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organic compounds
6-(4-Fluorophenyl)-8-phenyl-2,3-dihydro-4H-imidazo[5,1-b][1,3]thiazin-4-one: an unusual [6–5] fused-ring system
aSchool of Chemical Sciences, Dublin City University, Dublin 9, Ireland, and bCentre for Synthesis and Chemical Biology, School of Chemistry and Chemical Biology, University College Dublin, Dublin 4, Ireland
*Correspondence e-mail: john.gallagher@dcu.ie, donal.f.oshea@ucd.ie
The title compound, C18H13FN2OS, is the first structural example of a [6–5] fused ring incorporating the 2,3-dihydro-4H-imidazo[5,1-b][1,3]thiazin-4-one molecular scaffold. The six-membered 2,3-dihydro-1,3-thiazin-4-one ring adopts an with the S—CH2 C atom displaced by 0.761 (2) Å from the five-atom plane (all within 0.05 Å of the mean plane). The imidazole ring is planar. The phenyl ring is twisted from coplanarity with the imidazole ring by 23.84 (5)° and the 4-fluorophenyl ring is twisted by 53.36 (6)°, due to a close C(aryl)—H⋯O=C contact with the thiazin-4-one carbonyl O atom. The primary intermolecular interaction involves a CH2 group with the F atom [C⋯F = 3.256 (2) Å and C—H⋯F = 137°].
Comment
b]thiazol-3-ones, (II)] and [6–5] [imidazo[5,1-b]thiazin-4-ones, (I)
] fused-ring systems have been targeted (Le Bas et al., 2005
; Le Bas & O'Shea, 2005
; O'Shea et al., 2006
). The [5–5] imidazo[2,1-b]thiazoles have shown promise as anticancer therapeutics (Andreani et al., 2000
). However, the isomeric imidazo[5,1-b]thiazole systems have only recently been investigated and a reported [(IIa)
; Le Bas et al., 2005
]. We report here the first structural example of a [6–5] imidazo[5,1b]thiazin-4-one fused-ring system, viz. the title compound, (Ia)
.
The molecular structure of (Ia) is depicted in Fig. 1, with the atomic numbering scheme, and selected bond lengths and angles are given in Table 1
. Geometric data can be compared individually with different fused-ring systems. However, given that the [6–5] fused-ring in (Ia)
is thus far unique, our focus is on comparisons with both the key ring systems, i.e. the
![[link]](../../../../../../logos/arrows/c_arr.gif)
![[link]](../../../../../../logos/arrows/c_arr.gif)
![Orpen, A. G., Brammer, L., Allen, F. H., Kennard, O., Watson, D. G. & Taylor, R. (1994). Structure Correlation, Vol. 2, Appendix A, edited by H.-B. Bürgi & J. D. Dunitz. Weinheim: VCH. [Orpen, A. G., Brammer, L., Allen, F. H., Kennard, O., Watson, D. G. & Taylor, R. (1994). Structure Correlation, Vol. 2, Appendix A, edited by H.-B. Bürgi & J. D. Dunitz. Weinheim: VCH.]](../../../../../../logos/arrows/c_arr.gif)
![Orpen, A. G., Brammer, L., Allen, F. H., Kennard, O., Watson, D. G. & Taylor, R. (1994). Structure Correlation, Vol. 2, Appendix A, edited by H.-B. Bürgi & J. D. Dunitz. Weinheim: VCH. [Orpen, A. G., Brammer, L., Allen, F. H., Kennard, O., Watson, D. G. & Taylor, R. (1994). Structure Correlation, Vol. 2, Appendix A, edited by H.-B. Bürgi & J. D. Dunitz. Weinheim: VCH.]](../../../../../../logos/arrows/c_arr.gif)
![[{1\over 2}]](teximages/hj3028fi1.gif)
![[{1\over 2}]](teximages/hj3028fi1.gif)
![[link]](../../../../../../logos/arrows/c_arr.gif)
Reactivity studies reveal distinct differences between the [5–5] imidazo[5,1-b]thiazol-3-ones, (II), and [6–5] imidazo[5,1-b]thiazin-4-ones, (Ia)
–(Ic)
. Firstly, ring opening by nucleophilic attack at the C13=O1 amide carbonyl group occurs relatively quickly (under mild conditions) for the [5–5] fused rings, (II)
, but only under more testing conditions for the [6–5] derivatives, (I)
. Secondly, H/D exchange occurs at the methylene H atoms in (II)
at 323 K under facile conditions, but not for (I)
under similar conditions (Le Bas et al., 2005
). In order to rationalize these reactivity differences, the six-membered thiazin-4-one ring in (Ia)
is compared with the five-membered thiazol-3-one ring in (II)
. The mode of amide bond reactivity of (Ia)
is comparable with that observed for the hydrolysis and acyl transfer reactions of N-acetylimidazoles. This is attributed to the N-atom lone pair being part of the aromatic sextet, resulting in ineffective amide stabilization (Oakenfull & Jencks, 1971
; Oakenfull et al., 1971
). This is further substantiated by the IR carbonyl stretch peak being observed at 1743 cm−1 for (Ia)
, which is considerably higher than expected for a typical amide (1630–1670 cm−1; Williams & Fleming, 1989
) or six-membered lactam (1660–1690 cm−1).
