2-(6-Amino-7H-purin-7-yl)-1-phenyl­ethanone

In the title compound, C₁₃H₁₁N₅O, the exocyclic amino group of one purine mol­ecule forms two inter­molecular N—H...N hydrogen bonds to different ring N atoms of another mol­ecule. The purine system is orientated almost perpendicular [77.96 (6)°] to the phenyl­ethanone substituent. The preparation of the title compound occurred via a regioselective synthesis using the methyl(aqua)cobaloxime complex CH₃Co(DH)₂OH₂ as a temporary auxiliary, and its X-ray crystal structure confirmed the regioselective N-alkyl­ation of this mol­ecule.

Key indicators

• Single-crystal X-ray study
• T = 193 K
• Mean [sigma](C-C) = 0.003 Å
• R factor = 0.047
• wR factor = 0.136
• Data-to-parameter ratio = 13.2

checkCIF/PLATON results

No syntax errors found



Alert level C
ABSTY03_ALERT_1_C  The _exptl_absorpt_correction_type has been given as none.
            However values have been given for Tmin and Tmax. Remove
            these if an absorption correction has not been applied.
  From the CIF: _exptl_absorpt_correction_T_min   0.695
  From the CIF: _exptl_absorpt_correction_T_max   0.926

   0 ALERT level A = In general: serious problem
   0 ALERT level B = Potentially serious problem
   1 ALERT level C = Check and explain
   0 ALERT level G = General alerts; check

   1 ALERT type 1 CIF construction/syntax error, inconsistent or missing data
   0 ALERT type 2 Indicator that the structure model may be wrong or deficient
   0 ALERT type 3 Indicator that the structure quality may be low
   0 ALERT type 4 Improvement, methodology, query or suggestion
   0 ALERT type 5 Informative message, check

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S1. Comment

Protein kinases (PK) are favoured targets for the development of new drugs (Hopkins & Groon, 2002) because the reversible protein; phosphorylation by PK is an important control mechanism in signal pathways of a cell (Laufer et al., 2005). In the title compound, the purine system is combined with an acetophenone unit in order to interact with the active site of protein kinases (Laufer et al., 2005). Purine derivatives have been reported as inhibitors for other PK, mainly cyclin- dependent kinases (Meijer & Raymond, 2003). The general synthetic procedure for 3 and 5 is illustrated in Figure 3 (Dalby et al., 1993). The preparation of 1 and of the auxiliary methyl(aqua)cobaloxime- complex CH₃Co(DH)₂OH₂ (Marzilli et al., 1975) was performed according to the published procedures (Bader & Chiang, 1983; Schrauzer, 1968). The analogue compound 4 (Buehler et al., 2007) and further purine derivatives related to 5 have been published as crystal structures (Kowalska et al., 1999; Houlton et al., 1999; Takimoto et al., 1983; Hockova et al., 1999; Sood et al., 1998; Baumann et al., 1994).

Compound 5 was prepared as an inhibitor of the Vascular Endothelial Growth Factor Receptor (VEGF-R). In the design of compound 5 the purine system from the cosubstrat ATP of these protein kinase (PK) is combined with an acetophenone moiety in order to interact with the hydrophobic region of the PK. In general, the reversible protein - phosphorylation by PK is an important control mechanism in signal pathways of a cell.

The X-ray crystal structure of compound 5 was determined to investigate if an intramolecular 8-membered ring was formed by the interaction of the N19 amino- group to the neighbour carbonyl- oxygen-atom O-12 of the acetophenone moiety. This intramolecular H-bond may influence the conformation of 5 in the binding pocket, and thereby accounting for biological activity. However, this interaction was not detected in the crystal structure. In fact, these two functional groups are rotated in opposite directions. The analysis of the crystal structure of 5 shows that the amino- group of the one purine- molecule links another purine- ring system by the building of two intermolecular hydrogen bonds N—H···N to the nitrogen- atoms N-3 and N-9, whereas the N-3···H distance is 2.01 Å. The length of the second hydrogen bond N-9···H is 2.17 Å.

