2-(Difluoroboryloxy)benzamide

Abstract

The title compound has been fully characterised by NMR for the first time. Fully assigned ¹H and ¹³C NMR spectra, and the X-ray structure of two different polymorphs are presented. The polymorphs show similar molecular geometries but exhibit significantly different patterns of intermolecular interactions.

1. Introduction

A pioneering study in 1971 described the treatment of 2-ethoxydihydrobenzoxazinone 1 with boron trifluoride diethyl etherate in diethyl ether as a way of generating the reactive parent heterocycle 1,3-benzoxazin-4-one 2, which could be trapped in a Diels–Alder reaction with an added diene (Scheme 1) [1]. We have recently reinvestigated this chemistry and have been able to characterise a range of Diels–Alder adducts of 2, as well as obtain direct spectroscopic evidence for 2 itself for the first time. These studies will be described in detail elsewhere, but on a number of occasions a crystalline side-product was obtained in low yield from attempted cycloaddition reactions of 2, which turned out to be the title compound 3. This has only been described once before [2], when it was formed by direct reaction of salicylamide with boron trifluoride diethyl etherate in diethyl ether and characterised by its melting point, elemental analysis, IR spectrum and low resolution ¹H and ¹¹B NMR data. The precursor 1 is prepared by condensation of salicylamide with triethyl orthoformate and is somewhat moisture sensitive [3]. We assume that in the attempted Diels–Alder reactions of 2, competing hydrolysis of 1 to salicylamide is followed by reaction of the latter with BF₃ etherate to give 3. In this paper we present full NMR characterisation of 3 as prepared by the literature method, as well as X-ray structure determination of the crystals obtained from two separate reactions of 1, leading to two different polymorphs.

2. Results

The compound 3 was readily prepared for spectroscopic study by stirring a mixture of salicylamide and BF₃·Et₂O in diethyl ether at 0 °C. The resulting solid showed a melting point in good agreement with the literature value [2]. It was readily soluble in CDCl₃, but since the only literature NMR data were recorded in CD₃OD, we studied it also in that solvent. The simple one-dimensional spectra gave chemical shifts in the expected range for ¹H, ¹³C, ¹¹B and ¹⁹F and by obtaining COSY, HSQC and HMBC spectra (see Supplementary Materials) a complete unambiguous assignment was possible (Figure 1) showing good agreement between the data in the two different solvents.

Although the ¹H NMR spectra showed fairly complex patterns, particularly in CD₃OD due to peak overlap, simulation (see Supplementary Materials) allowed determination of all CH–CH coupling constants with good agreement between the values in the two solvents (

Table 1. Values of CH–CH coupling constants for 3 (Hz, numbering as in Figure 1).

Solvent	3JH3–H4	3JH4–H5	3JH5–H6	4JH3–H5	4JH4–H6	5JH3–H6
CDCl3	8.4	7.2	8.0	0.8	1.6	~0
CD3OD	8.4	7.2	8.0	1.2	2.0	0.4

).

Although it is difficult to find similar structures for comparison, the data for 3 agree very well with those for the silylated analogues 4–6 [4], such that we are able to assign the signals for these also with a fair degree of certainty (Figure 2), something not done by the original authors.

As mentioned in the introduction, crystals of 3 suitable for X-ray diffraction were obtained in low yield from reaction of 1 with BF₃·Et₂O in the presence of 1,3-dienes. Perhaps unexpectedly, the samples obtained with cyclohexa-1,3-diene (“Form A”) and 2,3-dimethylbuta-1,3-diene (“Form B”) gave different structures (Figure 3) with similar molecular dimensions (Table 2). Form B forms N-H···O $R_2^2$ (8) hydrogen-bonded dimers (Table 3), while Form A forms a series of weaker N-H···F hydrogen bonds. The stronger hydrogen bonding in Form B takes some of the electron density away from the O(2)–B(3) interaction, resulting in longer O(2)–B(3) and shorter B(3)–O(4) distances as compared to Form A.

A search of the Cambridge Structural Database (CSD) showed only very few comparable structures. In addition to the three silicon-containing analogues 4–6 [4] already mentioned, the tricyclic analogue 7 [5] and a dioxane adduct of the oxime analogue 8 [6] show some structural similarities (Figure 4). Worthy of particular mention is what appears on the face of it to be an 18-crown-6 adduct of 3 [7], but the structure of this is described both in the paper and the structure deposited at the CSD as 9, an ammonium cation hydrogen bonded to the crown ether but with no counter-ion. It seems clear that the authors have solved the structure with an extra proton on N, which is not in fact present. Unsurprisingly, the dimensions around the heterocyclic ring (Table 2) are remarkably similar to those for both forms of 3.

Table 2. Molecular dimensions for 3 and 9 [7] (Å, °).

