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DOI: 10.1055/s-0028-1083500
An Efficient One-Pot Synthetic Method for 2,4-Disubstituted 7-Arylpyrido[4,3-d]pyrimidines from 2,4-Disubstituted 6-(Arylethynyl)pyrimidine-5-carbaldehydes and tert-Butylamine
Publication History
Publication Date:
15 October 2008 (online)
Abstract
Unexpected thermal cyclization of 2,4-disubstituted 6-(aryl-ethynyl)pyrimidine-5-carbaldehydes with tert-butylamine proceeded to give 2,4-disubstituted 7-arylpyrido[4,3-d]pyrimidines in good yields in the absence of any catalysts. The intermediate compounds were isolated and possible mechanism of the reactions is discussed.
Key words
cyclization - alkynes - aldehydes - pyrido[4,3-d]pyrimidines - 1,6-electrocyclic reaction
-
1a
Modern Acetylene Chemistry
Stang PJ.Diederich F. VCH; Weinheim: 1995. -
1b
Chemistry
of Triple-Bonded Functional Groups
Patai S. Wiley; New York: 1994. -
2a
Takeda A.Kamijo S.Yamamoto Y. J. Am. Chem. Soc. 2000, 122: 5662 -
2b
Gabriele B.Salerno G.Fazio A. Org. Lett. 2000, 2: 351 -
2c
Arcadi A.Cacchi S.Del Rosario M.Fabrizi G.Marinelli F. J. Org. Chem. 1996, 61: 9280 -
2d
Cacchi S.Fabrizi G.Moro L. Tetrahedron Lett. 1998, 39: 5101 -
3a
Roesh KR.Larock RC. Org. Lett. 1999, 1: 553 -
3b
Roesh KR.Larock RC. J. Org. Chem. 2002, 67: 86 -
3c
Dai G.Larock RC. Org. Lett. 2001, 3: 4035 -
3d
Dai G.Larock RC. Org. Lett. 2002, 4: 193 -
3e
Zhang H.Larock RC. J. Org. Chem. 2002, 67: 7048 -
4a
Huang Q.Hunter JA.Larock RC. Org. Lett. 2001, 3: 2973 -
4b
Huang Q.Hunter JA.Larock RC. J. Org. Chem. 2002, 67: 3437 -
5a
Susvilo I.Brukstus A.Tumkevicius S. Synlett 2003, 1151 -
5b
Tumkevicius S.Susvilo I.Brukstus A. Chem. Heterocycl. Compd. 2004, 1546 -
5c
Cikotiene I.Morkunas M.Motiejaitis D.Rudys S.Brukstus A. Synlett 2008, 1693 - 6
Cikotiene I.Pudziuvelyte E.Brukstus A.Tumkevicius S. Tetrahedron 2007, 63: 8145 -
7a
Raymond E.Faivre S.Armand JP. Drugs 2000, 60: 15 -
7b
Smaill JB.Palmer BD.Rewcastle GW.Denny WA.McNamara DJ.Dobrusin EM.Bridges AJ.Zhou H.Showalter HDH.Winters RT.Leopold WR.Fry DW.Nelson JM.Slintak V.Elliot WL.Roberts BJ.Vincent PW.Patmore SJ. J. Med. Chem. 1999, 42: 1803
References and Notes
Typical Procedure
for the Preparation of 2,4-Disub-stituted 7-Arylpyrido[4,3-
d
]pyrimidines
2a-u
The mixture of the corresponding 2,4-disubstituted
6-(arylethynyl)pyrimidine-5-carbaldehyde 1a-u (0.2 mmol) and t-BuNH2 (3
mL) in tube was flushed with argon, and the tube was carefully sealed.
The mixture was heated at 110-120 ˚C
for 24 h. The solvent was evaporated under reduced pressure, residue
recrystallized to give compounds 2a-u.
2-(Methylthio)-4-morpholin-1-yl-7-phenylpyrido[4,3-
d
]-pyrimidine
(2b)
Yield 95%, mp 145-147 ˚C
(from 2-PrOH). ¹H NMR (300 MHz, CDCl3): δ = 2.66
(3 H, s, SCH3), 3.93 [4 H, t, J = 3.9 Hz,
N(CH2)2], 4.01 [4 H, t, J = 3.9 Hz,
O(CH2)2], 7.49-7.55 (3 H,
m, ArH), 7.95 (1 H, s, CH), 8.13-8.16 (2 H, m, ArH), 9.27
(1 H, s, CH). ¹³C NMR (75 Hz, CDCl3): δ = 14.3,
49.8, 66.6, 108.9, 115.4, 127.1, 128.9, 129.6, 138.2, 149.0, 157.1, 157.9,
161.9, 172.2. Anal. Calcd for C18H18N4OS:
C, 63.88; H, 5.36; N, 16.56. Found: C, 63.96; H, 5.44; N, 16.70.