The synthetis of 5 (Figure 3) starts from 6- chloropurine 1 showing a tautomerism between the 7H- and the 9H- purine, in which the 9H- isomer is the favoured form. Thus, the direct alkylation of 1 results in mainly N-9- substituted purines with the N-7 substitution as the minor product. In order to obtain a regioselective N-7- alkylation CH₃Co(DH)₂OH₂ was used as an auxiliary. The complex of CH₃Co(DH)₂OH₂ and purine forms an intramolecular N—H···O hydrogen bond from purine N-9 to dimethylglyoximato-O-1 and this indirect shielding prevents the N-9- alkylation of 1. As a consequence, the coordination of the cobalt- atom to the N-7 atom of the purine is not possible because of the sterical hindrance of the neighbour C-6 halogen substituent. Hence, due to the temporary protection of the N-3 and N-9 positions of 1, by addition of ω- bromoacetophenone, the solid 2 was obtained as the main product and the N-9 alkylated isomer 3 as the minor product. Subsequently, treatment of compound 2 with methanolic ammonia in a high pressure reactor yielded the 6- methoxy- substituted compound 4 (49,5%) as a main product, which crystal structure has been published (Buehler et al., 2007) and the adenine derivative 5 (34,9%) as a byproduct.

Related literature

Protein kinases (PK) are favoured targets for the development of new drugs (Hopkins & Groon, 2002) because the reversible protein; phosphorylation by PK is an important control mechanism in signal pathways of a cell (Laufer et al., 2005). In the title compound, the purine system is combined with an acetophenone unit in order to interact with the active site of protein kinases (Laufer et al., 2005). Purine derivatives have been reported as inhibitors for other PK, mainly cyclin- dependent kinases (Meijer & Raymond, 2003). A general synthetic procedure is given by Dalby et al. (1993). For preparation, see: Marzilli et al. (1975); Bader & Chiang (1983); Schrauzer (1968). The structures of an analoguous compound (Buehler et al., 2007) and further purine derivatives related to the title compound have been reported (Kowalska et al., 1999; Houlton et al., 1999; Takimoto et al., 1983; Hockova et al., 1999; Sood et al., 1998; Baumann et al., 1994).

S2. Experimental

Regioselective N-7- alkylation of 6- chloropurine 1 for the preparation of 2-(6-chlor-7H-purin-7-yl)-1-phenylethanone 2: To a solution of methyl(aqua)cobaloxime CH₃Co(DH)₂OH₂ (1.55 mmol) in anhydrous acetonitrile (10 ml) was added 6- chloropurine 1 (1.55 mmol) under vigorous stirring and under light exclusion. After the orange purinecobaloxime- complex had precipitated, K₂CO₃ (1.55 mmol) and acetonitrile (5 ml) were added and the reaction mixture was stirred for another 30 min. After the addition of ω- bromoacetophenone (1.55 mmol) the progress of the reaction was monitored by thin - layer chromatography (ethyl acetate: ethanol 9:1). After the reaction was completed, acetonitrile was evaporated and aqueous NaOH (20 ml, 4 M) was added. The aqueous layer was extracted with dichloromethane, and the combined organic extracts were dried over Na₂SO₄ and evaporated. The residue was purified by flash column chromatography using ethyl acetate: ethanol (9:1) to give 2 (R_f = 0.49 (ethyl acetate: ethanol 9:1)) as a colourless solid (45.0%). The byproduct 2-(6-chlor-9H-purin-9-yl)-1-phenylethanone 3 (R_f = 0.76 (ethyl acetate: ethanol 9:1)) was isolated with a yield of 4.7% (Dalby et al., 1993).

For the synthesis of 2-(6-amino-7H-purine-7-yl)-1-phenylethanone 5, NH₃ (5 ml) was added to a solution of 3 (1.36 mmol) in 15 ml me thanol. The reaction mixture was heated at T = 363 K in a high pressure reactor from BERGHOF. The progress was again monitored by thin - layer chromatography (ethyl acetate: ethanol 9:1). After cooling to rt, water was added and the mixture extracted with ethyl acetate, dried over Na₂SO₄ and evaporated. The residue was purified by flash column chromatography using ethyl acetate: ethanol (9:1) to yield 49.5% of 4 (R_f = 0.70, ethyl acetate: ethanol 1:1) and 2-(6-amino-7H-purine-7-yl)-1-phenylethanone 5 (34.9%, R_f = 0.43, ethyl acetate: ethanol 1:1) as a byproduct. Crystals of 5 for X-ray analysis precipitated as colourless needles by slow evaporation of ethanol- diethylether solution.

S3. Refinement

Hydrogen atoms attached to carbons were placed at calculated positions with C—H=0.95A% (aromatic) or 0.99–1.00 Å (sp³ C-atom). Hydrogen atom attached to N19 were located in diff. fourier maps. All H atoms were refined with isotropic displacement parameters (set at 1.2–1.5 times of the U_eq of the parent atom).

