2-(6-Meth­oxy-7H-purin-7-yl)-1-phenyl­ethanone monohydrate

The crystal structure of the title compound, C₁₄H₁₂N₄O₂·H₂O, was determined in the course of our studies of the synthesis and optimization of 7-aryl-7H-purines as inhibitors of the vascular endothelial growth factor receptor (VEGF-R), c-Jun NH₂-terminal protein kinase 3 (JNK3) and the p38α mitogen-activated protein kinase (MAPK). In the title compound, two mol­ecules are associated with each other through O—H...N hydrogen bonds to different N atoms in the purine ring system. The compound was prepared via a regioselective synthesis using the meth­yl(aqua)cobaloxime complex, CH₃Co(DH)₂OH₂, as a temporary auxiliary. The X-ray crystallographic results confirmed the regioselective N-7 alkyl­ation of this mol­ecule.

Key indicators

• Single-crystal X-ray study
• T = 193 K
• Mean [sigma](C-C) = 0.003 Å
• R factor = 0.044
• wR factor = 0.127
• Data-to-parameter ratio = 12.5

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   0.726
  From the CIF: _exptl_absorpt_correction_T_max   0.919
PLAT057_ALERT_3_C Correction for Absorption Required   RT(exp) ...       1.13

   0 ALERT level A = In general: serious problem
   0 ALERT level B = Potentially serious problem
   2 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
   1 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

Compound 4 was prepared as an inhibitor of the Vascular Endothelial Growth Factor Receptor (VEGF-R). In 4 the purine system from the cosubstrate ATP of these protein kinases (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.

In 4 a water links two symmetry related (2-fold screw axis) purine molecules by H-bonding to N6 and N8, respectively. In turn, each purine molecule hydrogen bonds to two water molecules such that the phenyl rings protrude from opposite sides of an infinite sheet of purine moieties. Thus, a layer-like structure is formed perpendicular to the a axis. The phenyl ring is oriented approximately perpendicular (67.33 (6)°) to the purine ring system.

Related literature

Background: Hopkins & Groon (2002); Laufer et al. (2005); Meijer & Raymond (2003). Synthesis: Dalby et al. (1993); Marzilli et al. (1975); Bader & Chiang (1983); Schrauzer (1968). Related purine derivatives: 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

The synthetis of 4 (scheme 1) 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 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 steric hindrance from the neighbouring C-6 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%) and the adenine derivative 5 (34,9%).

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 addded 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-methoxy-7H-purine-7-yl)-1-phenylethanone 4, 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 4 for X-ray analysis precipitated as colourless sheets 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 O1W were located in diff. fourier maps. H atoms attached to carbon atoms were refined with isotropic displacement parameters using a riding motion model with fixed C—H distance. The O1W—H distance was free to refine with fixed O1W—H vector direction.

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) and ORTEP (Johnson, 1968); software used to prepare material for publication: SHELXL97 (Sheldrick, 1997).

Figures

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

2-(6-Methoxy-7H-purine-7-yl)-1-phenylethanone

Crystal data

C14H12N4O2·H2O	F(000) = 600
Mr = 286.29	Dx = 1.416 Mg m^−3
Monoclinic, P21/c	Cu Kα radiation, λ = 1.54178 Å
Hall symbol: -P 2ybc	Cell parameters from 25 reflections
a = 12.2729 (6) Å	θ = 61–70°
b = 8.2830 (7) Å	µ = 0.86 mm^−1
c = 14.3335 (10) Å	T = 193 K
β = 112.851 (3)°	Plate, colourless
V = 1342.74 (16) Å^3	0.40 × 0.20 × 0.10 mm
Z = 4

