents in including silica gel chromatography. Following modifi-
pharmaceutical and medicinal sciences for a long time cation of the method described recently (Pfleiderer and
and, for example, the potency of methotrexate, which has Gerhard, 2007), starting materials 2 and 3 were prepared
been used as an antitumor agent for more than 60 years, by reactions of 4-amino-5-nitrosopyrimidine precursors
is widely expanding into rheumatism as well as malaria with 1,3-pentandione (Scheme 1).
(Goldberg, 2002; Zhang and Rathod, 2002).
6-Acetyl-1,3,7-trimethyllumazine (2) was allowed to
Methanopterin (1) was isolated from an archae- react with anilines 4a– c in the presence of excess of
bacteria, such as Methanosarcina thermophila, which trifluoroborane‧ether complex and freshly activated molec-
produces methane from CO2 under anaerobic condi- ular sieves (MS) 3A in dichloromethane at room temperature
tions to acquire ATP (Jones et al., 1987; White, 1996). to give corresponding imine derivatives 5a– c (Scheme 2).
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118ꢀ
ꢀY. Kuroda et al.: Reductive amination of 6-acetylpteridine
O
COOH
O
COOH
O
N
N
H
COOH
NH2
N
H
COOH
N
N
N
N
HN
N
H
N
N
CH3
H2N
H2N
N
folic acid
methotrexate
OH
O
HO
O
O
O
H
OH
P
COOH
O
O
O
N
CH3
N
N
OH OH
HN
N
H
CH3
COOH
H2N
methanopterin (1)
Figure 1ꢀStructures of folic acid, methotrexate, and methanopterin.
Dichloromethane was a suitable solvent for this reaction, Reductive amination as one-step procedure
and the attempted transformations in other solvents such
as toluene, THF, and acetonitrile did not afford satisfactory
for arylaminopteridines
results. Hydrolysis of the product 5a– c occurred during One-step reductive amination of ketone to amine is
usual column chromatographic purification on silica gel applicable to synthesis of arylaminopteridine, and
and standing under ambient conditions. These problems 2-picoline‧borane complex (Sato et al., 2004) is an effective
were eliminated by using a solvent containing 1–2% (v/v) reagent for the reaction of 6-acetylpteridine 2 or 3 with 4.
triethylamine for silica gel chromatography.
Reactions of lumazine 2 with aniline derivatives 4a– f pro-
6-Acetyl-4-cyclohexyloxy-7-methylpterin (3) has been ceeded in the presence of 2-picoline‧borane complex and
a precursor for synthesis of 1 (Pfleiderer and Gerhard, MS 3A in a mixture of methanol and acetic acid (10:1, v/v)
2007). In this work, compound 3 was allowed to react with to give desired amine 8a– f together with secondary alcohol
arylamines 4a–d under similar conditions as described 9 produced by reduction of the acetyl group of 2 (Scheme
above to give corresponding imine derivatives 6a–d in 4). The yields of 8a– c (Rꢀ=ꢀꢀH, CH3, and CH2CH2OH, respec-
moderate yields (Scheme 3). The products 6 were similarly tively) were good (ꢀ>ꢀ55%) when a large excess (7–10 equiv.)
unstable as 5, and the same careful handling was required of 4 was employed. Indeed, yields of 8b decreased to 32%
to avoid hydrolytic decomposition. Reaction of imine 6a to in the reaction using 2.5 equiv. of 4b. Yields of products
amine 7a was carried out by the treatment with a mixture 8e and 8f with non-protected and protected dihydroxypro-
of sodium tetrahydroborate and tetrachlorozirconium in pyl group were lower (24% and 29%, respectively) but, in
THF at 0°C in 50% yield. Because of the rather low yield of these cases, a smaller amount (2.5 equiv.) of 4e and 4f were
7a as well as the instability of imine 6a, it was concluded employed. The pterin precursor 3 was also allowed to react
that the stepwise process is inadequate for the synthesis with 2.5 equiv. of 4a– c under similar conditions to yield
of arylaminopteridine derivatives 7.
amine derivatives 7a– c in 30–38% yields. It is known that
removal of the cyclohexyl group from 7a– c proceeds under
acidic or basic conditions to give unprotected arylaminop-
terin derivatives such as 10a–c (Shiro et al., 2008).
