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The first crystal structure of the pyrrolo­[1,2-c]oxazole ring system

aDepartment of Chemistry, Faculty of Science, Zawia University, PO Box 16168, Zawia, Libya, and bDepartment of Chemistry, The University of Sheffield, Dainton Building, Sheffield S3 7HF, UK
*Correspondence e-mail: craig.robertson@sheffield.ac.uk

Edited by W. T. A. Harrison, University of Aberdeen, Scotland (Received 19 July 2019; accepted 9 August 2019; online 23 August 2019)

The title compound, C7H4F3NO2, 3-tri­fluoro­methyl-1H-pyrrolo­[1,2-c]oxazol-1-one, is the first crystal structure of the pyrrolo­[1,2-c]oxazole ring system: the fused ring system is almost planar (r.m.s. deviation = 0.006 Å). In the crystal, weak C—H⋯O and C—H⋯F hydrogen bonds link the mol­ecules into [001] chains and ππ stacking inter­actions consolidate the structure.

1. Chemical context

In the context of an approach to the synthesis of proline-derived ketones 3 by the proposed palladium-catalyzed Negishi coupling of organozinc reagent 1 with protected 4-hy­droxy­proline-derived acid chloride 2, we needed access to a suitably N,O-diprotected 4-hy­droxy­proline derivative (Fig. 1[link]). Our initial choice was to use TFA protection, since related cross-coupling reactions with the TFA-protected proline acid chloride had been successful (Deboves et al. 2001[Deboves, H. J. C., Montalbetti, C. A. G. N. & Jackson, R. F. W. (2001). J. Chem. Soc. Perkin Trans. 1, pp. 1876-1884.]), and so the preparation of N,O-bis-tri­fluoro­acetyl-4-hy­droxy-L-proline 4 was attempted. The preparation of this compound had been reported, but without a detailed procedure (Mori et al., 1986[Mori, M., Uozumi, Y., Kimura, M. & Ban, Y. (1986). Tetrahedron, 42, 3793-3806.]).

[Figure 1]
Figure 1
Proposed reaction scheme to access proline-derived ketones 3 from the Negishi coupling of organozinc reagents 1 with 4-hy­droxy­proline-derived acid chlorides 2, specifically towards the formation of compound 3

Treatment of (2S,4R)-4-hy­droxy­proline with tri­fluoro­acetic anhydride TFAA (3 eq.) in di­chloro­methane at 273 K, followed by heating at reflux, gave a mixture of two compounds, which could be separated by column chromatography (Fig. 2[link]). The more polar compound was the desired bis-TFA protected (2S,4R)-4-hy­droxy­proline 4 (47%), and the less polar material was an unknown by-product 5 (52%). This latter unknown compound exhibited signals in the aromatic region of the 1H NMR spectrum, suggesting that the hy­droxy group had been eliminated and a pyrrole derivative had been formed. The mass spectrum obtained for 5 showed a base peak at m/z 190 (100%), and the IR spectrum exhibited a stretching frequency in the carbonyl region at 1781 cm−1. A crystal structure was obtained (see below), which confirmed that the compound was a new bicycle, a rare representative of the pyrrolo­[1,2-c]oxazole ring system as first described by Katritzky et al. (2004[Katritzky, A. R., Singh, S. K. & Bobrov, S. (2004). J. Org. Chem. 69, 9313-9315.]).

[Figure 2]
Figure 2
Reaction scheme for the synthesis of 5 along with the desired product 4.

When the reaction was repeated under milder conditions, omitting the period of heating under reflux, the desired bis-TFA protected 4-hy­droxy-L-proline 4 was obtained in near qu­anti­tative yield, suggesting that it was partially converted into the novel pyrrolo­[1,2-c]oxazole 5 under reflux conditions, presumably by elimination from an inter­mediate of structure 6.