Data collection

Enraf–Nonius CAD-4 diffractometer	Rint = 0.083
Radiation source: rotating anode	θmax = 70.2°, θmin = 3.9°
Graphite monochromator	h = −13→14
ω/2θ scans	k = 0→10
2645 measured reflections	l = −17→0
2534 independent reflections	3 standard reflections every 60 min
2089 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)] = 0.044	Hydrogen site location: inferred from neighbouring sites
wR(F^2) = 0.127	Only H-atom displacement parameters refined
S = 1.08	w = 1/[σ^2(Fo^2) + (0.0712P)^2 + 0.325P] where P = (Fo^2 + 2Fc^2)/3
2534 reflections	(Δ/σ)max < 0.001
202 parameters	Δρmax = 0.23 e Å^−3
0 restraints	Δρmin = −0.27 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	0.18404 (12)	0.47672 (17)	0.62611 (10)	0.0285 (3)
C2	0.16775 (14)	0.32546 (19)	0.58263 (12)	0.0257 (4)
C3	0.18454 (14)	0.1669 (2)	0.61821 (12)	0.0262 (4)
N4	0.15423 (12)	0.04636 (17)	0.55245 (11)	0.0307 (3)
C5	0.10739 (15)	0.0839 (2)	0.45274 (13)	0.0330 (4)
H5	0.0840	−0.0050	0.4073	0.037 (5)*
N6	0.09001 (13)	0.22894 (19)	0.41046 (10)	0.0329 (4)
C7	0.12163 (14)	0.3509 (2)	0.47865 (12)	0.0282 (4)
N8	0.11165 (13)	0.51367 (19)	0.45755 (11)	0.0339 (4)
C9	0.14978 (15)	0.5824 (2)	0.54765 (13)	0.0331 (4)
H9	0.1509	0.6954	0.5624	0.031 (5)*
O10	0.23226 (11)	0.14118 (14)	0.71795 (9)	0.0325 (3)
C11	0.2425 (2)	−0.0240 (2)	0.75123 (15)	0.0488 (6)
H11A	0.1661	−0.0783	0.7185	0.068 (5)*
H11B	0.2664	−0.0271	0.8249	0.068 (5)*
H11C	0.3021	−0.0792	0.7329	0.068 (5)*
C12	0.23133 (15)	0.5177 (2)	0.73339 (12)	0.0294 (4)
H12A	0.2233	0.4235	0.7728	0.044 (4)*
H12B	0.1849	0.6077	0.7448	0.044 (4)*
C13	0.36068 (15)	0.5666 (2)	0.77075 (12)	0.0294 (4)
O14	0.41546 (12)	0.5476 (2)	0.71708 (10)	0.0485 (4)
C15	0.41426 (14)	0.6416 (2)	0.87259 (12)	0.0278 (4)
C16	0.52074 (16)	0.7238 (3)	0.89910 (15)	0.0397 (5)
H16	0.5591	0.7292	0.8530	0.049 (6)*
C17	0.57072 (18)	0.7978 (3)	0.99248 (17)	0.0478 (5)
H17	0.6427	0.8558	1.0099	0.077 (9)*
C18	0.51658 (17)	0.7878 (3)	1.06072 (15)	0.0435 (5)