O
O
Me
Me
O
NO
Me
O
N
N
N
N
O
Δ
58%
N
NH2
N
Me
N
Me
Me
Me
2
Experimental
O
O
Me
General
O
N
Me
O
N
N
Δ
1H (400 MHz) and 13C (100 MHz) NMR spectra were taken in CDCl3 on
a JEOL A-400 spectrometer with tetramethylsilane as internal stand-
ard. IR (KBr) and UV spectra were recorded in MeOH on JASCO FT/IR
460 and V550 spectrometers, respectively. Mass spectra and elemen-
tal analyses were obtained at Chemical Instrument Center, Nagoya
University.
NO
O
N
46%
H2N
N
Me
H2N
NH2
3
Scheme 1ꢀPreparation of 6-acetyl-7-methylpteridines.
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Y. Kuroda et al.: Reductive amination of 6-acetylpteridineꢀ
ꢀ119
R
H2N
R
O
Me
O
Me
Me
O
N
N
Me
O
N
N
4a-c
BF3•OEt2,
CH2Cl2, MS 3A
N
O
N
N
N
Me
Me
N
Me
Me
2
5a-c
5a
5b
5c
: R = H, 70%; : R = Me, 78%; : R = CH2CH2OH, 18%
Scheme 2ꢀReactions of 6-acetyl-7-methyllumazine with p-substituted anilines: formation of imine.
(tt, Jꢀ=ꢀꢀ9 and 3 Hz, 1H), 5.54 (brs, 2H); δ 23.6, 25.1, 25.4, 27.5, 31.2, 76.6,
121.0, 142.8, 156.8, 161.3, 162.9, 167.5, 200.0; IR: ν 3091, 2928, 2863,
1691, 1645, 1593, 1525, 1486, 1461, 1438, 1361, 1330, 1241, 1210, 1106,
1067, 1010, 936, 764, 693 cm-1; UV/Vis: λmax, nm (εꢀ×ꢀ10-3, m-1 cm-1): 209
(18), 255 (15), 301 (9.6), 358 (12); MS (ESI): m/z 324 [M+Na]+. Anal.
Calcd for C15H19N5O2: C, 59.79; H, 6.36; N, 23.24. Found: C, 59.72; H,
6.17; N, 22.83.
Preparation of 6-acetyl-1,3,7-
trimethyllumazine (2)
A mixture of 4-amino-1,3-dimethyl-5-nitrosouracil (1.85 g, 10.0 mmol)
and 1,3-pentadione (23 mL) was heated under reflux for 18 h. Excess
1,3-pentadione was removed on a rotary evaporator, and the residue
was treated with ethanol (10 mL). The resulting precipitate was col-
lected by filtration and crystallized from ethanol to give compound 2
as colorless powder: Isolated yield 1.45 g (58%); mp 167–169°C; NMR:
δ 2.80 (s, 3H), 2.94 (s, 3H), 3.55 (s, 3H), 3.74 (s, 3H); IR: ν 1715, 1679,
1595, 1548, 1489, 1399, 1379, 1361, 1344, 1282, 1259, 1217, 1119 cm-1.
Anal. Calcd for C11H12N4O3: C, 53.22; H, 4.87; N, 22.57. Found: C, 53.06;
H, 4.94; N, 22.68.
General procedure for synthesis of imine
derivatives 5a–c
A mixture of 6-acetyl-1,3,7-trimethyllumazine (2) (124 mg, 0.50 mmol),
an aniline (4a–c) (180 μL, 2.00 mmol), MS 3A (1.0 g), and BF3‧OEt2
(200 μL, 1.58 mmol) in dichloromethane (5 mL) was stirred 16 h at
room temperature. After removal of molecular sieves by filtration,
the crude product was purified by column chromatography on silica
gel using a 1:3 (v/v) mixture of ethyl acetate and hexanes containing
2 vol% triethylamine as an eluent.