2. Structural commentary

Compound 5 crystallizes in the monoclinic space group P21/c: its asymmetric unit comprises of a single mol­ecule (Fig. 3[link]). The fused bicyclic aromatic system is almost planar [r.m.s. deviation = 0.006 Å; dihedral angle between the five-membered rings = 0.86 (6)°]. Atom C7, which bears the fluorine atoms, is displaced from the ring plane by 1.282 (1) Å and F3 lies anti to O1 [O1—C1—C7—F3 = −176.33 (8)°]. In the arbitrarily chosen asymmetric mol­ecule, the stereogenic centre C1 has an R configuration but crystal symmetry generates a racemic mixture.

[Figure 3]
Figure 3
The mol­ecular structure of 5, showing displacement ellipsoids drawn at the 50% probability level.

3. Supra­molecular features

In the crystal, two weak hydrogen bonds (Table 1[link]) are observed between 5 and the adjacent mol­ecule related by the symmetry operation (x, −y + [{1\over 2}], z[{1\over 2}]). These form between the sp3 hydrogen atom H1 and the carbonyl oxygen atom O2 and the aromatic proton H6 and F1 of the triflomethyl group: together, they generate an [001] chain. The mol­ecules pack in sheets parallel to the (010) plane with alternating layers of inter­digitated CF3 groups and ππ stacked ring systems (Fig. 4[link]). The shortest ππ stacking inter­action between centrosymmetrically related N1/C3–C6 rings has a centroid–centroid separation of 3.5785 (7) Å with a vertical distance of 3.4196 (5) Å and a shift of 1.017 Å with an inter-planar angle of 0°.

Table 1
Hydrogen-bond geometry (Å, °)

D—H⋯A D—H H⋯A DA D—H⋯A
C1—H1⋯O2i 0.98 2.46 3.2683 (13) 140
C6—H6⋯F1i 0.93 2.53 3.4065 (13) 156
Symmetry code: (i) [x, -y+{\script{1\over 2}}, z-{\script{1\over 2}}].
[Figure 4]
Figure 4
View along the b axis of the crystal packing for 5, showing the alternating layers of inter­digitated CF3 groups and bicyclic ring systems. Hydrogen bonds are shown as dashed lines; hydrogen atoms not involved in forming these bonds are omitted for clarity.

4. Database survey

A search in the Cambridge Structural Database (CSD, V5.40, update February 2019; Groom et al., 2016[Groom, C. R., Bruno, I. J., Lightfoot, M. P. & Ward, S. C. (2016). Acta Cryst. B72, 171-179.]) was performed to confirm that there have been no previous crystal structures of the pyrrolo­[1,2-c]oxazole ring system.

5. Synthesis and crystallization

Tri­fluoro­acetic anhydride (0.33 ml, 2.31 mmol, 2.1 eq) was added dropwise to a stirred solution of trans-4-hy­droxy-L-proline (144 mg, 1.1 mmol) in CH2Cl2 (2 ml) at 273 K. The reaction mixture was warmed to room temperature, and then heated under reflux for 1.5 h. The excess of CH2Cl2 was removed under reduced pressure to give a crude product that was purified by column chromatography (petrol:ethyl acetate, 80:20%) to give 3-tri­fluoro­methyl-1H-pyrrolo­[1,2-c]oxazol-1-one (0.11 g, 52%) as a white powder, m.p. 338–340 K; Rf 0.27 (petrol:ethyl acetate, 80:20%); vmax(film)/cm−1 3150, 2977, 2918, 1781, 1548, 1318, 1276; δH (400 MHz; CDCl3) 6.20 (1H, q, J = 3.5), 6.62 (1H, dd, J = 2.5, 4.0), 6.91 (1H, dd, J = 1.0, 4.0), 7.12–7.15 (1H, m); δC (100 MHz; CDCl3) 111.2, 118.7, 119.2, 120.3 (CF3, q, J = 283.0), 121.7, 156.7. Analysis calculated for C7H3NO2F3: C, 43.9; H, 2.1; N, 7.3. Found: C, 43.92; H, 2.16; N, 7.10. m/z (ES) 190 (M − H), 100%). Found: [M − H] 190.0115 C7H3NO2F3 requires 190.0116. Recrystallization from petroleum ether:ethyl acetate 80:20% solution led to colourless blocks of 5.