The main difference is the nature of the thiazol-3-one and thiazin-4-one rings, with ring strain evident in the former. In (II) (Le Bas et al., 2005
), analysis of two related systems, viz. (IIa)
/(IIb)
, at the bridgehead atom N1 shows that all three C—N bonds range from 1.391 (2) to 1.409 (2) Å in (IIa)
and from 1.388 (3) to 1.407 (3) Å in (IIb)
, whereas in (Ia)
a range of 1.3986 (18)–1.4243 (19) Å reveals a distinct difference, with C13—N1 longer by 0.02 Å. In (Ia)
, the C1—N1—C2 angle is 105.7 (1)°, and C1—N1—C13 and C2—N1—C13 are similar [126.40 (12) and 126.84 (12)°, respectively], in contrast with the corresponding angles in (IIa)
/(IIb)
[106 and 115/138°, respectively], as C2—N1—C13 opens up by 11° in (IIa)
/(IIb)
compared with the value in (Ia)
. The N1—C13=O1 angles differ by 6°, with a value of 120.32 (14)° in (Ia)
versus 126.0 (2)/126.7 (2)° in (IIa)
/(IIb)
. Pyramidalization at atom N1 is negligible in both (Ia)
and (IIa)
/(IIb)
, as all three angles sum to 360°. Reactivity could be attributed to the more open and accessible N1—C13 bond, and greater ring strain facilitates increased susceptibility to nucleophilic ring opening in (IIa)
/(IIb)
. The H/D exchange at the CH2 group in (II)
can be explained by the formation of a 10-π aromatic enol intermediate which facilitates the exchange mechanism, and this is not possible for (I)
(see scheme
below).
An edge-on view of the [6–5] fused ring in (Ia) down the S1—C12 axis is depicted in Fig. 2
, showing the four-atom plane [S1/C1/C13/C12, atoms all within 0.005 (1) Å of the mean plane]. The of the C4NS ring has atom C11 at the flap position displaced by 0.738 (2) Å from the four-atom plane in the same direction as atom N1, which is displaced by 0.095 (2) Å and oriented in the same direction. This envelope description is adequate, however, albeit with a small distortion towards a screw-boat; ring puckering parameters (Cremer & Pople, 1975
) are Q = 0.560 (2) Å, θ = 120.5 (2)° and φ = 122.85 (18)°.
The primary intermolecular interaction involves a methylene CH2 group with a symmetry-related F atom, with C11⋯F1i = 3.256 (2) Å and C11—H11⋯F1i = 137° [symmetry code: (i) 1 − x, y + , −z +
] (Fig. 3
), in tandem with a C22⋯C24i contact (Table 2
), generating a zigzag chain along the (010) direction. Given the paucity of structural data for this and related rings, we are now developing synthetic routes to new [5–5] and [5–6] fused rings with a view to comparing structural data with reactivity in order to gain a more complete insight into the chemical reactivity of these systems.
![]() | Figure 1 A view of (Ia) ![]() |
![]() | Figure 2 An edge-on view of the [6–5] fused-ring system in (Ia) ![]() |
![]() | Figure 3 A packing diagram (with unit cell) of the hydrogen-bonding and contact geometry in the zigzag chain along (010) in (Ia) ![]() ![]() ![]() ![]() ![]() |
Experimental
Brief details of the synthesis of (Ia) have been reported previously (Le Bas et al., 2005
). The compound was recrystallized from ethanol as a pale-yellow solid in 72% yield (m.p. 495–497 K). IR (KBr disc, ν, cm−1): 1743, 1623; 1H NMR (CDCl3): δ 7.87 (d, J = 7.0 Hz, 2H), 7.60–7.64 (m, 2H), 7.41–7.44 (m, 2H), 7.31–7.34 (m, 1H), 7.05–7.10 (m, 2H), 3.27–3.15 (m, 4H); 19F NMR (CDCl3): δ −111; 13C NMR (CDCl3): δ 166.4, 163.6 (d, JCF = 250.0 Hz), 149.8, 138.4, 132.6, 131.6 (d, JCF = 8.6 Hz), 128.8, 128.7, 127.9, 127.1, 119.8, 115.2 (d, JCF = 22.4 Hz), 37.3, 26.0. ES+–MS: m/z 325 (M + H)+; HRMS found: 323.0641 (M − H)−; C18H12FN2OS requires: 323.0654. Analysis calculated for C18H13FN2OS: C 66.65, H 4.04, N 8.64, S 9.89%; found: C 66.42, H 4.01, N 8.54, S 10.07%.
Crystal data
|
Data collection
|
Refinement
|
|
|
In (Ia), all H atoms bound to carbon were treated as riding atoms, using SHELXL97 (Sheldrick, 1997
) defaults for C—H bond lengths (range 0.93–0.97 Å), and with Uiso(H) = 1.5Ueq(C) for methylene H atoms or 1.2Ueq(C) for aromatic H atoms.