Preparation of 6-acetyl-4-cyclohexyloxy-
7-methylpterin (3)
A
mixture of 2,6-diamino-4-cyclohexyloxy-5-nitrosopyrimidine
(950 mg, 4.0 mmol) and 1,3-pentadione (8 mL) was heated under
reflux for 14 h, then cooled, treated with water (30 mL), and extracted
with ethyl acetate (3ꢀ×ꢀ30 mL). The extract was dried over MgSO4 and
concentrated on a rotary evaporator. The residue was subjected to
silica gel column chromatography eluting with ethyl acetate, and
then the purified product 3 was crystallized from toluene. Compound
3 was obtained as yellow powder: Isolated yield 0.55 g (46%); mp
203–205°C; NMR: δ 1.56–1.35 (m, 3H), 1.70–1.56 (m, 1H), 1.82–1.70 (m,
2H), 1.95–1.82 (m, 2H), 2.13–2.02 (m, 2H), 2.76 (s, 3H), 2.92 (s, 3H), 5.34
6-[1-(Phenylimino)ethyl]-1,3,7-trimethyllumazineꢀ(5a)ꢁYellow
powder; isolated yield 113 mg (70%); mp 140–145°C; NMR δ 2.39
(s, 3H), 2.97 (s, 3H), 3.53 (s, 3H), 3.72 (s, 3H), 6.80 (d, Jꢀ=ꢀꢀ7 Hz, 2H), 7.11
(t, Jꢀ=ꢀꢀ7 Hz, 1H), 7.37 (t, Jꢀ=ꢀꢀ7 Hz, 2H); δ 24.8, 28.1, 29.3, 29.7, 124.1, 142.9,
148.2, 151.1, 159.7, 160.2, 199.9; IR: ν 1725, 1679, 1595, 1548, 1489, 1399,
1379, 1361, 1344, 1282, 1217, 1119 cm-1; UV/Vis: λmax, nm (εꢀ×ꢀ10-3, m-1 cm-1)
203 (31), 247 (17), 273 (13), 338 (12). Anal. Calcd for C17H17N5O2: C, 63.15;
H, 5.30; N, 21.66. Found: C, 62.56; H, 5.37; N, 21.67.
R
H2N
R
O
N
Me
O
N
Me
N
N
N
-
4a d
BF3•OEt2,
CH2Cl2, MS 3A
N
O
N
N
H2N
Me
H2N
N
Me
3
6a-d
6a
: R = H, 62%
O
N
Me
6b
: R = Me, 60%
NaBH4, ZrCl4
R = H, 50%
N
N
N
N
H
Me
6c
: R = CH2CH2OH, 50%
6d
: R = Et, 30%
H2N
7a
Scheme 3ꢀStepwise arylamination of 6-acetyl-7-methylpterin via imine intermediates.
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120ꢀ
ꢀY. Kuroda et al.: Reductive amination of 6-acetylpteridine
R
O
Me
O
Me
OH
Me
Me
O
N
N
Me
O
N
N
N
N
N
N
2
H
N
Me
N
H2N
R
Me
Me
8
7
9
4a-f
pic-BH3
R
O
N
Me
MeOH, AcOH
N
N
3
N
H
H2N
Me
8a: R = H, 90%
8b: R= Me, 55%
aqNaOH/MeOH
8c
: R = CH2CH2OH, 58%
7a
: R = H, 31%
or
8e: R = CH2CH(OH)CH2OH, 29%
7b: R = Me, 30%
aqHCl/MeOH
7c
: R = CH2CH2OH, 38%
O
Me
, 24%
8f: R =
R
O
Me
O
N
Me
N
N
HN
H2N
N
H
Me
10a-c
Scheme 4ꢀOne-step stepwise arylamination of 6-acetyl-7-methylpterin.
