Ethyl 2-[({[4-amino-5-cyano-6-(methyl­sulfan­yl)pyridin-2-yl]carbamo­yl}meth­yl)sulfan­yl]acetate monohydrate

The title compound, C₁₃H₁₆N₄O₃S₂·H₂O, crystallizes in a `folded' conformation with the ester group lying over the carbamoyl moiety, with one solvent water mol­ecule. The mol­ecular conformation is stabilized by an intra­molecular C—H...O hydrogen bond, and an N—H...O hydrogen-bonding inter­action involving the lattice water mol­ecule. The packing involves N—H...N, N—H...O, O—H...N and O—H...O hydrogen bonds and consists of tilted layers running approximately parallel to the c axis, with the ester groups on the outer sides of the layers and with channels running parallel to (101).

Key indicators

• Single-crystal X-ray study
• T = 150 K
• Mean [sigma](C-C) = 0.002 Å
• R factor = 0.037
• wR factor = 0.099
• Data-to-parameter ratio = 20.4

checkCIF/PLATON results

No syntax errors found



Alert level C
PLAT250_ALERT_2_C Large U3/U1 Ratio for Average U(i,j) Tensor ....        2.1 Note
PLAT413_ALERT_2_C Short Inter XH3 .. XHn     H6B    ..  H12B    ..       2.12 Ang.
PLAT911_ALERT_3_C Missing # FCF Refl Between THmin & STh/L=  0.600          4 Why ?

Alert level G
PLAT005_ALERT_5_G No _iucr_refine_instructions_details  in the CIF     Please Do !
PLAT007_ALERT_5_G Number of Unrefined Donor-H Atoms ..............          5 Why ?
PLAT230_ALERT_2_G Hirshfeld Test Diff for    C2     --  C7      ..        5.3 su
PLAT912_ALERT_4_G Missing # of FCF Reflections Above STh/L=  0.600        197 Note

   0 ALERT level A = Most likely a serious problem - resolve or explain
   0 ALERT level B = A potentially serious problem, consider carefully
   3 ALERT level C = Check. Ensure it is not caused by an omission or oversight
   4 ALERT level G = General information/check it is not something unexpected

   0 ALERT type 1 CIF construction/syntax error, inconsistent or missing data
   3 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
   1 ALERT type 4 Improvement, methodology, query or suggestion
   2 ALERT type 5 Informative message, check

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S1. Comment

A great deal of interest has been focused on the synthesis of functionalized pyridine derivatives due to their biological activities (Shi et al., 2005). For example, some 2-pyridine radicals are incorporated into the structures of cardiotonic agents such as milrinone (Dorigo et al., 1993) and HIV-1 specific transcriptase inhibitors (Dolle et al., 1995). Amino-cyanopyridines have been identified as IKK-β inhibitors (Murata et al., 2003). Many pyridine derivatives are of commercial interest being used as herbicides, fungicides, pesticides, and dyes (Lohray et al., 2004; Merja et al., 2004; Chaki et al., 1995; Thomae et al., 2007). Besides, pyridine derivatives are important and useful intermediates in the preparation of a variety of heterocyclic compounds (Konda et al., 2010). In view of these observations and in continuation of our work on the synthesis of heterocyclic systems for biological evaluations, we report here the synthesis and crystal structure of the title compound.

The title compound (Fig. 1) crystallizes in a "folded" conformation with the ester group lying over the carbamoyl moiety such that the dihedral angle between the best planes through the pyridyl ring and the C11–C13/O3 unit is 22.4 (1)°.

Molecular conformation is stabilized by an intramolecular C—H···O hydrogen bond, forming a S(6) motif, Fig. 1, (Bernstein et al., 1995) and an N—H···O hydrogen bonding interaction involving the lattice water molecule.

This conformation appears to result from the several hydrogen bonding interactions involving the lattice water molecule, Fig. 2 and Table 1. The packing consists of tilted layers running approximately parallel to the c axis, Fig. 3, with the ester groups on the outsides of the layers and having channels running parallel to (101), Fig. 4.

Related literature

For the synthesis of amino-cyano pyridines, see: Shi et al. (2005). For pyridines as intermediates in the synthesis of different heterocyclic compounds, see: Konda et al. (2010). For the pharmaceutical activity of functionalized pyridine derivatives, see: Dorigo et al. (1993); Dolle et al. (1995); Murata et al. (2003). For industrial applications of pyridine compounds, see: Lohray et al. (2004); Merja et al. (2004); Chaki et al. (1995); Thomae et al. (2007). For hydrogen-bond motifs, see: Bernstein et al. (1995).

