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

Zreigh, M.M.; Adams, H.; Jackson, R.F.W.; Robertson, C.C.

doi:10.1107/S2056989019011095

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Volume 75| Part 9| September 2019| Pages 1336-1338

https://doi.org/10.1107/S2056989019011095

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

Mohamed M. Zreigh,^a Harry Adams,^b Richard F. W. Jackson ^b and Craig C. Robertson ^b ^*

^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 π–π stacking interactions consolidate the structure.

Keywords: crystal structure; pyrrolo[1,2-c]oxazole; hydrogen bonds.

CCDC reference: 1919738

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). 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 ), 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 ).

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). 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 ).

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). 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
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) 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 π–π stacked ring systems (Fig. 4). The shortest π–π 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	D⋯A	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
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 ) 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; R_f 0.27 (petrol:ethyl acetate, 80:20%); v_max(film)/cm⁻¹ 3150, 2977, 2918, 1781, 1548, 1318, 1276; δ_H (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); δ_C (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).

6. Refinement

Crystal data, data collection and structure refinement details are summarized in Table 2. 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 U_iso(H) = 1.2U_eq of the parent atoms.

Table 2
Experimental details

Crystal data
Chemical formula	C₇H₄F₃NO₂
M_r	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)
V (Å³)	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 )
T_min, T_max	0.700, 0.746
No. of measured, independent and observed [I > 2σ(I)] reflections	13286, 1681, 1595
R_int	0.033
(sin θ/λ)_max (Å⁻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
Δρ_max, Δρ_min (e Å⁻³)	0.39, −0.30
Computer programs: APEX2 and SAINT (Bruker, 2009), SHELXT (Sheldrick, 2015a ), SHELXL (Sheldrick, 2015b ) and OLEX2 (Dolomanov et al., 2009 ).

Supporting information

CCDC reference: 1919738

Crystal structure: contains datablock I. DOI: https://doi.org/10.1107/S2056989019011095/hb7843sup1.cif

Structure factors: contains datablock I. DOI: https://doi.org/10.1107/S2056989019011095/hb7843Isup2.hkl

Supporting information file. DOI: https://doi.org/10.1107/S2056989019011095/hb7843Isup3.cml

checkCIF report

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

C₇H₄F₃NO₂	F(000) = 384
M_r = 191.11	D_x = 1.732 Mg m⁻³
Monoclinic, P2₁/c	Mo Kα radiation, λ = 0.71073 Å
a = 8.2767 (5) Å	Cell parameters from 9927 reflections
b = 8.5106 (5) Å	θ = 3.1–27.6°
c = 10.5500 (7) Å	µ = 0.18 mm⁻¹
β = 99.443 (3)°	T = 100 K
V = 733.07 (8) Å³	Block, colourless
Z = 4	0.43 × 0.32 × 0.32 mm

Data collection top

Bruker APEXII CCD diffractometer	1595 reflections with I > 2σ(I)
φ and ω scans	R_int = 0.033
Absorption correction: multi-scan (SADABS; Bruker, 2009)	θ_max = 27.5°, θ_min = 2.5°
T_min = 0.700, T_max = 0.746	h = −10→10
13286 measured reflections	k = −11→11
1681 independent reflections	l = −13→13

Refinement top

Refinement on F²	0 restraints
Least-squares matrix: full	Hydrogen site location: inferred from neighbouring sites
R[F² > 2σ(F²)] = 0.030	H-atom parameters constrained
wR(F²) = 0.078	w = 1/[σ²(F_o²) + (0.0348P)² + 0.3122P] where P = (F_o² + 2F_c²)/3
S = 1.08	(Δ/σ)_max < 0.001
1681 reflections	Δρ_max = 0.39 e Å⁻³
118 parameters	Δρ_min = −0.30 e Å⁻³

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

	x	y	z	U_iso*/U_eq
N1	0.20468 (11)	0.42629 (11)	0.56351 (8)	0.0174 (2)
O1	0.14217 (9)	0.27976 (9)	0.72729 (7)	0.01878 (18)
O2	0.08840 (11)	0.47329 (9)	0.86114 (7)	0.02351 (19)
C1	0.19006 (13)	0.26514 (12)	0.60398 (10)	0.0173 (2)
H1	0.107086	0.208458	0.544158	0.021*
C2	0.12893 (12)	0.43833 (12)	0.76072 (10)	0.0176 (2)
C3	0.17020 (12)	0.52963 (12)	0.65500 (9)	0.0168 (2)
C4	0.18460 (13)	0.68045 (13)	0.61032 (10)	0.0197 (2)
H4	0.167818	0.773574	0.652411	0.024*
C5	0.22998 (13)	0.66468 (14)	0.48775 (11)	0.0221 (2)
H5	0.248941	0.747088	0.434193	0.027*
C6	0.24167 (14)	0.50640 (14)	0.46028 (10)	0.0215 (2)
H6	0.269396	0.463188	0.385775	0.026*
C7	0.35527 (14)	0.18148 (13)	0.61947 (11)	0.0211 (2)
F1	0.34284 (9)	0.03455 (8)	0.66179 (7)	0.03022 (19)
F2	0.46888 (8)	0.25554 (9)	0.70256 (7)	0.03067 (19)
F3	0.40810 (8)	0.17430 (9)	0.50653 (7)	0.02723 (18)