6-[1-(4-Methylphenylimino)ethyl]-1,3,7-trimethyllumazineꢀ(5b)
Orange powder; isolated yield 1.05 g (78%); mp 162–164°C; NMR:
δ 2.37 (s, 3H), 2.40 (s, 3H), 2.98 (s, 3H), 3.56 (s, 3H), 3.75 (s, 3H), 6.74
(d, Jꢀ=ꢀꢀ8 Hz, 2H), 7.20 (d, Jꢀ=ꢀꢀ8 Hz, 2H); IR: ν 3001, 1723, 1676, 1548,
1506, 1396, 1376, 1361, 1344, 1282, 1260, 1221, 1185, 1117, 1054, 1031,
1009 cm-1; λmax, nm (εꢀ×ꢀ10-3, m-1 cm-1) 203 (76), 246 (34), 276 (24), 343
(23). Anal. Calcd for C18H19N5O2: C, 64.08; H, 5.68; N, 20.76. Found: C,
64.14; H, 5.70; N, 20.86.
167.02, 167.25; IR: ν 3485, 3282, 3065, 2936, 2859, 1637, 1584, 1533,
1486, 1460, 1426, 1362, 1208, 1107, 713 cm-1; λmax, nm (εꢀ×ꢀ10-3, m-1 cm-1)
203 (26), 250 (19), 288 (12), 367 (12); MS (ESI): m/z 399 [M+Na]+. Anal.
Calcd for C21H24N6O: C, 67.00; H, 6.43; N, 22.32. Found: C, 66.25; H,
6.55; N, 22.27.
4-(Cyclohexyloxy)-7-methyl-6-[1-(4-methylphenylimino)ethyl]
pterin (6b)ꢁYellow powder; isolated yield: 45 mg (60%); mp
208–212°C; NMR: δ (400 MHz, CDCl3) 1.56–1.29 (m, 3H), 1.68–1.56
(m, 1H), 1.81–1.68 (m, 1H), 1.95–1.81 (m, 2H), 2.22–1.99 (m, 3H), 2.36
(s, 3H), 2.37 (s, 3H), 2.97 (s, 3H), 5.32 (tt, Jꢀ=ꢀꢀ9.0, 3.9 Hz, 1H), 5.69
(brs, 2H), 6.75 (d, Jꢀ=ꢀꢀ7.8 Hz, 1H), 7.19 (d, Jꢀ=ꢀꢀ8.0 Hz, 2H); IR (KBr): ν
3495, 2936, 1635, 1601, 1583, 1533, 1490, 1456, 1435, 1363, 1313, 1239,
1202, 1161, 1105, 1045, 825 cm-1; λmax, nm (εꢀ×ꢀ10-3, m-1 cm-1) 204 (36), 250
(18), 368 (16). HRMS (FAB). Calcd for C22H26N6O [M]+: m/z 390.2168,
found m/z 390.2162.
6-{1-[4-(2-Hydroxyethyl)phenylimino]ethyl}-1,3,7-trimethyl-
lumazine (5c)ꢁPale yellow powder; isolated yield 233 mg (18%); mp
152–157°C; NMR: δ 1.40 (s, 3H), 2.89 (t, Jꢀ=ꢀꢀ7 Hz, 2H), 2.98 (s, 3H), 3.56
(s, 3H), 3.75 (s, 3H), 3.89 (t, Jꢀ=ꢀꢀ7 Hz, 2H), 4.72 (br, 1H), 6.80 (d, Jꢀ=ꢀꢀ8
Hz, 2H), 7.25 (d, Jꢀ=ꢀꢀ2 Hz, 2H); IR: ν 3853, 3675, 3487, 2940, 1724, 1684,
1558, 1505, 1455, 1400, 1375, 1361, 1330, 1285, 1257, 1226, 1185, 1120,
1043 cm-1; λmax, nm (εꢀ×ꢀ10-3, m-1 cm-1) 204 (53), 245 (27), 277 (19), 346
(17). Anal. Calcd for C19H21N5O3: C, 61.77; H, 6.28; N, 18.96. Found: C,
61.77; H, 6.30; N, 18.86.