H18	0.5517	0.8378	1.1252	0.051 (6)*
C19	0.41193 (17)	0.7056 (3)	1.03499 (14)	0.0425 (5)
H19	0.3749	0.6983	1.0820	0.069 (8)*
C20	0.36001 (16)	0.6333 (2)	0.94135 (14)	0.0367 (4)
H20	0.2870	0.5778	0.9238	0.048 (6)*
O1W	0.04215 (13)	0.77041 (17)	0.30574 (9)	0.0418 (4)
H1W	0.0523 (2)	0.670 (2)	0.3418 (7)	0.068 (6)*
H2W	−0.0121 (12)	0.7424 (6)	0.2431 (13)	0.068 (6)*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
N1	0.0327 (7)	0.0265 (7)	0.0236 (7)	0.0001 (6)	0.0079 (6)	−0.0012 (5)
C2	0.0244 (8)	0.0289 (8)	0.0228 (8)	0.0008 (6)	0.0081 (6)	−0.0006 (6)
C3	0.0233 (7)	0.0295 (9)	0.0242 (8)	0.0001 (6)	0.0075 (6)	−0.0013 (6)
N4	0.0296 (7)	0.0298 (7)	0.0300 (8)	0.0000 (6)	0.0087 (6)	−0.0044 (6)
C5	0.0313 (9)	0.0377 (10)	0.0286 (9)	−0.0013 (7)	0.0100 (7)	−0.0091 (8)
N6	0.0332 (8)	0.0404 (9)	0.0229 (7)	−0.0004 (6)	0.0085 (6)	−0.0041 (6)
C7	0.0259 (8)	0.0350 (9)	0.0219 (8)	0.0001 (7)	0.0074 (6)	0.0002 (7)
N8	0.0368 (8)	0.0342 (8)	0.0270 (7)	−0.0006 (6)	0.0081 (6)	0.0040 (6)
C9	0.0364 (9)	0.0286 (9)	0.0314 (9)	0.0020 (7)	0.0101 (7)	0.0041 (7)
O10	0.0399 (7)	0.0281 (6)	0.0231 (6)	−0.0008 (5)	0.0055 (5)	0.0030 (5)
C11	0.0731 (15)	0.0312 (10)	0.0331 (10)	−0.0064 (10)	0.0109 (10)	0.0067 (8)
C12	0.0342 (9)	0.0300 (9)	0.0239 (8)	−0.0013 (7)	0.0112 (7)	−0.0038 (7)
C13	0.0325 (9)	0.0295 (8)	0.0264 (8)	0.0029 (7)	0.0116 (7)	0.0036 (7)
O14	0.0405 (7)	0.0767 (11)	0.0337 (7)	−0.0043 (7)	0.0203 (6)	−0.0095 (7)
C15	0.0285 (8)	0.0275 (8)	0.0259 (8)	0.0038 (6)	0.0088 (7)	0.0028 (7)
C16	0.0321 (9)	0.0485 (12)	0.0407 (10)	−0.0040 (8)	0.0164 (8)	−0.0058 (9)
C17	0.0323 (10)	0.0568 (13)	0.0518 (12)	−0.0133 (9)	0.0136 (9)	−0.0167 (11)
C18	0.0375 (10)	0.0517 (12)	0.0356 (10)	−0.0015 (9)	0.0080 (8)	−0.0142 (9)
C19	0.0398 (10)	0.0588 (13)	0.0307 (10)	−0.0053 (9)	0.0158 (8)	−0.0084 (9)
C20	0.0338 (9)	0.0459 (11)	0.0312 (9)	−0.0086 (8)	0.0136 (7)	−0.0047 (8)
O1W	0.0568 (9)	0.0334 (7)	0.0272 (6)	−0.0036 (6)	0.0075 (6)	−0.0010 (5)