The mass balance (47%) was the known bis-TFA-4-hy­droxy-L-proline 4 (Mori et al., 1986[Mori, M., Uozumi, Y., Kimura, M. & Ban, Y. (1986). Tetrahedron, 42, 3793-3806.]).

6. Refinement

Crystal data, data collection and structure refinement details are summarized in Table 2[link]. The H atoms were positioned geometrically (C—H = 0.93 Å for sp2 aromatic and 0.98 Å for sp3 methine CH atoms) and refined as riding atoms with relative isotropic displacement parameters Uiso(H) = 1.2Ueq of the parent atoms.

Table 2
Experimental details

Crystal data
Chemical formula C7H4F3NO2
Mr 191.11
Crystal system, space group Monoclinic, P21/c
Temperature (K) 100
a, b, c (Å) 8.2767 (5), 8.5106 (5), 10.5500 (7)
β (°) 99.443 (3)
V3) 733.07 (8)
Z 4
Radiation type Mo Kα
μ (mm−1) 0.18
Crystal size (mm) 0.43 × 0.32 × 0.32
 
Data collection
Diffractometer Bruker APEXII CCD
Absorption correction Multi-scan (SADABS; Bruker, 2009[Bruker (2009). APEX2, SAINT and SADABS. Bruker AXS Inc., Madison, Wisconsin, USA.])
Tmin, Tmax 0.700, 0.746
No. of measured, independent and observed [I > 2σ(I)] reflections 13286, 1681, 1595
Rint 0.033
(sin θ/λ)max−1) 0.650
 
Refinement
R[F2 > 2σ(F2)], wR(F2), S 0.030, 0.078, 1.08
No. of reflections 1681
No. of parameters 118
H-atom treatment H-atom parameters constrained
Δρmax, Δρmin (e Å−3) 0.39, −0.30
Computer programs: APEX2 and SAINT (Bruker, 2009[Bruker (2009). APEX2, SAINT and SADABS. Bruker AXS Inc., Madison, Wisconsin, USA.]), SHELXT (Sheldrick, 2015a[Sheldrick, G. M. (2015a). Acta Cryst. A71, 3-8.]), SHELXL (Sheldrick, 2015b[Sheldrick, G. M. (2015b). Acta Cryst. C71, 3-8.]) and OLEX2 (Dolomanov et al., 2009[Dolomanov, O. V., Bourhis, L. J., Gildea, R. J., Howard, J. A. K. & Puschmann, H. (2009). J. Appl. Cryst. 42, 339-341.]).

Supporting information


Computing details top

Data collection: APEX2 (Bruker, 2009); cell refinement: SAINT (Bruker, 2009); data reduction: SAINT (Bruker, 2009); program(s) used to solve structure: SHELXT (Sheldrick, 2015a); program(s) used to refine structure: SHELXL (Sheldrick, 2015b); molecular graphics: OLEX2 (Dolomanov et al., 2009); software used to prepare material for publication: OLEX2 (Dolomanov et al., 2009).

3-Trifluoromethyl-1H-pyrrolo[1,2-c]oxazol-1-one top
Crystal data top
C7H4F3NO2F(000) = 384
Mr = 191.11Dx = 1.732 Mg m3
Monoclinic, P21/cMo Kα radiation, λ = 0.71073 Å
a = 8.2767 (5) ÅCell parameters from 9927 reflections
b = 8.5106 (5) Åθ = 3.1–27.6°
c = 10.5500 (7) ŵ = 0.18 mm1
β = 99.443 (3)°T = 100 K
V = 733.07 (8) Å3Block, colourless
Z = 40.43 × 0.32 × 0.32 mm
Data collection top
Bruker APEXII CCD
diffractometer
1595 reflections with I > 2σ(I)
φ and ω scansRint = 0.033
Absorption correction: multi-scan
(SADABS; Bruker, 2009)
θmax = 27.5°, θmin = 2.5°
Tmin = 0.700, Tmax = 0.746h = 1010
13286 measured reflectionsk = 1111
1681 independent reflectionsl = 1313
Refinement top
Refinement on F20 restraints
Least-squares matrix: fullHydrogen site location: inferred from neighbouring sites
R[F2 > 2σ(F2)] = 0.030H-atom parameters constrained
wR(F2) = 0.078 w = 1/[σ2(Fo2) + (0.0348P)2 + 0.3122P]
where P = (Fo2 + 2Fc2)/3
S = 1.08(Δ/σ)max < 0.001
1681 reflectionsΔρmax = 0.39 e Å3
118 parametersΔρmin = 0.30 e Å3
Special details top