4-Cyclohexyloxy-6-{1-[4-(2-hydroxyethyl)phenylimino]ethyl}-
7-methylpterin (6c)ꢁYellow powder; isolated yield 42 mg (50%);
mp 214–217°C; NMR: δ 1.47 (m, 2H), 1.60 (m, 2H), 1.74 (m, 2H), 1.87
(m, 2H), 2.10 (m, 2H), 2.37 (s, 3H), 2.89 (t, Jꢀ=ꢀꢀ7 Hz, 2H), 2.97 (s, 3H),
3.90 (t, Jꢀ=ꢀꢀ7 Hz, 2H), 5.31 (m, 1H), 5.33 (br, 2H), 6.80 (d, Jꢀ=ꢀꢀ8 Hz, 2H),
7.25 (d, Jꢀ=ꢀꢀ8 Hz, 2H); δC 18.5, 23.7, 25.3, 25.5, 31.2, 38.6, 63.5, 76.2, 119.1,
120.6, 129.5, 133.9, 147.0, 148.8, 155.9, 160.4, 162.1, 167.0, 167.0; IR: ν
3445, 3223, 2939, 1652, 1582, 1527, 1496, 1483, 1362, 1328, 1208, 1105,
1034, 824 cm-1; λmax, nm (εꢀ×ꢀ10-3, m-1 cm-1) 204 (32), 251 (24), 286 (16),
366 (14). HRMS (FAB). Calcd for C23H28N6O2 [M]+: m/z 420.2274, found
General procedure for synthesis of imine
derivatives 6a–d
The procedure described above for the reaction of 2 with 4a–c was
used for the reaction of substrate 3 with anilines 4a–d.
4-(Cyclohexyloxy)-7-methyl-6-[1-(phenylimino)ethyl]pterin m/z 420.2272.
(6a) Yellow solid; isolated yield 234 mg (62%); mp 207–213°C (dec.);
4-Cyclohexyloxy-6-[1-(4-ethylphenylimino)ethyl]-7-methyl-
NMR: δ 1.56–1.29 (m, 3H), 1.68–1.56 (m, 1H), 1.81–1.68 (m, 1H), 1.95–
1.81 (m, 2H), 2.22–1.99 (m, 3H), 2.37 (s, 3H), 2.99 (s, 3H), 5.33 (tt, Jꢀ=ꢀꢀ9 pterin (6d)ꢁYellow solid; isolated yield 24 mg (30%); NMR: δ 1.27
Hz and 4 Hz, 1H), 5.55 (brs, 2H), 6.84 (d, Jꢀ=ꢀꢀ8 Hz, 1H), 7.13 (t, Jꢀ=ꢀꢀ8 (t, Jꢀ=ꢀꢀ7 Hz, 3H), 1.56–1.29 (m, 3H), 1.68–1.56 (m, 1H), 1.81–1.68 (m, 1H),
Hz, 1H), 7.39 (t, Jꢀ=ꢀꢀ8 Hz, 2H); δ 18.56, 23.83, 25.45, 25.65, 31.27, 76.54, 1.95–1.81 (m, 2H), 2.22–1.99 (m, 3H), 2.38 (s, 3H), 2.67 (q, Jꢀ=ꢀꢀ7 Hz, 2H),
118.93, 120.75, 123.74, 129.04, 147.38, 150.67, 155.60, 160.75, 161.81, 2.97 (s, 3H), 5.32 (tt, Jꢀ=ꢀꢀ9 and 4 Hz, 1H), 5.35 (brs, 2H), 6.78 (d, Jꢀ=ꢀꢀ8 Hz,
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Y. Kuroda et al.: Reductive amination of 6-acetylpteridineꢀ
ꢀ121
4-Cyclohexyloxy-6-{1-[4-[2-(hydroxyethyl)phenylamino]ethyl]}-
7-methylpterin (7c)ꢁYellow powder; isolated yield 35 mg (38%); mp
110–112°C; NMR: δ 1.24 (m, 1H), 1.45 (m, 2H), 1.52 (d, Jꢀ=ꢀꢀ6 Hz, 3H), 1.63
(m, 1H), 1.75 (m, 2H), 1.86 (m, 2H), 2.06 (m, 2H), 2.73 (t, Jꢀ=ꢀꢀ6 Hz, 2H),
2.74 (s, 3H), 3.77 (t, Jꢀ=ꢀꢀ6 Hz, 2H), 4.94 (q, Jꢀ=ꢀꢀ6 Hz, 1H), 5.29 (m, 1H), 5.33
(br, 2H), 6.66 (d, Jꢀ=ꢀꢀ8 Hz, 2H), 7.00 (d, Jꢀ=ꢀꢀ8 Hz, 2H); δ 20.7, 22.5, 23.7,
23.7, 25.5, 31.2, 31.3, 38.3, 50.8, 63.8, 75.9, 114.4, 121.5, 127.4, 129.9, 145.7,
152.3, 155.8, 158.4, 161.3, 167.0; IR: ν 3343, 2933, 2857, 1589, 1519, 1454,
1365, 1307, 1205, 1124, 1046, 930, 824, 736 cm-1; UV/Vis λmax, nm (εꢀ×ꢀ10-3,
m-1 cm-1) 204 (32), 242 (29), 362 (9). Anal. Calcd for C23H30N6O2: C, 65.38;
H, 7.16; N, 19.89. Found: C, 64.99; H, 7.23; N, 19.54.