Data collection: XSCANS (Siemens, 1994); cell XSCANS; data reduction: XSCANS; program(s) used to solve structure: SHELXS97 (Sheldrick, 1997
); program(s) used to refine structure: SHELXL97 (Sheldrick, 1997
) and SORTX (McArdle, 1995
); molecular graphics: PLATON (Spek, 2003
); software used to prepare material for publication: SHELXL97 and PREP8 (Ferguson, 1998
).
Supporting information
10.1107/S0108270107002375/hj3028sup1.cif
contains datablocks global, Ia. DOI:Structure factors: contains datablock Ia. DOI: 10.1107/S0108270107002375/hj3028Iasup2.hkl
Brief details of the synthesis of (Ia) have previously been reported by us (Le Bas et al., 2005). The compound was recrystallized from ethanol as a pale-yellow solid in 72% yield (m.p. 495–497 K). Spectroscopic analysis: IR (KBr disc, ν, cm-1): 1743, 1623; 1H NMR (CDCl3, δ, p.p.m.): 7.87 (d, J = 7.0 Hz, 2H), 7.60–7.64 (m, 2H), 7.41–7.44 (m, 2H), 7.31–7.34 (m, 1H), 7.05–7.10 (m, 2H), 3.27–3.15 (m, 4H); 19F NMR (CDCl3, δ, p.p.m.): -111; 13C NMR (CDCl3, δ, p.p.m.): 166.4, 163.6 (d, JCF = 250.0 Hz), 149.8, 138.4, 132.6, 131.6 (d, JCF = 8.6 Hz), 128.8, 128.7, 127.9, 127.1, 119.8, 115.2 (d, JCF = 22.4 Hz), 37.3, 26.0. ES+—MS: m/z 325 (M+H)+; HRMS found: 323.0641 (M-H)-; C18H12FN2OS requires: 323.0654. Analysis, calculated for C18H13FN2OS: C 66.65, H 4.04, N 8.64, S 9.89%; found: C 66.42, H 4.01, N 8.54, S 10.07%.
In (Ia), all H atoms bound to C were treated as riding atoms, with the SHELXL97 (Sheldrick, 1997) defaults for C—H lengths (range 0.93–0.97 Å), and with Uiso(H) = 1.5Ueq(C) for methylene H atoms or 1.2Ueq(C) for aromatic H atoms.
Data collection: XSCANS (Siemens, 1994); cell
XSCANS; data reduction: XSCANS; program(s) used to solve structure: SHELXS97 (Sheldrick, 1997); program(s) used to refine structure: SHELXL97 (Sheldrick, 1997); molecular graphics: PLATON (Spek, 2003); software used to prepare material for publication: SHELXL97 and PREP8 (Ferguson, 1998).C18H13FN2OS | F(000) = 672 |
Mr = 324.36 | Dx = 1.444 Mg m−3 |
Monoclinic, P21/c | Melting point: 496 K |
Hall symbol: -P 2ybc | Mo Kα radiation, λ = 0.71073 Å |
a = 11.5195 (13) Å | Cell parameters from 79 reflections |
b = 8.6516 (7) Å | θ = 5.8–19.2° |
c = 15.9173 (11) Å | µ = 0.23 mm−1 |
β = 109.865 (5)° | T = 294 K |
V = 1492.0 (2) Å3 | Block, colourless |
Z = 4 | 0.45 × 0.45 × 0.35 mm |
Bruker P4 diffractometer | Rint = 0.017 |
Radiation source: X-ray tube | θmax = 26.1°, θmin = 1.9° |
Graphite monochromator | h = −14→1 |
ω scans | k = −1→10 |
4084 measured reflections | l = −18→19 |
2938 independent reflections | 4 standard reflections every 296 reflections |
2501 reflections with I > 2σ(I) | intensity decay: 1% |
Refinement on F2 | Primary atom site location: structure-invariant direct methods |
Least-squares matrix: full | Secondary atom site location: difference Fourier map |
R[F2 > 2σ(F2)] = 0.035 | Hydrogen site location: inferred from neighbouring sites |
wR(F2) = 0.093 | H-atom parameters constrained |
S = 1.04 | w = 1/[σ2(Fo2) + (0.0448P)2 + 0.385P] where P = (Fo2 + 2Fc2)/3 |
2938 reflections | (Δ/σ)max = 0.001 |
208 parameters | Δρmax = 0.29 e Å−3 |
0 restraints | Δρmin = −0.16 e Å−3 |
C18H13FN2OS | V = 1492.0 (2) Å3 |
Mr = 324.36 | Z = 4 |
Monoclinic, P21/c | Mo Kα radiation |
a = 11.5195 (13) Å | µ = 0.23 mm−1 |