Computing details

Data collection: CAD-4 Software(Enraf–Nonius, 1989); cell refinement: CAD-4 Software(Enraf–Nonius, 1989); data reduction: CORINC (Dräger & Gattow, 1971); program(s) used to solve structure: SIR92 (Altomare et al., 1994); program(s) used to refine structure: SHELXL97 (Sheldrick, 1997); molecular graphics: PLATON (Spek, 2003); software used to prepare material for publication: SHELXL97 (Sheldrick, 1997).

Figures

	Fig. 1. ORTEPII (Johnson, 1968) view of one molecule of 5. Displacement ellipsoids are drawn at the 50% probability level. H atoms are depicted as circles of arbitrary size.
	Fig. 2. Part of the crystal packing of compound 5. Only important H atoms are shown.
	Fig. 3. Synthesis of compounds 4 and 5.

2-(6-Amino-7H-purin-7-yl)-1-phenylethanone

Crystal data

C13H11N5O	F(000) = 528
Mr = 253.27	Dx = 1.409 Mg m^−3
Monoclinic, P21/n	Cu Kα radiation, λ = 1.54178 Å
Hall symbol: -P 2yn	Cell parameters from 25 reflections
a = 5.2098 (9) Å	θ = 25–39°
b = 17.738 (3) Å	µ = 0.79 mm^−1
c = 13.046 (3) Å	T = 193 K
β = 97.998 (19)°	Needle, colourless
V = 1193.9 (4) Å^3	0.50 × 0.10 × 0.10 mm
Z = 4

Data collection

Enraf–Nonius CAD-4 diffractometer	Rint = 0.040
Radiation source: rotating anode	θmax = 70.1°, θmin = 4.2°
Graphite monochromator	h = −6→0
ω/2θ scans	k = 0→21
2521 measured reflections	l = −15→15
2266 independent reflections	3 standard reflections every 60 min
1715 reflections with I > 2σ(I)	intensity decay: 5%

Refinement

Refinement on F^2	Primary atom site location: structure-invariant direct methods
Least-squares matrix: full	Secondary atom site location: difference Fourier map
R[F^2 > 2σ(F^2)] = 0.047	Hydrogen site location: inferred from neighbouring sites
wR(F^2) = 0.136	H-atom parameters constrained
S = 1.03	w = 1/[σ^2(Fo^2) + (0.0801P)^2 + 0.080P] where P = (Fo^2 + 2Fc^2)/3
2266 reflections	(Δ/σ)max < 0.001
172 parameters	Δρmax = 0.20 e Å^−3
0 restraints	Δρmin = −0.23 e Å^−3

Special details

Geometry. All e.s.d.'s (except the e.s.d. in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell e.s.d.'s are taken into account individually in the estimation of e.s.d.'s in distances, angles and torsion angles; correlations between e.s.d.'s in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell e.s.d.'s is used for estimating e.s.d.'s involving l.s. planes.

Refinement. Refinement of F² against ALL reflections. The weighted R-factor wR and goodness of fit S are based on F², conventional R-factors R are based on F, with F set to zero for negative F². The threshold expression of F² > σ(F²) is used only for calculating R-factors(gt) etc. and is not relevant to the choice of reflections for refinement. R-factors based on F² are statistically about twice as large as those based on F, and R- factors based on ALL data will be even larger.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Ų)