1H), 7.21 (d, Jꢀ=ꢀꢀ8 Hz, 2H); δ 15.6, 18.5, 23.8, 25.4, 25.6, 28.3, 31.2, 76.3,
119.0, 120.7, 128.3, 139.6, 147.3, 148.2, 155.9, 160.5, 162.1, 166.9, 167.1; IR:
ν 3500, 3289, 3099, 2931, 2858, 1635, 1585, 1531, 1489, 1455, 1365, 1310,
1239, 1223, 1205, 1165, 1106, 1068, 1045, 1010, 954, 931, 912, 844, 825,
765, 669 cm-1.
Hydrogenation of imine 6a to amine 7a
A suspension of zirconium tetrachloride (37 mg, 0.16 mmol) and
sodium tetrahydroborate (25 mg, 0.66 mmol) in THF (1 mL) was
stirred at room temperature for 1 h and then treated with a solu-
tion of 6a (40 mg, 0.11 mmol) in THF (1 mL). After stirring for 1 h
the mixture was treated with water (5 mL) and extracted with ethyl
acetate (3ꢀ×ꢀ30 mL). The extract was dried over MgSO4 and concen-
trated. Silica gel column chromatography eluting with ethyl acetate
gave 4-cyclohexyloxy-6-[1-(phenylamino)ethyl]-7-methylpterin (7a)
as yellow powder. Isolated yield 21 mg (50%); mp 100–106°C (dec.);
NMR: δ 1.54 (d, Jꢀ=ꢀꢀ6 Hz, 3H), 1.58–1.35 (m, 2H), 1.68–1.58 (m, 1H),
1.97–1.68 (m, 5H), 2.15–1.99 (m, 2H), 2.76 (s, 3H), 4.98 (q, Jꢀ=ꢀꢀ6 Hz, 1H),
5.30 (tt, Jꢀ=ꢀꢀ9 Hz and 4 Hz, 1H), 5.43 (br, 2H), 6.70 (t, Jꢀ=ꢀꢀ8 Hz, 1H),
6.72 (d, Jꢀ=ꢀꢀ8 Hz, 2H), 7.16 (t, Jꢀ=ꢀꢀ8 Hz, 2H); δ 20.6, 22.5, 23.7, 2.75, 25.5,
31.2, 31.3, 50.6, 75.9, 114.1, 117.8, 121.5, 129.3, 147.0, 152.3, 155.9, 158.3,
161.3, 167.0; IR: ν 3327, 3173, 2932, 2858, 1739, 1632, 1600, 1587, 1541,
1506, 1459, 1438, 1365, 1311, 1250, 1207, 1123, 1072, 1031, 1010, 927, 825,
749, 692 cm-1; λmax, nm (εꢀ×ꢀ10-3, m-1 cm-1) 204 (31), 242 (28), 271 (11), 362
(9). HRMS (FAB). Calcd for C21H26N6O [M]+: m/z 378.2168, found m/z
378.2159.