b = 8.6516 (7) Å | T = 294 K |
c = 15.9173 (11) Å | 0.45 × 0.45 × 0.35 mm |
β = 109.865 (5)° |
Bruker P4 diffractometer | Rint = 0.017 |
4084 measured reflections | 4 standard reflections every 296 reflections |
2938 independent reflections | intensity decay: 1% |
2501 reflections with I > 2σ(I) |
R[F2 > 2σ(F2)] = 0.035 | 0 restraints |
wR(F2) = 0.093 | H-atom parameters constrained |
S = 1.04 | Δρmax = 0.29 e Å−3 |
2938 reflections | Δρmin = −0.16 e Å−3 |
208 parameters |
Geometry. Mean plane data ex-SHELXL97 for molecule (I) ############################################ |
x | y | z | Uiso*/Ueq | ||
C1 | 0.95656 (13) | 0.28746 (18) | 0.29047 (10) | 0.0388 (3) | |
N1 | 0.83290 (11) | 0.23798 (15) | 0.26081 (8) | 0.0381 (3) | |
C2 | 0.80720 (13) | 0.19936 (18) | 0.33801 (10) | 0.0379 (3) | |
N2 | 0.90323 (11) | 0.22051 (15) | 0.40947 (8) | 0.0412 (3) | |
C3 | 0.99766 (13) | 0.27604 (18) | 0.38139 (10) | 0.0390 (3) | |
S1 | 1.03241 (4) | 0.34442 (6) | 0.21794 (3) | 0.05373 (15) | |
C11 | 0.89858 (15) | 0.3857 (2) | 0.12204 (11) | 0.0499 (4) | |
C12 | 0.81006 (16) | 0.2506 (2) | 0.09991 (11) | 0.0508 (4) | |
C13 | 0.75842 (14) | 0.20520 (19) | 0.17095 (10) | 0.0435 (4) | |
O1 | 0.66082 (11) | 0.14194 (18) | 0.15508 (8) | 0.0663 (4) | |
F1 | 0.35036 (10) | 0.04056 (14) | 0.36147 (9) | 0.0763 (4) | |
C21 | 0.68498 (13) | 0.15453 (17) | 0.34110 (9) | 0.0371 (3) | |
C22 | 0.58199 (14) | 0.24579 (19) | 0.30130 (10) | 0.0436 (4) | |
C23 | 0.46930 (15) | 0.2098 (2) | 0.30904 (11) | 0.0482 (4) | |
C24 | 0.46229 (15) | 0.0807 (2) | 0.35643 (12) | 0.0482 (4) | |
C25 | 0.56080 (16) | −0.0113 (2) | 0.39737 (12) | 0.0531 (4) | |
C26 | 0.67402 (15) | 0.02637 (19) | 0.38989 (11) | 0.0462 (4) | |
C31 | 1.11685 (13) | 0.32005 (17) | 0.44758 (10) | 0.0396 (3) | |
C32 | 1.12381 (15) | 0.3586 (2) | 0.53391 (11) | 0.0470 (4) | |
C33 | 1.23423 (16) | 0.4031 (2) | 0.59667 (12) | 0.0550 (4) | |
C34 | 1.34041 (16) | 0.4106 (2) | 0.57479 (13) | 0.0559 (5) | |
C35 | 1.33527 (15) | 0.3728 (2) | 0.48963 (13) | 0.0530 (4) | |
C36 | 1.22485 (14) | 0.3272 (2) | 0.42633 (12) | 0.0469 (4) | |
H11A | 0.8571 | 0.4764 | 0.1339 | 0.060* | |
H11B | 0.9241 | 0.4082 | 0.0712 | 0.060* | |
H12A | 0.7418 | 0.2756 | 0.0461 | 0.061* | |
H12B | 0.8523 | 0.1619 | 0.0866 | 0.061* | |
H22 | 0.5889 | 0.3326 | 0.2689 | 0.052* | |
H23 | 0.4004 | 0.2715 | 0.2828 | 0.058* | |
H25 | 0.5526 | −0.0977 | 0.4297 | 0.064* | |
H26 | 0.7428 | −0.0347 | 0.4178 | 0.055* | |
H32 | 1.0531 | 0.3543 | 0.5495 | 0.056* | |
H33 | 1.2373 | 0.4282 | 0.6542 | 0.066* | |
H34 | 1.4147 | 0.4410 | 0.6173 | 0.067* | |
H35 | 1.4064 | 0.3780 | 0.4745 | 0.064* | |
H36 | 1.2226 | 0.3011 | 0.3691 | 0.056* |
U11 | U22 | U33 | U12 | U13 | U23 | |
C1 | 0.0325 (7) | 0.0420 (8) | 0.0431 (8) | −0.0004 (6) | 0.0146 (6) | −0.0020 (6) |
N1 | 0.0332 (6) | 0.0455 (7) | 0.0363 (6) | −0.0019 (5) | 0.0128 (5) | −0.0026 (5) |
C2 | 0.0356 (7) | 0.0419 (8) | 0.0373 (7) | −0.0008 (6) | 0.0136 (6) | −0.0001 (6) |
N2 | 0.0358 (6) | 0.0481 (7) | 0.0388 (6) | −0.0019 (6) | 0.0117 (5) | 0.0016 (6) |
C3 | 0.0333 (7) | 0.0419 (8) | 0.0417 (8) | 0.0017 (6) | 0.0129 (6) | −0.0002 (6) |
S1 | 0.0399 (2) | 0.0782 (3) | 0.0471 (2) | −0.0052 (2) | 0.01998 (18) | 0.0044 (2) |
C11 | 0.0502 (9) | 0.0585 (10) | 0.0436 (8) | −0.0001 (8) | 0.0193 (7) | 0.0041 (8) |