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

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å2) top
xyzUiso*/Ueq
N10.20468 (11)0.42629 (11)0.56351 (8)0.0174 (2)
O10.14217 (9)0.27976 (9)0.72729 (7)0.01878 (18)
O20.08840 (11)0.47329 (9)0.86114 (7)0.02351 (19)
C10.19006 (13)0.26514 (12)0.60398 (10)0.0173 (2)
H10.1070860.2084580.5441580.021*
C20.12893 (12)0.43833 (12)0.76072 (10)0.0176 (2)
C30.17020 (12)0.52963 (12)0.65500 (9)0.0168 (2)
C40.18460 (13)0.68045 (13)0.61032 (10)0.0197 (2)
H40.1678180.7735740.6524110.024*
C50.22998 (13)0.66468 (14)0.48775 (11)0.0221 (2)
H50.2489410.7470880.4341930.027*
C60.24167 (14)0.50640 (14)0.46028 (10)0.0215 (2)
H60.2693960.4631880.3857750.026*
C70.35527 (14)0.18148 (13)0.61947 (11)0.0211 (2)
F10.34284 (9)0.03455 (8)0.66179 (7)0.03022 (19)
F20.46888 (8)0.25554 (9)0.70256 (7)0.03067 (19)
F30.40810 (8)0.17430 (9)0.50653 (7)0.02723 (18)
Atomic displacement parameters (Å2) top
U11U22U33U12U13U23
N10.0210 (4)0.0154 (4)0.0160 (4)0.0006 (3)0.0032 (3)0.0002 (3)
O10.0248 (4)0.0147 (4)0.0178 (4)0.0008 (3)0.0064 (3)0.0003 (3)
O20.0321 (4)0.0207 (4)0.0193 (4)0.0014 (3)0.0089 (3)0.0002 (3)
C10.0204 (5)0.0153 (5)0.0163 (5)0.0018 (4)0.0034 (4)0.0002 (4)
C20.0179 (5)0.0149 (5)0.0195 (5)0.0003 (4)0.0019 (4)0.0002 (4)
C30.0168 (5)0.0167 (5)0.0169 (5)0.0008 (4)0.0023 (4)0.0014 (4)
C40.0180 (5)0.0166 (5)0.0243 (5)0.0009 (4)0.0024 (4)0.0014 (4)
C50.0201 (5)0.0217 (5)0.0243 (5)0.0020 (4)0.0028 (4)0.0071 (4)
C60.0242 (5)0.0241 (5)0.0168 (5)0.0007 (4)0.0049 (4)0.0039 (4)
C70.0229 (5)0.0185 (5)0.0221 (5)0.0003 (4)0.0044 (4)0.0000 (4)
F10.0360 (4)0.0185 (4)0.0383 (4)0.0071 (3)0.0122 (3)0.0059 (3)
F20.0220 (3)0.0351 (4)0.0319 (4)0.0010 (3)0.0045 (3)0.0043 (3)
F30.0265 (4)0.0300 (4)0.0275 (4)0.0021 (3)0.0113 (3)0.0018 (3)
Geometric parameters (Å, º) top
N1—C11.4474 (13)C3—C41.3792 (15)
N1—C31.3700 (13)C4—H40.9300
N1—C61.3617 (14)C4—C51.4108 (15)
O1—C11.4262 (12)C5—H50.9300
O1—C21.4036 (13)C5—C61.3846 (16)
O2—C21.2000 (13)C6—H60.9300
C1—H10.9800C7—F11.3374 (13)
C1—C71.5265 (15)C7—F21.3339 (13)
C2—C31.4456 (14)C7—F31.3363 (13)
C3—N1—C1111.31 (8)C3—C4—H4127.0
C6—N1—C1138.68 (9)C3—C4—C5106.00 (9)
C6—N1—C3110.01 (9)C5—C4—H4127.0
C2—O1—C1110.98 (8)C4—C5—H5125.6
N1—C1—H1111.1C6—C5—C4108.82 (10)
N1—C1—C7110.90 (9)C6—C5—H5125.6
O1—C1—N1103.62 (8)N1—C6—C5106.68 (10)
O1—C1—H1111.1N1—C6—H6126.7
O1—C1—C7108.73 (8)C5—C6—H6126.7
C7—C1—H1111.1F1—C7—C1110.80 (9)
O1—C2—C3106.55 (8)F2—C7—C1111.87 (9)
O2—C2—O1120.33 (9)F2—C7—F1107.88 (9)
O2—C2—C3133.12 (10)F2—C7—F3108.00 (9)
N1—C3—C2107.54 (9)F3—C7—C1110.14 (9)
N1—C3—C4108.48 (9)F3—C7—F1108.01 (9)
C4—C3—C2143.96 (10)
N1—C1—C7—F1177.53 (8)C1—O1—C2—O2179.38 (9)
N1—C1—C7—F257.11 (12)C1—O1—C2—C30.12 (11)
N1—C1—C7—F363.02 (11)C2—O1—C1—N10.25 (11)
N1—C3—C4—C50.21 (12)C2—O1—C1—C7117.77 (9)
O1—C1—C7—F164.22 (11)C2—C3—C4—C5178.20 (14)
O1—C1—C7—F256.21 (11)C3—N1—C1—O10.55 (11)
O1—C1—C7—F3176.33 (8)C3—N1—C1—C7115.95 (9)
O1—C2—C3—N10.46 (11)C3—N1—C6—C50.03 (12)
O1—C2—C3—C4178.46 (14)C3—C4—C5—C60.20 (13)
O2—C2—C3—N1178.94 (11)C4—C5—C6—N10.11 (13)
O2—C2—C3—C40.9 (2)C6—N1—C1—O1178.81 (12)
C1—N1—C3—C20.64 (11)C6—N1—C1—C764.69 (16)
C1—N1—C3—C4179.40 (8)C6—N1—C3—C2178.91 (9)
C1—N1—C6—C5179.34 (11)C6—N1—C3—C40.15 (12)
Hydrogen-bond geometry (Å, º) top
D—H···AD—HH···AD···AD—H···A
C1—H1···O2i0.982.463.2683 (13)140
C6—H6···F1i0.932.533.4065 (13)156
Symmetry code: (i) x, y+1/2, z1/2.
 