S2. Experimental

To a solution of N-[4-amino-5-cyano-6-(methylthio)pyridin-2-yl]-2-chloroacetamide (0.5 g, 1.95 mmol) in 30 ml ethanol and a few drops of triethylamine as a catalyst, ethyl mercaptoacetate (0.23 g, 1.95 mmol) was added. The reaction mixture was refluxed for 3 h at 350 K. The reaction mixture was allowed to cool down and the excess solvent was evaporated under reduced pressure. The precipitate which formed was filtered off, dried under vacuum and recrystallized from ethanol to furnish colourless crystals (yield 0.62 g; 95%). Mp. 423 – 425 K.

IR (ν_max, cm^-1): 3431, 3335, 3227, (NH₂+NH), 2915 (CH aliph.), 2203 (C≡N), 1728 (C=O ester), 1641 (C=O amidic); ¹HNMR (DMSO-d₆), δ, p.p.m.: 10.34 (s, 1H, NH exchanged by D₂O), 7.28 (s, 1H, CH pyridyl), 7.00 (s, 2H, NH₂ exchanged by D₂O), 4.11- 4.06(q, J = 8 Hz, 2H, CH₂), 3.50 (s, 2H, CH₂), 3.49 (s, 2H, CH₂), 2.53 (s, 3H, CH₃), 1.2–1.17 (t, J = 8 Hz, 3H, CH₃).

S3. Refinement

H-atoms attached to carbon were placed in calculated positions (C—H = 0.95 - 0.98 Å) while those attached to nitrogen were placed in locations derived from a difference map and their coordinates adjusted to give N—H = 0.91 Å. All were included as riding contributions with isotropic displacement parameters 1.2 - 1.5 times those of the attached atoms.

Computing details

Data collection: APEX2 (Bruker, 2013); cell refinement: SAINT (Bruker, 2013); data reduction: SAINT (Bruker, 2013); program(s) used to solve structure: SHELXT (Sheldrick, 2008); program(s) used to refine structure: SHELXL2014 (Sheldrick, 2008); molecular graphics: DIAMOND (Brandenburg & Putz, 2012); software used to prepare material for publication: SHELXTL (Sheldrick, 2008).

Figures

	Fig. 1. Perspective view of the asymmetric unit with 50% probability ellipsoids and hydrogen bonds depicted by dashed lines.
	Fig. 2. Packing projected down the b axis showing the inter- and intramolecular hydrogen bonds as dashed lines.
	Fig. 3. Packing projected along the c axis showing the tilted layers.
	Fig. 4. Packing viewed along the axis of the channels. Displacement ellipsoids for non-H atoms are drawn at the 50% probability level.

Ethyl 2-[({[4-amino-5-cyano-6-(methylsulfanyl)pyridin-2-yl]carbamoyl}methyl)sulfanyl]acetate monohydrate

Crystal data

C13H16N4O3S2·H2O	Z = 2
Mr = 358.45	F(000) = 376
Triclinic, P1	Dx = 1.442 Mg m^−3
Hall symbol: -P 1	Mo Kα radiation, λ = 0.71073 Å
a = 9.0806 (12) Å	Cell parameters from 9913 reflections
b = 9.2444 (12) Å	θ = 2.4–29.2°
c = 10.7856 (14) Å	µ = 0.35 mm^−1
α = 101.843 (2)°	T = 150 K
β = 100.1750 (19)°	Plate, colourless
γ = 105.9480 (19)°	0.26 × 0.26 × 0.12 mm
V = 825.48 (19) Å^3

Data collection

Bruker SMART APEX CCD diffractometer	4292 independent reflections
Graphite monochromator	3773 reflections with I > 2σ(I)
Detector resolution: 8.3660 pixels mm^-1	Rint = 0.034
φ and ω scans	θmax = 29.2°, θmin = 2.0°
Absorption correction: multi-scan (SADABS; Bruker, 2013)	h = −12→12
Tmin = 0.83, Tmax = 0.96	k = −12→12
15313 measured reflections	l = −14→14

Refinement

Refinement on F^2	0 restraints
Least-squares matrix: full	Hydrogen site location: mixed
R[F^2 > 2σ(F^2)] = 0.037	H-atom parameters constrained
wR(F^2) = 0.099	w = 1/[σ^2(Fo^2) + (0.0515P)^2 + 0.3031P] where P = (Fo^2 + 2Fc^2)/3
S = 1.05	(Δ/σ)max = 0.001
4292 reflections	Δρmax = 0.44 e Å^−3
210 parameters	Δρmin = −0.37 e Å^−3