C12 | 0.0529 (9) | 0.0632 (11) | 0.0377 (8) | −0.0052 (8) | 0.0170 (7) | −0.0051 (8) |
C13 | 0.0402 (8) | 0.0514 (9) | 0.0393 (8) | −0.0008 (7) | 0.0141 (6) | −0.0082 (7) |
O1 | 0.0465 (7) | 0.1063 (11) | 0.0477 (7) | −0.0260 (7) | 0.0180 (5) | −0.0247 (7) |
F1 | 0.0541 (6) | 0.0745 (8) | 0.1170 (10) | −0.0151 (6) | 0.0509 (7) | −0.0063 (7) |
C21 | 0.0356 (7) | 0.0412 (8) | 0.0348 (7) | −0.0043 (6) | 0.0124 (6) | −0.0044 (6) |
C22 | 0.0427 (8) | 0.0454 (9) | 0.0438 (8) | 0.0002 (7) | 0.0161 (7) | 0.0056 (7) |
C23 | 0.0376 (8) | 0.0546 (10) | 0.0527 (9) | 0.0042 (7) | 0.0159 (7) | 0.0001 (8) |
C24 | 0.0413 (8) | 0.0515 (9) | 0.0593 (10) | −0.0106 (7) | 0.0270 (8) | −0.0112 (8) |
C25 | 0.0594 (10) | 0.0438 (9) | 0.0626 (11) | −0.0080 (8) | 0.0292 (9) | 0.0052 (8) |
C26 | 0.0438 (8) | 0.0435 (9) | 0.0501 (9) | 0.0007 (7) | 0.0142 (7) | 0.0044 (7) |
C31 | 0.0337 (7) | 0.0385 (8) | 0.0437 (8) | 0.0032 (6) | 0.0092 (6) | 0.0023 (6) |
C32 | 0.0391 (8) | 0.0541 (10) | 0.0458 (8) | 0.0032 (7) | 0.0119 (7) | 0.0006 (7) |
C33 | 0.0487 (9) | 0.0610 (11) | 0.0471 (9) | 0.0033 (8) | 0.0057 (7) | −0.0063 (8) |
C34 | 0.0396 (9) | 0.0534 (10) | 0.0616 (11) | −0.0001 (8) | 0.0000 (8) | −0.0039 (8) |
C35 | 0.0341 (8) | 0.0533 (10) | 0.0681 (11) | 0.0019 (7) | 0.0131 (8) | 0.0043 (9) |
C36 | 0.0376 (8) | 0.0506 (9) | 0.0516 (9) | 0.0030 (7) | 0.0138 (7) | 0.0002 (7) |
S1—C1 | 1.7392 (15) | C31—C32 | 1.390 (2) |
S1—C11 | 1.7986 (17) | C31—C36 | 1.397 (2) |
C11—C12 | 1.512 (2) | C32—C33 | 1.379 (2) |
C12—C13 | 1.498 (2) | C33—C34 | 1.382 (3) |
N1—C1 | 1.4065 (18) | C34—C35 | 1.376 (3) |
N1—C2 | 1.3986 (18) | C35—C36 | 1.385 (2) |
N1—C13 | 1.4243 (19) | C22—H22 | 0.93 |
O1—C13 | 1.1976 (19) | C23—H23 | 0.93 |
C1—C3 | 1.365 (2) | C25—H25 | 0.93 |
N2—C2 | 1.3023 (19) | C26—H26 | 0.93 |
N2—C3 | 1.3943 (19) | C32—H32 | 0.93 |
C2—C21 | 1.4772 (19) | C33—H33 | 0.93 |
C3—C31 | 1.469 (2) | C34—H34 | 0.93 |
C21—C22 | 1.386 (2) | C11—H11A | 0.97 |
C21—C26 | 1.384 (2) | C11—H11B | 0.97 |
C22—C23 | 1.381 (2) | C12—H12A | 0.97 |
C23—C24 | 1.366 (2) | C12—H12B | 0.97 |
F1—C24 | 1.3636 (17) | C35—H35 | 0.93 |
C24—C25 | 1.358 (2) | C36—H36 | 0.93 |
C25—C26 | 1.388 (2) | ||
S1—C1—N1 | 122.92 (11) | C32—C33—C34 | 120.54 (17) |
S1—C1—C3 | 130.76 (12) | C33—C34—C35 | 119.43 (16) |
N1—C1—C3 | 106.30 (12) | C34—C35—C36 | 120.39 (16) |
C1—N1—C2 | 105.70 (11) | C31—C36—C35 | 120.66 (16) |
C1—N1—C13 | 126.40 (12) | C23—C22—H22 | 119.5 |
C2—N1—C13 | 126.84 (12) | C21—C22—H22 | 119.5 |
N1—C2—N2 | 111.29 (12) | C24—C23—H23 | 121.1 |
N1—C2—C21 | 125.50 (13) | C22—C23—H23 | 121.1 |
N2—C2—C21 | 122.97 (13) | C24—C25—H25 | 120.7 |
N2—C3—C31 | 120.03 (13) | C26—C25—H25 | 120.7 |
C2—N2—C3 | 106.99 (12) | C21—C26—H26 | 119.9 |
C1—C3—N2 | 109.73 (13) | C25—C26—H26 | 119.9 |
C1—C3—C31 | 130.14 (14) | C33—C32—H32 | 119.6 |
C1—S1—C11 | 98.08 (7) | C31—C32—H32 | 119.6 |
S1—C11—C12 | 111.10 (13) | C32—C33—H33 | 119.7 |
C11—C12—C13 | 115.87 (14) | C34—C33—H33 | 119.7 |
O1—C13—N1 | 120.32 (14) | C35—C34—H34 | 120.3 |
O1—C13—C12 | 123.08 (15) | C33—C34—H34 | 120.3 |
N1—C13—C12 | 116.59 (13) | C34—C35—H35 | 119.8 |
C26—C21—C22 | 119.06 (14) | C36—C35—H35 | 119.8 |
C26—C21—C2 | 119.92 (14) | C12—C11—H11A | 109.4 |
C22—C21—C2 | 120.84 (14) | S1—C11—H11A | 109.4 |