2-(Methylthio)-7-phenyl-4-piperidin-1-ylpyrido[4,3-
d
]-pyrimidine
(2c)
Yield 85%, mp 126-128 ˚C
(from 2-PrOH). ¹H NMR (300 MHz, CDCl3): δ = 1.84 [4
H, br s, (CH2)3], 2.65 (3 H, s, SCH3),
3.94 [4 H, br s, N(CH2)2],
7.49-7.54 (3 H, m, ArH), 7.90 (1 H, s, CH), 8.13 (2 H,
d, J = 6.9
Hz, ArH), 9.24 (1 H, s, CH). ¹H NMR (300 MHz,
DMSO-d
6): δ = 1.74 [4
H, br s, (CH2)3], 2.56 (3 H, s, SCH3),
3.92 [4 H, br s, N(CH2)2],
7.49-7.54 (3 H, m, ArH), 7.94 (1 H, s, CH), 8.22-8.25
(2 H, m, ArH), 9.25 (1 H, s, CH). ¹³C
NMR (75 Hz, CDCl3): δ = 14.2, 24.6,
26.0, 50.5, 115.3, 127.1, 128.8, 129.5, 138.4, 149.3, 157.2, 157.6,
161.7, 172.0. Anal. Calcd for C19H20N4S:
C, 67.83; H, 5.99; N, 16.65. Found: C, 67.90; H, 6.07; N, 16.59.
4-
N
,
N
-Dimethylamino-2-(methylthio)-7-phenylpyrido-[4,3-
d
]pyrimidine
(2f)
Yield 92%, mp 155-156 ˚C
(from 2-PrOH). ¹H NMR (300 MHz, CDCl3): δ = 2.65
(3 H, s, SCH3), 3.51 [6 H, s, N(CH3)2],
7.49-7.53 (3 H, m, ArH), 7.90 (1 H, s, CH), 8.13 (2 H,
d, J = 7.2
Hz, ArH), 9.41 (1 H, s, CH). ¹³C NMR
(75 Hz, CDCl3): δ = 14.2,
41.8, 109.3, 115.3, 127.1, 128.8, 129.5, 138.4, 149.6, 157.2, 157.4,
160.8, 171.7. Anal. Calcd for C16H16N4S:
C, 64.84; H, 5.44; N, 18.90. Found: C, 64.79; H, 5.32; N, 18.99.
7-(4-Ethylphenyl)-2-(methylthio)-4-morpholin-1-yl-pyrido-[4,3-
d
]pyrimidine
(2l)
Yield 90%, mp 127-128 ˚C
(from hexane). ¹H NMR (300 MHz, CDCl3): δ = 1.32
(3 H, t, J = 7.5
Hz, CH3), 2.63 (3 H, s, SCH3), 2.76 (2 H,
q, J = 7.5
Hz, CH2), 3.92 [4 H, t, J = 2.1 Hz,
N(CH2)2], 3.96 [4 H, t, J = 2.1 Hz,
O(CH2)2], 7.38 (2 H, d, J = 8.1 Hz,
ArH), 7.72 (1 H, s, CH), 7.79 (2 H, d, J = 8.1 Hz,
ArH), 9.04 (1 H, s, CH). ¹³C NMR (75
Hz, CDCl3): δ = 14.3,
15.4, 28.7, 49.8, 66.7, 108.8, 114.5, 127.1, 128.4, 135.6, 146.2,
148.9, 157.1, 158.0, 161.9, 172.1. Anal. Calcd for C20H22N4OS:
C, 65.55; H, 6.05; N, 15.29. Found: C, 65.76; H, 5.93; N, 15.44.
Typical Procedure
for the Preparation of
N
-{4-[(
Z
)-2-(
tert
-butylamino)-2-phenylvinyl]-2-(methylthio)-pyrimidin-5-ylmethylene}-2-methylpropan-2-amines 3a-c
The
mixture of the corresponding 2,4-disubstituted 6-(arylethynyl)pyrimidine-5-carbaldehyde 1a-c (0.2
mmol) and t-BuNH2 (3 mL) in
tube was flushed with argon, and the tube was carefully sealed.