Special details

Geometry. Bond distances, angles etc. have been calculated using the rounded fractional coordinates. All su's are estimated from the variances of the (full) variance-covariance matrix. The cell e.s.d.'s are taken into account in the estimation of distances, angles and torsion angles

Refinement. Refinement on F² for ALL reflections except those flagged by the user for potential systematic errors. Weighted R-factors wR and all goodnesses of fit S are based on F², conventional R-factors R are based on F, with F set to zero for negative F². The observed criterion of F² > σ(F²) is used only for calculating -R-factor-obs 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
S1	1.14877 (5)	0.74276 (5)	0.62470 (3)	0.0316 (1)
S2	0.40426 (4)	0.82259 (4)	0.00905 (3)	0.0218 (1)
O1	0.50975 (12)	0.88281 (13)	0.30154 (9)	0.0263 (3)
O2	0.16728 (13)	0.58384 (14)	0.15365 (11)	0.0325 (3)
O3	0.38626 (12)	0.51837 (12)	0.14447 (9)	0.0244 (3)
N1	0.91851 (13)	0.79013 (14)	0.46377 (11)	0.0200 (3)
N2	1.05234 (16)	0.87115 (18)	0.92745 (12)	0.0330 (4)
N3	0.73517 (14)	0.97498 (15)	0.76432 (11)	0.0257 (3)
N4	0.73715 (13)	0.82181 (14)	0.30697 (10)	0.0204 (3)
C1	0.98222 (15)	0.80180 (16)	0.58659 (13)	0.0193 (3)
C2	0.92486 (15)	0.86183 (16)	0.69216 (12)	0.0192 (3)
C3	0.79351 (15)	0.91523 (16)	0.66734 (12)	0.0194 (3)
C4	0.72390 (15)	0.89929 (16)	0.53540 (12)	0.0207 (4)
C5	0.79125 (15)	0.83911 (15)	0.44086 (12)	0.0185 (3)
C6	1.1786 (2)	0.6781 (3)	0.46517 (17)	0.0480 (7)
C7	0.99695 (16)	0.86718 (17)	0.82188 (13)	0.0225 (4)
C8	0.60550 (15)	0.84739 (16)	0.24588 (12)	0.0194 (3)
C9	0.59280 (16)	0.82956 (17)	0.10018 (13)	0.0215 (4)
C10	0.28999 (17)	0.61849 (17)	−0.02404 (13)	0.0247 (4)
C11	0.27024 (16)	0.57242 (17)	0.09924 (13)	0.0237 (4)
C12	0.3870 (2)	0.4842 (2)	0.27094 (15)	0.0315 (5)
C13	0.5180 (2)	0.4186 (2)	0.30413 (16)	0.0335 (5)
O4	0.91965 (12)	0.72768 (13)	0.12641 (10)	0.0287 (3)
H3A	0.79320	1.00160	0.84830	0.0310*
H3B	0.65660	1.01610	0.74450	0.0310*
H4	0.63290	0.92930	0.51240	0.0250*
H4A	0.79970	0.79450	0.25550	0.0240*
H6A	1.08460	0.59240	0.41090	0.0720*
H6B	1.27060	0.64170	0.47300	0.0720*