C21—C22—C23 | 121.03 (15) | C12—C11—H11B | 109.4 |
C22—C23—C24 | 117.88 (15) | S1—C11—H11B | 109.4 |
F1—C24—C23 | 118.36 (16) | H11A—C11—H11B | 108.0 |
F1—C24—C25 | 118.39 (16) | C13—C12—H12A | 108.3 |
C23—C24—C25 | 123.24 (15) | C11—C12—H12A | 108.3 |
C24—C25—C26 | 118.52 (16) | C13—C12—H12B | 108.3 |
C21—C26—C25 | 120.26 (15) | C11—C12—H12B | 108.3 |
C32—C31—C36 | 118.16 (15) | H12A—C12—H12B | 107.4 |
C32—C31—C3 | 119.81 (14) | C35—C36—H36 | 119.7 |
C36—C31—C3 | 122.02 (14) | C31—C36—H36 | 119.7 |
C31—C32—C33 | 120.83 (15) | ||
N1—C1—S1—C11 | 20.39 (14) | C2—N1—C13—C12 | −176.47 (15) |
C1—S1—C11—C12 | −52.19 (13) | C11—C12—C13—O1 | 153.51 (18) |
S1—C11—C12—C13 | 61.22 (18) | N1—C2—C21—C26 | 133.05 (16) |
C11—C12—C13—N1 | −27.8 (2) | N2—C2—C21—C22 | 121.96 (17) |
C1—N1—C13—C12 | −10.0 (2) | N1—C2—C21—C22 | −51.9 (2) |
S1—C1—N1—C13 | 9.9 (2) | C26—C21—C22—C23 | −0.6 (2) |
N1—C2—N2—C3 | 0.38 (17) | C2—C21—C22—C23 | −175.68 (14) |
C2—N2—C3—C1 | −0.31 (18) | C21—C22—C23—C24 | −0.6 (2) |
N2—C2—C21—C26 | −53.1 (2) | C22—C23—C24—C25 | 1.3 (3) |
N2—C3—C31—C32 | −22.5 (2) | C22—C23—C24—F1 | −177.39 (15) |
C3—C1—N1—C2 | 0.11 (16) | F1—C24—C25—C26 | 177.91 (15) |
S1—C1—N1—C2 | 178.65 (11) | C23—C24—C25—C26 | −0.8 (3) |
C3—C1—N1—C13 | −168.68 (14) | C22—C21—C26—C25 | 1.1 (2) |
C1—N1—C2—N2 | −0.31 (17) | C2—C21—C26—C25 | 176.26 (15) |
C13—N1—C2—N2 | 168.41 (14) | C24—C25—C26—C21 | −0.4 (3) |
C1—N1—C2—C21 | 174.16 (14) | C1—C3—C31—C32 | 153.46 (17) |
C13—N1—C2—C21 | −17.1 (2) | C1—C3—C31—C36 | −25.4 (3) |
C21—C2—N2—C3 | −174.25 (14) | N2—C3—C31—C36 | 158.59 (15) |
N1—C1—C3—N2 | 0.11 (17) | C36—C31—C32—C33 | 0.2 (3) |
S1—C1—C3—N2 | −178.27 (12) | C3—C31—C32—C33 | −178.75 (16) |
N1—C1—C3—C31 | −176.17 (15) | C31—C32—C33—C34 | 0.2 (3) |
S1—C1—C3—C31 | 5.4 (3) | C32—C33—C34—C35 | −0.2 (3) |
C2—N2—C3—C31 | 176.42 (14) | C33—C34—C35—C36 | −0.2 (3) |
C3—C1—S1—C11 | −161.45 (16) | C34—C35—C36—C31 | 0.5 (3) |
C2—N1—C13—O1 | 2.3 (3) | C32—C31—C36—C35 | −0.5 (2) |
C1—N1—C13—O1 | 168.73 (16) | C3—C31—C36—C35 | 178.38 (15) |
D—H···A | D—H | H···A | D···A | D—H···A |
C11—H11A···F1i | 0.97 | 2.48 | 3.256 (2) | 137 |
C22—H22···C24i | 0.93 | 2.85 | 3.753 (2) | 164 |
C32—H32···N2 | 0.93 | 2.58 | 2.896 (2) | 100 |
C36—H36···S1 | 0.93 | 2.67 | 3.3078 (18) | 126 |
Symmetry code: (i) −x+1, y+1/2, −z+1/2. |
Experimental details
Crystal data | |
Chemical formula | C18H13FN2OS |
Mr | 324.36 |
Crystal system, space group | Monoclinic, P21/c |
Temperature (K) | 294 |
a, b, c (Å) | 11.5195 (13), 8.6516 (7), 15.9173 (11) |
β (°) | 109.865 (5) |
V (Å3) | 1492.0 (2) |
Z | 4 |
Radiation type | Mo Kα |
µ (mm−1) | 0.23 |
Crystal size (mm) | 0.45 × 0.45 × 0.35 |
Data collection | |
Diffractometer | Bruker P4 diffractometer |
Absorption correction | – |
No. of measured, independent and observed [I > 2σ(I)] reflections | 4084, 2938, 2501 |
Rint | 0.017 |
(sin θ/λ)max (Å−1) | 0.618 |
Refinement | |
R[F2 > 2σ(F2)], wR(F2), S | 0.035, 0.093, 1.04 |
No. of reflections | 2938 |
No. of parameters | 208 |
H-atom treatment | H-atom parameters constrained |
Δρmax, Δρmin (e Å−3) | 0.29, −0.16 |
Computer programs: XSCANS (Siemens, 1994), XSCANS, SHELXS97 (Sheldrick, 1997), SHELXL97 (Sheldrick, 1997), PLATON (Spek, 2003), SHELXL97 and PREP8 (Ferguson, 1998).