6-[1-(Phenylamino)ethyl]-1,3,7-trimethyllumazine (8a)ꢁYellow
powder; isolated yield 58 mg (93%); mp 138–140°C; NMR: δ 1.56
(d, Jꢀ=ꢀꢀ7 Hz, 3H), 2.77 (s, 3H), 3.52 (s, 3H), 3.69 (s, 3H), 5.02 (q, Jꢀ=ꢀꢀ7 Hz,
1H), 6.62–6.75 (m, 3H), 7.14 (t, Jꢀ=ꢀꢀ8 Hz, 2H); IR: ν 3372, 2923, 1715, 1676,
1601, 1554, 1496, 1408, 1283, 1240, 748 cm-1; UV/Vis λmax, nm (εꢀ×ꢀ10-3,
m-1 cm-1) 205 (37), 242 (30), 333 (10). HRMS (FAB). Calcd for C17H19N5O2
[M]+: m/z 325.1539, found m/z 325.1548.
6-[1-(4-Tolylamino)ethyl]-1,3,7-trimethyllumazine (8b)ꢁOrange
powder; isolated yield 91 mg (55%); mp 162–164°C; NMR: δ 1.55
(d, Jꢀ=ꢀꢀ7 Hz, 3H), 2.20 (s, 3H), 2.77 (s, 3H), 3.52 (s, 3H), 3.68 (s, 3H),
4.62 (br, 1H), 4.98 (br, 1H), 6.60 (d, Jꢀ=ꢀꢀ8 Hz, 2H), 6.95 (d, Jꢀ=ꢀꢀ8 Hz, 2H);
δ 20.6, 20.9, 22.3, 29.1, 29.4, 51.1, 114.6, 125.1, 127.8, 130.2, 144.8, 146.6,
151.2, 153.3, 156.4; IR: ν 3336, 2976, 1721, 1679, 1617, 1554, 1521, 1406,
1372, 1354, 1319, 1284, 1240, 1180, 1136, 1007 cm-1; UV/Vis λmax, nm
(εꢀ×ꢀ10-3, m-1 cm-1) 205 (32), 242 (27), 333 (9). Anal. Calcd for C18H21N5O2:
C, 63.51; H, 6.24; N, 20.64. Found: C, 63.51; H, 6.38; N, 20.63.
6-{1-[4-[2-(Hydroxyethyl)phenylamino]ethyl]}-1,3,7-trimethyl-
lumazine (8c)ꢁOrange powder; isolated yield: 327 mg (58%); mp
170–173°C; NMR: δ 1.55 (d, Jꢀ=ꢀꢀ7 Hz, 3H), 2.72 (t, Jꢀ=ꢀꢀ7 Hz, 2H), 2.77 (s,
3H), 3.52 (s, 3H), 3.68 (s, 3H), 3.77 (q, Jꢀ=ꢀꢀ6 Hz, 2H), 4.78 (d, Jꢀ=ꢀꢀ9 Hz, 1H),
4.91–5.05 (m, 1H), 6.63 (d, Jꢀ=ꢀꢀ8 Hz, 2H), 7.00 (d, Jꢀ=ꢀꢀ8 Hz, 2H); δ 20.9,
22.2, 29.08, 29.4, 38.9, 50.7, 64.1, 114.5, 125.0, 128.1, 130.2, 145.7, 146.5,
151.1, 153.2, 156.4, 160.6; IR: ν 3440, 3308, 2942, 1716, 1667, 1615, 1556,
1517, 1405, 1356, 1288, 1240, 1008 cm-1; UV/Vis λmax, nm (εꢀ×ꢀ10-3, m-1
cm-1) 205 (49), 247 (34), 343 (10). Anal. Calcd for C19H23N5O3: C, 61.77;
H, 6.28; N, 18.96. Found: C, 61.77; H, 6.30; N, 18.86.