H6C	1.19680	0.76500	0.42460	0.0720*
H9A	0.61410	0.73250	0.06270	0.0260*
H9B	0.67560	0.91820	0.08960	0.0260*
H10A	0.18450	0.59830	−0.08140	0.0300*
H10B	0.34350	0.55330	−0.07120	0.0300*
H12A	0.28430	0.40770	0.26670	0.0380*
H12B	0.40330	0.58080	0.33910	0.0380*
H13A	0.50470	0.32690	0.23340	0.0500*
H13B	0.51520	0.38810	0.38570	0.0500*
H13C	0.61990	0.49790	0.31490	0.0500*
H4B	0.94980	0.77280	0.07090	0.0340*
H4C	0.99220	0.69030	0.14630	0.0340*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
S1	0.0310 (2)	0.0527 (3)	0.0213 (2)	0.0314 (2)	0.0049 (1)	0.0089 (2)
S2	0.0225 (2)	0.0265 (2)	0.0184 (2)	0.0128 (1)	0.0009 (1)	0.0072 (1)
O1	0.0212 (5)	0.0418 (6)	0.0196 (5)	0.0182 (4)	0.0036 (4)	0.0063 (4)
O2	0.0282 (5)	0.0444 (7)	0.0334 (6)	0.0193 (5)	0.0132 (5)	0.0134 (5)
O3	0.0255 (5)	0.0313 (5)	0.0225 (5)	0.0142 (4)	0.0094 (4)	0.0108 (4)
N1	0.0184 (5)	0.0261 (6)	0.0182 (5)	0.0121 (4)	0.0041 (4)	0.0054 (4)
N2	0.0328 (7)	0.0520 (9)	0.0211 (6)	0.0253 (6)	0.0055 (5)	0.0097 (6)
N3	0.0227 (6)	0.0408 (7)	0.0167 (5)	0.0186 (5)	0.0037 (4)	0.0041 (5)
N4	0.0185 (5)	0.0299 (6)	0.0156 (5)	0.0132 (5)	0.0038 (4)	0.0053 (4)
C1	0.0171 (6)	0.0242 (6)	0.0188 (6)	0.0111 (5)	0.0032 (5)	0.0055 (5)
C2	0.0168 (6)	0.0253 (6)	0.0167 (6)	0.0098 (5)	0.0024 (4)	0.0054 (5)
C3	0.0159 (6)	0.0238 (6)	0.0180 (6)	0.0075 (5)	0.0030 (4)	0.0039 (5)
C4	0.0175 (6)	0.0281 (7)	0.0179 (6)	0.0119 (5)	0.0022 (5)	0.0047 (5)
C5	0.0158 (5)	0.0225 (6)	0.0168 (6)	0.0078 (5)	0.0010 (4)	0.0046 (5)
C6	0.0526 (11)	0.0851 (15)	0.0276 (8)	0.0544 (11)	0.0149 (7)	0.0128 (9)
C7	0.0190 (6)	0.0314 (7)	0.0202 (6)	0.0135 (5)	0.0053 (5)	0.0056 (5)
C8	0.0180 (6)	0.0226 (6)	0.0178 (6)	0.0088 (5)	0.0022 (4)	0.0050 (5)
C9	0.0190 (6)	0.0309 (7)	0.0190 (6)	0.0128 (5)	0.0047 (5)	0.0097 (5)
C10	0.0264 (7)	0.0266 (7)	0.0197 (6)	0.0094 (6)	0.0026 (5)	0.0045 (5)
C11	0.0223 (6)	0.0249 (7)	0.0235 (6)	0.0087 (5)	0.0043 (5)	0.0053 (5)
C12	0.0360 (8)	0.0431 (9)	0.0269 (7)	0.0198 (7)	0.0151 (6)	0.0184 (7)
C13	0.0391 (9)	0.0396 (9)	0.0301 (8)	0.0198 (7)	0.0100 (6)	0.0161 (7)
O4	0.0258 (5)	0.0376 (6)	0.0301 (5)	0.0171 (5)	0.0113 (4)	0.0116 (5)