S1—C1 | 1.7392 (15) | N1—C13 | 1.4243 (19) |
S1—C11 | 1.7986 (17) | O1—C13 | 1.1976 (19) |
C11—C12 | 1.512 (2) | C1—C3 | 1.365 (2) |
C12—C13 | 1.498 (2) | N2—C2 | 1.3023 (19) |
N1—C1 | 1.4065 (18) | N2—C3 | 1.3943 (19) |
N1—C2 | 1.3986 (18) | ||
S1—C1—N1 | 122.92 (11) | C1—S1—C11 | 98.08 (7) |
S1—C1—C3 | 130.76 (12) | S1—C11—C12 | 111.10 (13) |
N1—C1—C3 | 106.30 (12) | C11—C12—C13 | 115.87 (14) |
C1—N1—C2 | 105.70 (11) | O1—C13—N1 | 120.32 (14) |
C1—N1—C13 | 126.40 (12) | O1—C13—C12 | 123.08 (15) |
C2—N1—C13 | 126.84 (12) | N1—C13—C12 | 116.59 (13) |
N1—C1—S1—C11 | 20.39 (14) | C1—N1—C13—C12 | −10.0 (2) |
C1—S1—C11—C12 | −52.19 (13) | S1—C1—N1—C13 | 9.9 (2) |
S1—C11—C12—C13 | 61.22 (18) | N2—C2—C21—C26 | −53.1 (2) |
C11—C12—C13—N1 | −27.8 (2) | N2—C3—C31—C32 | −22.5 (2) |
D—H···A | D—H | H···A | D···A | D—H···A |
C11—H11A···F1i | 0.97 | 2.48 | 3.256 (2) | 137 |
C22—H22···C24i | 0.93 | 2.85 | 3.753 (2) | 164 |
C32—H32···N2 | 0.93 | 2.58 | 2.896 (2) | 100 |
C36—H36···S1 | 0.93 | 2.67 | 3.3078 (18) | 126 |
Symmetry code: (i) −x+1, y+1/2, −z+1/2. |
Acknowledgements
JFG thanks Dublin City University for the purchase in 1998 of the Siemens P4 diffractometer and computer system. The synthetic research was funded by Enterprise Ireland and PRTLI-3 (Programme for Research in Third-Level Institutions) administered by the Higher Education Authority, Ireland.
References
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Heterocyclic compounds have been a traditional focal point for the development of new anticancer agents, with combinatorial (high-throughput) approaches to new ring systems being of current interest. In our research to develop new routes to diversely substituted drug-like heterocyclic scaffolds, classes of [5–5] [imidazo[5,1-b]thiazol-3-ones, (II)] and [6–5] [imidazo[5,1-b]thiazin-4-ones, (I)] fused-ring systems have been targeted (Le Bas et al., 2005; Le Bas & O'Shea, 2005; O'Shea et al., 2006). The [5–5] imidazo[2,1-b]thiazoles have shown promise as anticancer therapeutics (Andreani et al., 2000). However, the isomeric [5,1-b] systems have only recently been investigated and a crystal structure reported [(IIa); Le Bas et al., 2005]. Here, we report the first structural example of a [6–5] imidazo[5,1b]thiazin-4-one fused-ring system, the title compound, (Ia).