One-step reductive aminations of 2 and 3
with anilines 4a–f: a general procedure for
preparation of 7 (from 3) and 8 (from 2)
A suspension of 3 or 2 (0.17 mmol) and MS 3A (1 g) in a 10:1 (v/v)
mixture of methanol and acetic acid (11 mL) was treated with an
aniline 4a–f (0.43 mmol) and 2-picoline‧borane (25 mg, 0.23 mmol)
at room temperature. After stirring for 20 h the molecular sieves
were removed by filtration, and the solution was neutralized with
a saturated solution of NaHCO3 (15 mL). The mixture was extracted
with ethyl acetate (20 mL), and the extract was dried over MgSO4.
After removal of the solvent on a rotary evaporator, the crude
product was subjected to silica gel column chromatography eluting
with ethyl acetate. Compound 7a was obtained in a 31% yield
(13 mg).
6-{1-[4-[2,3-(Dihydroxypropyl)phenylamino]ethyl]}-1,3,7-tri-
methyllumazine (8e)ꢁOrange powder; isolated yield 19 mg (24%);
NMR: δ 1.55 (d, Jꢀ=ꢀꢀ7 Hz, 2 H), 1.85 (br, 1H) 1.87 (br, 1H), 2.56–2.71
(m, 2H), 2.78 (s, 3H), 3.44–3.51 (m, 2H), 3.52 (s, 3H), 3.65 (dd, Jꢀ=ꢀꢀ11 Hz
and 3 Hz, 1H), 3.69 (s, 3H), 4.68 (br, 2H), 6.64 (d, Jꢀ=ꢀꢀ8 Hz, 2H), 6.99
(d, Jꢀ=ꢀꢀ9.0 Hz, 2H).
4-Cyclohexyloxy-6-[1-(4-tolylamino)ethyl]-7-methylpterin (7b)
Yellow powder; isolated yield 47 mg (30%); mp 144–147°C; NMR:
δ 1.26 (m, 1H), 1.44 (m, 2H), 1.53 (d, Jꢀ=ꢀꢀ6 Hz, 3H), 1.63 (m, 1H), 1.76 (m,
2H), 1.88 (m, 2H), 2.06 (m, 2H), 2.21 (s, 3H), 2.74 (s, 3H), 4.94 (q, Jꢀ=ꢀꢀ6
Hz, 1H), 5.27 (br, 2H), 5.30 (tt, Jꢀ=ꢀꢀ9 and 4 Hz, 1H), 6.64 (d, Jꢀ=ꢀꢀ8 Hz, 2H),
6.96 (d, Jꢀ=ꢀꢀ8 Hz, 2 H); IR: ν 3393, 2952, 2919, 2849, 1618, 1590, 1559,
1539, 1521, 1457, 1437, 1312, 1209, cm-1; UV/Vis λmax, nm (εꢀ×ꢀ10-3, m-1 cm-1)
204 (35), 240 (29), 361 (3). HRMS (FAB). Calcd for C22H28N6O [M]+: m/z
392.2325, found m/z 392.2319.
6-{1-[4-((2,2-Dimethyl-1,3-dioxolan-4-yl)methyl)phenylamino]
ethyl}-1,3,7-trimethyllumazine (8f)ꢁOrange powder; isolated yield
25 mg (29%); NMR: δ 1.33 (s, 3H), 1.41 (s, 3H), 1.55 (d, Jꢀ=ꢀꢀ7 Hz, 3H), 2.62
(dd, Jꢀ=ꢀꢀ14 Hz and 7 Hz, 1H), 2.77 (s, 3H), 2.88 (dd, Jꢀ=ꢀꢀ14 Hz and 6 Hz,
1H), 3.52 (s, 3H), 3.59 (t, Jꢀ=ꢀꢀ7 Hz, 1H), 3.69 (s, 3H), 3.92 (dd, Jꢀ=ꢀꢀ8 Hz and
6 Hz, 1H), 4.17–4.33 (m, 1H), 6.61(d, Jꢀ=ꢀꢀ8 Hz, 2H), 6.98 (d, J ꢀ=ꢀꢀ8 Hz, 2H).
Received March 28, 2012; accepted April 26, 2012
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122ꢀ
ꢀY. Kuroda et al.: Reductive amination of 6-acetylpteridine
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