	x	y	z	Uiso*/Ueq
N1	0.2317 (3)	0.32674 (9)	0.53914 (12)	0.0271 (4)
C2	0.4370 (3)	0.27657 (10)	0.55492 (13)	0.0242 (4)
C3	0.5890 (3)	0.23729 (10)	0.49112 (14)	0.0251 (4)
N4	0.7799 (3)	0.19328 (10)	0.53861 (12)	0.0327 (4)
C5	0.8118 (4)	0.18891 (12)	0.64190 (16)	0.0369 (5)
H5	0.9491	0.1572	0.6717	0.044*
N6	0.6790 (4)	0.22254 (10)	0.70889 (12)	0.0346 (4)
C7	0.4892 (4)	0.26716 (10)	0.66170 (14)	0.0278 (4)
N8	0.3232 (3)	0.30991 (10)	0.71111 (13)	0.0347 (4)
C9	0.1762 (4)	0.34381 (12)	0.63502 (16)	0.0345 (5)
H9	0.0415	0.3777	0.6462	0.041*
C10	0.1080 (4)	0.36032 (11)	0.44408 (15)	0.0295 (4)
H10A	−0.0544	0.3853	0.4570	0.035*
H10B	0.0618	0.3201	0.3921	0.035*
C11	0.2806 (3)	0.41779 (11)	0.40063 (15)	0.0278 (4)
O12	0.5035 (3)	0.42658 (9)	0.44132 (11)	0.0388 (4)
C13	0.1692 (4)	0.46102 (11)	0.30769 (15)	0.0300 (4)
C14	0.3089 (4)	0.52134 (11)	0.27538 (17)	0.0365 (5)
H14	0.4693	0.5352	0.3146	0.044*
C15	0.2178 (5)	0.56100 (13)	0.18757 (18)	0.0446 (6)
H15	0.3139	0.6024	0.1668	0.054*
C16	−0.0146 (5)	0.54055 (13)	0.12922 (17)	0.0449 (6)
H16	−0.0768	0.5674	0.0677	0.054*
C17	−0.1551 (5)	0.48118 (14)	0.16068 (18)	0.0460 (6)
H17	−0.3144	0.4672	0.1206	0.055*
C18	−0.0666 (4)	0.44154 (12)	0.25024 (17)	0.0378 (5)
H18	−0.1664	0.4013	0.2722	0.045*
N19	0.5613 (3)	0.24173 (10)	0.38802 (11)	0.0302 (4)
H19A	0.4165	0.2622	0.3426	0.045*
H19B	0.6721	0.2107	0.3557	0.045*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
N1	0.0213 (8)	0.0339 (8)	0.0278 (8)	0.0003 (6)	0.0092 (6)	−0.0004 (6)
C2	0.0205 (8)	0.0287 (9)	0.0238 (9)	−0.0023 (7)	0.0043 (7)	0.0006 (7)
C3	0.0220 (9)	0.0298 (9)	0.0235 (9)	−0.0036 (7)	0.0034 (7)	−0.0015 (7)
N4	0.0298 (9)	0.0376 (9)	0.0299 (9)	0.0054 (7)	0.0010 (7)	−0.0022 (7)
C5	0.0349 (11)	0.0398 (11)	0.0334 (11)	0.0052 (9)	−0.0046 (9)	0.0020 (9)
N6	0.0378 (10)	0.0411 (9)	0.0233 (8)	−0.0046 (8)	−0.0016 (7)	0.0031 (7)
C7	0.0292 (10)	0.0315 (9)	0.0232 (9)	−0.0096 (8)	0.0059 (7)	−0.0002 (7)
N8	0.0392 (10)	0.0404 (9)	0.0276 (8)	−0.0044 (8)	0.0154 (7)	−0.0014 (7)
C9	0.0329 (11)	0.0390 (11)	0.0360 (11)	−0.0021 (9)	0.0196 (9)	−0.0024 (9)
C10	0.0192 (9)	0.0358 (10)	0.0343 (10)	0.0013 (8)	0.0064 (8)	0.0035 (8)
C11	0.0206 (9)	0.0299 (9)	0.0339 (10)	0.0035 (7)	0.0067 (8)	−0.0015 (8)
O12	0.0214 (7)	0.0450 (8)	0.0494 (9)	−0.0019 (6)	0.0033 (6)	0.0074 (7)
C13	0.0276 (10)	0.0320 (10)	0.0324 (10)	0.0053 (8)	0.0109 (8)	0.0001 (8)
C14	0.0342 (11)	0.0324 (10)	0.0444 (12)	0.0018 (9)	0.0110 (9)	0.0028 (9)
C15	0.0523 (14)	0.0366 (11)	0.0480 (13)	0.0032 (10)	0.0181 (11)	0.0085 (10)
C16	0.0589 (16)	0.0415 (12)	0.0355 (11)	0.0150 (11)	0.0104 (11)	0.0092 (9)
C17	0.0403 (13)	0.0553 (14)	0.0410 (13)	0.0072 (11)	0.0012 (10)	0.0062 (10)
C18	0.0285 (10)	0.0422 (11)	0.0422 (12)	0.0019 (9)	0.0037 (9)	0.0089 (9)
N19	0.0287 (9)	0.0408 (9)	0.0218 (8)	0.0040 (7)	0.0060 (7)	−0.0041 (6)

Geometric parameters (Å, º)