The molecular structure of (Ia) is depicted in Fig. 1, with the atomic numbering scheme, and selected bond lengths and angles are given in Table 1. Geometric data can be compared individually with different fused-ring systems. However, given that the [6–5] fused-ring in (Ia) is thus far unique, our focus is on comparisons with both the key ring systems, i.e. the imidazole ring, and the [5–5] fused-ring relatives, (II). In (Ia), geometric data for the bis-aryl(imidazo) rings differ from the average values for imidazoles (Orpen et al., 1994). The C1═C3 and C2═N2 bond lengths of 1.365 (2) Å (longer) and 1.3023 (19) Å (shorter) differ, though not significantly, from the expected values of 1.36 and 1.313 Å. However, the three C—N bond lengths for C1/C2—N1 and C3—N2 are ca 0.03 Å longer [1.4065 (18)/1.3986 (18) and 1.3943 (19) Å, respectively] than the corresponding average values in imidazoles [1.370/1.349 and 1.376 Å, respectively] (Orpen et al., 1994), reflecting the effect of the extra ring attached at C1/N1. The imidazole ring is planar, with all five atoms within 0.002 (1) Å of the C3N2 mean plane. The phenyl ring is twisted from co-planarity with the imidazole ring by 23.84 (5)°, while the para-FC6H4 ring is twisted by 53.36 (6)° away from the central ring due to a close contact with the thiazin-4-one carbonyl atom O1 and an intermolecular interaction with a neighbouring π-arene, C22—H22···C24i [symmetry code: (i) 1 - x, 1/2 + y, 1/2 - z; Table 2].
Reactivity studies reveal distinct differences between the [5–5] imidazo[5,1-b]thiazol-3-ones, (II), and [6–5] imidazo[5,1-b]thiazin-4-ones, (Ia)–(Ic). Firstly, ring opening by nucleophilic attack at the amide carbonyl C13═O1 occurs relatively quickly (under mild conditions) for the [5–5] fused rings, (II), but only under more testing conditions for the [6–5] derivatives, (I). Secondly, H/D exchange occurs at the methylene H atoms in (II) at 323 K under facile conditions, but not for (I) under similar conditions (Le Bas et al., 2005). In order to rationalize these reactivity differences, the six-membered thiazin-4-one ring in (Ia) is compared with the five-membered thiazol-3-one ring in (II). The amide bond reactivity of (Ia) is comparable with that observed for the hydrolysis and acyl transfer reactions of N-acetylimidazoles. This is attributed to the N lone pair being part of the aromatic sextet, resulting in ineffective amide stabilization (Oakenfull & Jencks, 1971; Oakenfull et al., 1971). This is further substantiated by the IR carbonyl stretch peak being observed at 1743 cm-1 for (Ia), which is considerably higher than expected for a typical amide (1630–1670 cm-1; Reference?) or six-membered lactam (1660–1690 cm-1; Reference?).
The main difference is the nature of the thiazol-3-one and thiazin-4-one rings, with ring strain evident in the former. In (II) (Le Bas et al., 2005), analysis of two related systems, (IIa)/(IIb), at the bridgehead atom N1 shows that all three C—N bonds range from 1.391 (2) to 1.409 (2) Å in (IIa) and from 1.388 (3) to 1.407 (3) Å in (IIb), whereas in (Ia) a range of 1.3986 (18) to 1.4243 (19) Å reveals a distinct difference, with C13—N1 longer by 0.02 Å. In (Ia), the C1—N1—C2 angle is 105.7 (1)°, and C1—N1—C13 and C2—N1—C13 are similar [126.40 (12) and 126.84 (12)°, respectively], in contrast with the corresponding angles in (IIa)/(IIb) [106° and 115/138°, respectively], as C2—N1—C13 opens up by 11° in (IIa)/(IIb) compared with the value in (Ia). The N1—C13═O1 angles differ by 6°, with a value of 120.32 (14)° in (Ia) versus 126.0 (2)/126.7 (2)° in (IIa)/(IIb). Pyramidalization at atom N1 is negligible in both (Ia) and (IIa)/(IIb), as all three angles sum to 360°. Reactivity could be attributed to the more open and accessible N1—C13 bond, and greater ring strain facilitates increased susceptibility to nucleophilic ring opening in (IIa)/(IIb). The H/D exchange at the CH2 group in (II) can be explained by the formation of a 10-π aromatic enol intermediate which facilitates the exchange mechanism, and this is not possible for (I) (see scheme).
An edge-on view of the [6–5] fused ring in (Ia) is depicted in Fig. 2 with the four-atom plane [S1/C1/C13/C12, atoms all within 0.005 (1) Å of the mean plane] and down the S1—C12 axis. The envelope conformation of the C4NS ring has atom C11 at the flap position and displaced by 0.738 (2) Å from the four-atom plane and in the same direction as atom N1, which is displaced by 0.095 (2) Å and oriented in the same direction. This envelope description is adequate, however, although with a small distortion towards a screw-boat; ring puckering parameters (Cremer & Pople, 1975) are Q = 0.560 (2) Å, θ = 120.5 (2)° and ϕ = 122.85 (18)°.
The primary intermolecular interaction involves a methylene CH2 group with a symmetry-related F atom, with C11···F1i = 3.256 (2) Å and C11—H11.·F1i = 137° [symmetry code: (i) 1 - x, y + 1/2, -z + 1/2] (Fig. 3), in tandem with a C22.·C24i contact (Table 2), generating a zigzag chain along the (010) direction. Given the paucity of structural data for this and related rings, we are now developing synthetic routes to new [5–5] and [5–6] fused rings with a view to comparing structural data with reactivity in order to gain a more complete insight into the chemical reactivity of these systems.