Geometric parameters (Å, º)

S1—C1	1.7550 (15)	C2—C3	1.415 (2)
S1—C6	1.7952 (18)	C2—C7	1.4208 (19)
S2—C9	1.7945 (15)	C3—C4	1.4111 (18)
S2—C10	1.8113 (16)	C4—C5	1.3776 (19)
O1—C8	1.2181 (18)	C8—C9	1.5262 (18)
O2—C11	1.2051 (19)	C10—C11	1.502 (2)
O3—C11	1.3436 (19)	C12—C13	1.499 (3)
O3—C12	1.4613 (19)	C4—H4	0.9500
O4—H4C	0.8400	C6—H6B	0.9800
O4—H4B	0.8400	C6—H6A	0.9800
N1—C1	1.3181 (18)	C6—H6C	0.9800
N1—C5	1.3543 (19)	C9—H9B	0.9900
N2—C7	1.1494 (19)	C9—H9A	0.9900
N3—C3	1.3414 (18)	C10—H10B	0.9900
N4—C5	1.4013 (16)	C10—H10A	0.9900
N4—C8	1.3639 (19)	C12—H12B	0.9900
N3—H3A	0.9100	C12—H12A	0.9900
N3—H3B	0.9100	C13—H13C	0.9800
N4—H4A	0.9100	C13—H13A	0.9800
C1—C2	1.4088 (19)	C13—H13B	0.9800
C1—S1—C6	101.26 (8)	O2—C11—C10	125.82 (14)
C9—S2—C10	101.89 (7)	O3—C12—C13	108.59 (14)
C11—O3—C12	115.32 (12)	C5—C4—H4	121.00
H4B—O4—H4C	102.00	C3—C4—H4	121.00
C1—N1—C5	116.87 (12)	S1—C6—H6A	109.00
C5—N4—C8	127.62 (12)	S1—C6—H6B	109.00
H3A—N3—H3B	120.00	H6A—C6—H6B	110.00
C3—N3—H3B	119.00	H6A—C6—H6C	109.00
C3—N3—H3A	119.00	S1—C6—H6C	109.00
C5—N4—H4A	116.00	H6B—C6—H6C	109.00
C8—N4—H4A	116.00	S2—C9—H9B	109.00
S1—C1—N1	119.69 (11)	C8—C9—H9A	109.00
S1—C1—C2	116.86 (10)	S2—C9—H9A	109.00
N1—C1—C2	123.45 (13)	H9A—C9—H9B	108.00
C1—C2—C3	119.22 (12)	C8—C9—H9B	109.00
C1—C2—C7	120.40 (13)	S2—C10—H10A	109.00
C3—C2—C7	120.38 (12)	C11—C10—H10A	109.00
N3—C3—C4	121.32 (13)	C11—C10—H10B	109.00
N3—C3—C2	121.69 (12)	H10A—C10—H10B	108.00
C2—C3—C4	116.98 (12)	S2—C10—H10B	109.00
C3—C4—C5	118.29 (13)	O3—C12—H12A	110.00
N1—C5—N4	110.75 (11)	C13—C12—H12A	110.00
N4—C5—C4	124.09 (13)	C13—C12—H12B	110.00
N1—C5—C4	125.16 (12)	O3—C12—H12B	110.00
N2—C7—C2	178.60 (17)	H12A—C12—H12B	108.00
O1—C8—C9	123.62 (13)	C12—C13—H13B	110.00
O1—C8—N4	123.88 (12)	C12—C13—H13C	109.00
N4—C8—C9	112.49 (12)	C12—C13—H13A	109.00
S2—C9—C8	114.23 (10)	H13A—C13—H13C	109.00
S2—C10—C11	111.95 (10)	H13B—C13—H13C	109.00
O3—C11—C10	110.84 (12)	H13A—C13—H13B	109.00
O2—C11—O3	123.32 (13)
C6—S1—C1—N1	−0.35 (15)	S1—C1—C2—C7	−2.41 (19)
C6—S1—C1—C2	−179.63 (14)	N1—C1—C2—C3	−1.0 (2)
C10—S2—C9—C8	−83.84 (12)	N1—C1—C2—C7	178.34 (14)
C9—S2—C10—C11	63.79 (12)	C1—C2—C3—N3	−179.28 (14)
C12—O3—C11—O2	−4.3 (2)	C1—C2—C3—C4	2.2 (2)
C12—O3—C11—C10	174.39 (12)	C7—C2—C3—N3	1.4 (2)
C11—O3—C12—C13	177.43 (13)	C7—C2—C3—C4	−177.10 (14)
C5—N1—C1—S1	−179.33 (11)	N3—C3—C4—C5	179.07 (14)
C5—N1—C1—C2	−0.1 (2)	C2—C3—C4—C5	−2.4 (2)
C1—N1—C5—N4	179.28 (13)	C3—C4—C5—N1	1.5 (2)
C1—N1—C5—C4	−0.2 (2)	C3—C4—C5—N4	−177.88 (13)
C8—N4—C5—N1	174.69 (14)	O1—C8—C9—S2	−13.0 (2)
C8—N4—C5—C4	−5.9 (2)	N4—C8—C9—S2	168.00 (10)
C5—N4—C8—O1	−3.9 (2)	S2—C10—C11—O2	86.96 (18)
C5—N4—C8—C9	175.09 (13)	S2—C10—C11—O3	−91.73 (13)
S1—C1—C2—C3	178.25 (11)

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
N3—H3A···N2^i	0.91	2.43	3.3291 (18)	168
N3—H3B···O1^ii	0.91	2.03	2.9345 (18)	177
N4—H4A···O4	0.91	2.01	2.9212 (16)	174
O4—H4B···N2^iii	0.84	2.17	3.0032 (19)	172
O4—H4C···O2^iv	0.84	2.09	2.9122 (18)	168
C4—H4···O1	0.95	2.25	2.8484 (17)	121

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