The mixture was heated at 80-90 ˚C for
20 h. The solvent was evaporated under reduced pressure, compounds 3a-c were
isolated by column flash chromatography.
N
-{4-(
Z
)-2-[(
tert-
butylamino)-2-phenylvinyl]-2-(methyl-thio)-6-morpholin-1-ylpyrimidin-5-ylmethylene}-2-methylpropan-2-amine
(3b)
Yield 62%, mp 140-142 ˚C
(from MeOH-H2O); R
f
= 0.78 (toluene-EtOAc,
1:1). IR (KBr): 3442 (NH) cm-¹. ¹H
NMR (300 MHz, CDCl3): δ = 1.19
(9 H, s, t-Bu), 1.22 (9 H, s, t-Bu), 2.57 (3 H, s, SCH3),
3.46 [4 H, t, J = 4.2
Hz, N(CH2)2], 3.79 [4 H,
t, J = 4.2
Hz, O(CH2)2], 6.17 (1 H, s, CH),
7.34-7.36 (3 H, m, ArH), 7.46-7.49 (2 H, m, ArH),
8.15 (1 H, s, CH), 10.08 (1 H, br s, NH). ¹³C
NMR (75 Hz, CDCl3): δ = 13.9,
29.5, 32.1, 49.8, 53.9, 57.7, 66.8, 96.3, 105.5, 127.3, 128.2, 128.8,
140.9, 153.4, 160.6, 162.2, 164.2, 168.0. Anal. Calcd for C26H37N5OS:
C, 66.77; H, 7.97; N, 14.95. Found: C, 66.49; H, 8.08; N, 15.10.
N -{4-( Z )-2-[( tert -butylamino)-2-phenylvinyl]-2-(methyl-thio)-6-piperidin-1-ylpyrimidin-5-ylmethylene}-2-methylpropan-2-amine (3c) Yield 58%, mp 109-110 ˚C (from 2-PrOH); R f = 0.81 (toluene-EtOAc, 1:1). IR (KBr): 3443 (NH) cm-¹. ¹H NMR (300 MHz, CDCl3): δ = 1.17 (9 H, s, t-Bu), 1.23 (9 H, s, t-Bu), 1.65 [6 H, br s, (CH2)3], 2.57 (3 H, s, SCH3), 3.41 [4 H, br s, N(CH2)2], 6.31 (1 H, s, CH), 7.32-7.34 (3 H, m, ArH), 7.48-7.51 (2 H, m, ArH), 8.07 (1 H, s, CH), 9.98 (1 H, br s, NH). ¹H NMR (300 MHz, DMSO-d 6): δ = 1.09 (9 H, s, t-Bu), 1.14 (9 H, s, t-Bu), 1.61 [6 H, br s, (CH2)3], 2.52 (3 H, s, SCH3), 3.37 [4 H, br s, N(CH2)2], 6.50 (1 H, s, CH), 7.40 (5 H, s, ArH), 7.99 (1 H, s, CH), 9.88 (1 H, br s, NH). ¹³C NMR (75 Hz, CDCl3): δ = 13.9, 24.6, 26.1, 29.6, 32.1, 50.5, 53.9, 57.5, 97.3, 105.5, 127.3, 128.0, 128.9, 141.3, 153.9, 160.1, 161.9, 164.8, 167.7. Anal. Calcd for C27H39N5S: C, 69.63; H, 8.44; N, 15.04. Found: C, 69.42; H, 8.59; N, 15.19.
11
Typical Procedure
for the Cyclization of
N
-{4-[(
Z
)-2-(
tert
-butylamino)-2-phenylvinyl]pyrimidin-5-yl-methylene}-2-methylpropan-2-amines
3a-c into4-Substituted 2-(Methylthio)-7-phenylpyrido[4,3-
d
]-pyrimidines
2a-c
The solution of compounds 3a-c (2
mmol) in DMSO (2 mL) was heated at 110-120 ˚C
for 15 min. After cooling, reaction mixture was diluted with H2O
(10 mL), precipitate collected by filtration and recrystallyzed
to give compounds 2a-c.
Compounds 2a,d-e,g-k,m-u and 3a were also fully characterized by IR, ¹H NMR, and ¹³C NMR spectroscopic and microanalytical data.