N1—C9	1.357 (2)	C13—C14	1.392 (3)
N1—C2	1.384 (2)	C14—C15	1.372 (3)
N1—C10	1.444 (2)	C15—C16	1.386 (4)
C2—C7	1.392 (2)	C16—C17	1.377 (3)
C2—C3	1.411 (2)	C17—C18	1.386 (3)
C3—N19	1.335 (2)	N19—H19A	0.9600
C3—N4	1.346 (2)	N19—H19B	0.9400
N4—C5	1.337 (3)	C5—H5	0.9500
C5—N6	1.329 (3)	C9—H9	0.9500
N6—C7	1.347 (3)	C10—H10A	0.9900
C7—N8	1.376 (3)	C10—H10B	0.9900
N8—C9	1.312 (3)	C14—H14	0.9500
C10—C11	1.520 (3)	C15—H15	0.9500
C11—O12	1.218 (2)	C16—H16	0.9500
C11—C13	1.483 (3)	C17—H17	0.9500
C13—C18	1.391 (3)	C18—H18	0.9500
C9—N1—C2	105.41 (16)	C17—C16—C15	119.8 (2)
C9—N1—C10	124.94 (17)	C16—C17—C18	120.7 (2)
C2—N1—C10	129.50 (15)	C17—C18—C13	119.6 (2)
N1—C2—C7	105.39 (16)	H19A—N19—H19B	115.00
N1—C2—C3	135.67 (17)	C3—N19—H19A	127.00
C7—C2—C3	118.93 (17)	C3—N19—H19B	116.00
N19—C3—N4	117.87 (17)	N4—C5—H5	115.00
N19—C3—C2	125.07 (17)	N6—C5—H5	115.00
N4—C3—C2	117.04 (17)	N1—C9—H9	123.00
C5—N4—C3	118.54 (17)	N8—C9—H9	123.00
N6—C5—N4	129.34 (19)	N1—C10—H10A	109.00
C5—N6—C7	112.29 (16)	N1—C10—H10B	109.00
N6—C7—N8	125.38 (17)	C11—C10—H10A	109.00
N6—C7—C2	123.84 (18)	C11—C10—H10B	109.00
N8—C7—C2	110.78 (17)	H10A—C10—H10B	108.00
C9—N8—C7	103.70 (15)	C13—C14—H14	120.00
N8—C9—N1	114.73 (18)	C15—C14—H14	120.00
N1—C10—C11	112.35 (16)	C14—C15—H15	120.00
O12—C11—C13	122.09 (18)	C16—C15—H15	120.00
O12—C11—C10	120.06 (18)	C15—C16—H16	120.00
C13—C11—C10	117.84 (16)	C17—C16—H16	120.00
C18—C13—C14	119.2 (2)	C16—C17—H17	120.00
C18—C13—C11	121.87 (18)	C18—C17—H17	120.00
C14—C13—C11	118.91 (19)	C13—C18—H18	120.00
C15—C14—C13	120.8 (2)	C17—C18—H18	120.00
C14—C15—C16	119.9 (2)
C9—N1—C2—C7	0.1 (2)	C7—N8—C9—N1	0.1 (2)
C10—N1—C2—C7	175.72 (18)	C2—N1—C9—N8	−0.2 (2)
C9—N1—C2—C3	−179.6 (2)	C10—N1—C9—N8	−176.00 (17)
C10—N1—C2—C3	−4.0 (3)	C9—N1—C10—C11	104.5 (2)
N1—C2—C3—N19	0.3 (3)	C2—N1—C10—C11	−70.3 (2)
C7—C2—C3—N19	−179.34 (17)	N1—C10—C11—O12	5.6 (3)
N1—C2—C3—N4	178.9 (2)	N1—C10—C11—C13	−175.16 (16)
C7—C2—C3—N4	−0.8 (3)	O12—C11—C13—C18	167.90 (19)
N19—C3—N4—C5	179.31 (18)	C10—C11—C13—C18	−11.3 (3)
C2—C3—N4—C5	0.7 (3)	O12—C11—C13—C14	−10.1 (3)
C3—N4—C5—N6	0.1 (3)	C10—C11—C13—C14	170.72 (17)
N4—C5—N6—C7	−0.6 (3)	C18—C13—C14—C15	−0.6 (3)
C5—N6—C7—N8	−178.92 (18)	C11—C13—C14—C15	177.45 (18)
C5—N6—C7—C2	0.4 (3)	C13—C14—C15—C16	−0.8 (3)
N1—C2—C7—N6	−179.52 (17)	C14—C15—C16—C17	1.0 (3)
C3—C2—C7—N6	0.2 (3)	C15—C16—C17—C18	0.0 (4)
N1—C2—C7—N8	−0.1 (2)	C16—C17—C18—C13	−1.3 (3)
C3—C2—C7—N8	179.68 (16)	C14—C13—C18—C17	1.6 (3)
N6—C7—N8—C9	179.42 (19)	C11—C13—C18—C17	−176.35 (19)
C2—C7—N8—C9	0.0 (2)

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
N19—H19A···N6^i	0.96	2.01	2.922 (2)	157
N19—H19B···N8^ii	0.94	2.17	2.984 (2)	144

Symmetry codes: (i) x−1/2, −y+1/2, z−1/2; (ii) x+1/2, −y+1/2, z−1/2.