Geometric parameters (Å, º)

N1—C9	1.357 (2)	C12—C13	1.520 (2)
N1—C2	1.379 (2)	C12—H12A	0.9900
N1—C12	1.457 (2)	C12—H12B	0.9900
C2—C7	1.389 (2)	C13—O14	1.213 (2)
C2—C3	1.395 (2)	C13—C15	1.484 (2)
C3—N4	1.323 (2)	C15—C20	1.389 (2)
C3—O10	1.335 (2)	C15—C16	1.389 (3)
N4—C5	1.353 (2)	C16—C17	1.380 (3)
C5—N6	1.325 (2)	C16—H16	0.9500
C5—H5	0.9500	C17—C18	1.382 (3)
N6—C7	1.353 (2)	C17—H17	0.9500
C7—N8	1.377 (2)	C18—C19	1.372 (3)
N8—C9	1.320 (2)	C18—H18	0.9500
C9—H9	0.9588	C19—C20	1.379 (3)
O10—C11	1.438 (2)	C19—H19	0.9500
C11—H11A	0.9800	C20—H20	0.9500
C11—H11B	0.9800	O1W—H1W	0.9625
C11—H11C	0.9800	O1W—H2W	0.9160
C9—N1—C2	105.53 (14)	N1—C12—C13	111.55 (13)
C9—N1—C12	126.35 (15)	N1—C12—H12A	109.3
C2—N1—C12	128.10 (14)	C13—C12—H12A	109.3
N1—C2—C7	105.92 (14)	N1—C12—H12B	109.3
N1—C2—C3	135.67 (15)	C13—C12—H12B	109.3
C7—C2—C3	118.40 (15)	H12A—C12—H12B	108.0
N4—C3—O10	121.82 (15)	O14—C13—C15	122.37 (16)
N4—C3—C2	119.29 (15)	O14—C13—C12	120.15 (15)
O10—C3—C2	118.88 (15)	C15—C13—C12	117.46 (14)
C3—N4—C5	117.73 (15)	C20—C15—C16	119.30 (16)
N6—C5—N4	128.18 (16)	C20—C15—C13	121.72 (16)
N6—C5—H5	115.9	C16—C15—C13	118.97 (16)
N4—C5—H5	115.9	C17—C16—C15	119.96 (18)
C5—N6—C7	113.35 (14)	C17—C16—H16	120.0
N6—C7—N8	126.59 (15)	C15—C16—H16	120.0
N6—C7—C2	123.01 (16)	C16—C17—C18	120.34 (18)
N8—C7—C2	110.39 (15)	C16—C17—H17	119.8
C9—N8—C7	103.88 (14)	C18—C17—H17	119.8
N8—C9—N1	114.27 (16)	C19—C18—C17	119.77 (18)
N8—C9—H9	127.3	C19—C18—H18	120.1
N1—C9—H9	118.3	C17—C18—H18	120.1
C3—O10—C11	116.91 (14)	C18—C19—C20	120.52 (18)
O10—C11—H11A	109.5	C18—C19—H19	119.7
O10—C11—H11B	109.5	C20—C19—H19	119.7
H11A—C11—H11B	109.5	C19—C20—C15	120.10 (17)
O10—C11—H11C	109.5	C19—C20—H20	120.0
H11A—C11—H11C	109.5	C15—C20—H20	120.0
H11B—C11—H11C	109.5	H1W—O1W—H2W	101.6
C9—N1—C2—C7	−1.15 (18)	C2—N1—C9—N8	0.7 (2)
C12—N1—C2—C7	−179.42 (15)	C12—N1—C9—N8	179.03 (15)
C9—N1—C2—C3	−179.88 (19)	N4—C3—O10—C11	−3.8 (2)
C12—N1—C2—C3	1.9 (3)	C2—C3—O10—C11	177.03 (16)
N1—C2—C3—N4	177.35 (17)	C9—N1—C12—C13	−78.3 (2)
C7—C2—C3—N4	−1.3 (2)	C2—N1—C12—C13	99.68 (19)
N1—C2—C3—O10	−3.5 (3)	N1—C12—C13—O14	−9.8 (2)
C7—C2—C3—O10	177.92 (14)	N1—C12—C13—C15	168.46 (14)
O10—C3—N4—C5	−179.43 (15)	O14—C13—C15—C20	−166.61 (18)
C2—C3—N4—C5	−0.3 (2)	C12—C13—C15—C20	15.2 (2)
C3—N4—C5—N6	2.0 (3)	O14—C13—C15—C16	14.2 (3)
N4—C5—N6—C7	−1.8 (3)	C12—C13—C15—C16	−164.03 (16)
C5—N6—C7—N8	−178.59 (16)	C20—C15—C16—C17	−0.8 (3)
C5—N6—C7—C2	0.0 (2)	C13—C15—C16—C17	178.45 (19)
N1—C2—C7—N6	−177.56 (15)	C15—C16—C17—C18	1.3 (3)
C3—C2—C7—N6	1.4 (2)	C16—C17—C18—C19	−0.7 (3)
N1—C2—C7—N8	1.25 (19)	C17—C18—C19—C20	−0.3 (3)
C3—C2—C7—N8	−179.76 (14)	C18—C19—C20—C15	0.8 (3)
N6—C7—N8—C9	177.95 (17)	C16—C15—C20—C19	−0.3 (3)
C2—C7—N8—C9	−0.81 (19)	C13—C15—C20—C19	−179.46 (18)
C7—N8—C9—N1	0.1 (2)

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
O1W—H1W···N8	0.96	2.00	2.923 (2)	159
O1W—H2W···N6^i	0.92	2.03	2.9066 (19)	159

Symmetry code: (i) −x, y+1/2, −z+1/2.