Acknowledgements

We thank Zawia University for support (MMZ).

References

First citationBruker (2009). APEX2, SAINT and SADABS. Bruker AXS Inc., Madison, Wisconsin, USA.  Google Scholar
First citationDeboves, H. J. C., Montalbetti, C. A. G. N. & Jackson, R. F. W. (2001). J. Chem. Soc. Perkin Trans. 1, pp. 1876–1884.  Web of Science CrossRef Google Scholar
First citationDolomanov, O. V., Bourhis, L. J., Gildea, R. J., Howard, J. A. K. & Puschmann, H. (2009). J. Appl. Cryst. 42, 339–341.  Web of Science CrossRef CAS IUCr Journals Google Scholar
First citationGroom, C. R., Bruno, I. J., Lightfoot, M. P. & Ward, S. C. (2016). Acta Cryst. B72, 171–179.  Web of Science CrossRef IUCr Journals Google Scholar
First citationKatritzky, A. R., Singh, S. K. & Bobrov, S. (2004). J. Org. Chem. 69, 9313–9315.  CrossRef PubMed CAS Google Scholar
First citationMori, M., Uozumi, Y., Kimura, M. & Ban, Y. (1986). Tetrahedron, 42, 3793–3806.  CrossRef CAS Google Scholar
First citationSheldrick, G. M. (2015a). Acta Cryst. A71, 3–8.  Web of Science CrossRef IUCr Journals Google Scholar
First citationSheldrick, G. M. (2015b). Acta Cryst. C71, 3–8.  Web of Science CrossRef IUCr Journals Google Scholar

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