Atomic displacement parameters (Å²) top

	U¹¹	U²²	U³³	U¹²	U¹³	U²³
N1	0.0210 (4)	0.0154 (4)	0.0160 (4)	−0.0006 (3)	0.0032 (3)	0.0002 (3)
O1	0.0248 (4)	0.0147 (4)	0.0178 (4)	−0.0008 (3)	0.0064 (3)	0.0003 (3)
O2	0.0321 (4)	0.0207 (4)	0.0193 (4)	0.0014 (3)	0.0089 (3)	−0.0002 (3)
C1	0.0204 (5)	0.0153 (5)	0.0163 (5)	−0.0018 (4)	0.0034 (4)	−0.0002 (4)
C2	0.0179 (5)	0.0149 (5)	0.0195 (5)	−0.0003 (4)	0.0019 (4)	0.0002 (4)
C3	0.0168 (5)	0.0167 (5)	0.0169 (5)	−0.0008 (4)	0.0023 (4)	−0.0014 (4)
C4	0.0180 (5)	0.0166 (5)	0.0243 (5)	−0.0009 (4)	0.0024 (4)	0.0014 (4)
C5	0.0201 (5)	0.0217 (5)	0.0243 (5)	−0.0020 (4)	0.0028 (4)	0.0071 (4)
C6	0.0242 (5)	0.0241 (5)	0.0168 (5)	−0.0007 (4)	0.0049 (4)	0.0039 (4)
C7	0.0229 (5)	0.0185 (5)	0.0221 (5)	0.0003 (4)	0.0044 (4)	0.0000 (4)
F1	0.0360 (4)	0.0185 (4)	0.0383 (4)	0.0071 (3)	0.0122 (3)	0.0059 (3)
F2	0.0220 (3)	0.0351 (4)	0.0319 (4)	0.0010 (3)	−0.0045 (3)	−0.0043 (3)
F3	0.0265 (4)	0.0300 (4)	0.0275 (4)	0.0021 (3)	0.0113 (3)	−0.0018 (3)

Geometric parameters (Å, º) top

N1—C1	1.4474 (13)	C3—C4	1.3792 (15)
N1—C3	1.3700 (13)	C4—H4	0.9300
N1—C6	1.3617 (14)	C4—C5	1.4108 (15)
O1—C1	1.4262 (12)	C5—H5	0.9300
O1—C2	1.4036 (13)	C5—C6	1.3846 (16)
O2—C2	1.2000 (13)	C6—H6	0.9300
C1—H1	0.9800	C7—F1	1.3374 (13)
C1—C7	1.5265 (15)	C7—F2	1.3339 (13)
C2—C3	1.4456 (14)	C7—F3	1.3363 (13)

C3—N1—C1	111.31 (8)	C3—C4—H4	127.0
C6—N1—C1	138.68 (9)	C3—C4—C5	106.00 (9)
C6—N1—C3	110.01 (9)	C5—C4—H4	127.0
C2—O1—C1	110.98 (8)	C4—C5—H5	125.6
N1—C1—H1	111.1	C6—C5—C4	108.82 (10)
N1—C1—C7	110.90 (9)	C6—C5—H5	125.6
O1—C1—N1	103.62 (8)	N1—C6—C5	106.68 (10)
O1—C1—H1	111.1	N1—C6—H6	126.7
O1—C1—C7	108.73 (8)	C5—C6—H6	126.7
C7—C1—H1	111.1	F1—C7—C1	110.80 (9)
O1—C2—C3	106.55 (8)	F2—C7—C1	111.87 (9)
O2—C2—O1	120.33 (9)	F2—C7—F1	107.88 (9)
O2—C2—C3	133.12 (10)	F2—C7—F3	108.00 (9)
N1—C3—C2	107.54 (9)	F3—C7—C1	110.14 (9)
N1—C3—C4	108.48 (9)	F3—C7—F1	108.01 (9)
C4—C3—C2	143.96 (10)

N1—C1—C7—F1	177.53 (8)	C1—O1—C2—O2	179.38 (9)
N1—C1—C7—F2	57.11 (12)	C1—O1—C2—C3	−0.12 (11)
N1—C1—C7—F3	−63.02 (11)	C2—O1—C1—N1	−0.25 (11)
N1—C3—C4—C5	−0.21 (12)	C2—O1—C1—C7	117.77 (9)
O1—C1—C7—F1	64.22 (11)	C2—C3—C4—C5	−178.20 (14)
O1—C1—C7—F2	−56.21 (11)	C3—N1—C1—O1	0.55 (11)
O1—C1—C7—F3	−176.33 (8)	C3—N1—C1—C7	−115.95 (9)
O1—C2—C3—N1	0.46 (11)	C3—N1—C6—C5	−0.03 (12)
O1—C2—C3—C4	178.46 (14)	C3—C4—C5—C6	0.20 (13)
O2—C2—C3—N1	−178.94 (11)	C4—C5—C6—N1	−0.11 (13)
O2—C2—C3—C4	−0.9 (2)	C6—N1—C1—O1	−178.81 (12)
C1—N1—C3—C2	−0.64 (11)	C6—N1—C1—C7	64.69 (16)
C1—N1—C3—C4	−179.40 (8)	C6—N1—C3—C2	178.91 (9)
C1—N1—C6—C5	179.34 (11)	C6—N1—C3—C4	0.15 (12)

Hydrogen-bond geometry (Å, º) top

D—H···A	D—H	H···A	D···A	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+1/2, z−1/2.

Acknowledgements

We thank Zawia University for support (MMZ).

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