Bond Lengths (Å)	3 Form A	3 Form B	9
C(1)–N(1)	1.304(3)	1.3049(14)	1.297(3)
C(1)–O(2)	1.298(3)	1.2949(13)	1.284(3)
O(2)–B(3)	1.496(3)	1.5163(15)	1.505(4)
B(3)–O(4)	1.446(4)	1.4332(16)	1.449(4)
O(4)–C(10)	1.348(3)	1.3444(14)	1.340(3
C(10)–C(9)	1.409(4)	1.4052(15)	1.395(3)
C(9)–C(1)	1.448(4)	1.4476(16)	1.461(4)
B(3)–F(3)	1.383(3)	1.3641(16)	1.372(4)
B(3)–F(5)	1.398(4)	1.3926(16)	1.375(4)
Angles (°)
C(9)–C(1)–O(2)	120.7(2)	120.03(9)	119.6(2)
C(9)–C(1)–N(1)	122.2(3)	123.31(10)	122.8(2)
O(2)–C(1)–N(1)	117.1(3)	116.66(10)	117.6(2)
C(1)–O(2)–B(3)	121.5(2)	121.46(9)	122.3(2)
O(2)–B(3)–O(4)	112.1(2)	110.77(9)	111.5(2)
B(3)–O(4)–C(10)	119.8(2)	119.04(9)	118.3(2)
O(4)–C(10)–C(9)	121.0(3)	121.57(10)	121.8(2)
C(10)–C(9)–C(1)	117.4(2)	117.43(10)	117.2(2)

Table 2. Molecular dimensions for 3 and 9 [7] (Å, °).

Bond Lengths (Å)	3 Form A	3 Form B	9
C(1)–N(1)	1.304(3)	1.3049(14)	1.297(3)
C(1)–O(2)	1.298(3)	1.2949(13)	1.284(3)
O(2)–B(3)	1.496(3)	1.5163(15)	1.505(4)
B(3)–O(4)	1.446(4)	1.4332(16)	1.449(4)
O(4)–C(10)	1.348(3)	1.3444(14)	1.340(3
C(10)–C(9)	1.409(4)	1.4052(15)	1.395(3)
C(9)–C(1)	1.448(4)	1.4476(16)	1.461(4)
B(3)–F(3)	1.383(3)	1.3641(16)	1.372(4)
B(3)–F(5)	1.398(4)	1.3926(16)	1.375(4)
Angles (°)
C(9)–C(1)–O(2)	120.7(2)	120.03(9)	119.6(2)
C(9)–C(1)–N(1)	122.2(3)	123.31(10)	122.8(2)
O(2)–C(1)–N(1)	117.1(3)	116.66(10)	117.6(2)
C(1)–O(2)–B(3)	121.5(2)	121.46(9)	122.3(2)
O(2)–B(3)–O(4)	112.1(2)	110.77(9)	111.5(2)
B(3)–O(4)–C(10)	119.8(2)	119.04(9)	118.3(2)
O(4)–C(10)–C(9)	121.0(3)	121.57(10)	121.8(2)
C(10)–C(9)–C(1)	117.4(2)	117.43(10)	117.2(2)

Table 3. Hydrogen bonding parameters for 3 (Å, °).

D–H···A	D–H	H···A	D···A	D–H···A	Symmetry Operator
Form A
N(1)–H(1B)···F(4)	0.93(3)	1.91(3)	2.829(3)	170(3)	2 − x, 1⁄2 + y, 3⁄2 − z
N(1)–H(1A)···F(3)	0.95(3)	2.02(3)	2.919(3)	159(3)	x, 3⁄2 − y, 1⁄2 − z
Form B
N(1)–H(1A)···O(2)	0.929(15)	2.088(15)	3.0074(14)	170.1(13)	1 − x, −y, 1 − z
N(1)–H(1B)···F(4)	0.910(14)	2.009(14)	2.8690(12)	156.9(14)	1 + x, y, z

Table 3. Hydrogen bonding parameters for 3 (Å, °).

D–H···A	D–H	H···A	D···A	D–H···A	Symmetry Operator
Form A
N(1)–H(1B)···F(4)	0.93(3)	1.91(3)	2.829(3)	170(3)	2 − x, 1⁄2 + y, 3⁄2 − z
N(1)–H(1A)···F(3)	0.95(3)	2.02(3)	2.919(3)	159(3)	x, 3⁄2 − y, 1⁄2 − z
Form B
N(1)–H(1A)···O(2)	0.929(15)	2.088(15)	3.0074(14)	170.1(13)	1 − x, −y, 1 − z
N(1)–H(1B)···F(4)	0.910(14)	2.009(14)	2.8690(12)	156.9(14)	1 + x, y, z

The crystal structure of Form A consists of slip-stacked sheets in the (1 0 0) plane (Figure 5) formed by $R_4^4$ (12) rings of N–H···F hydrogen bonds (Table 3). In contrast, Form B’s hydrogen-bonded dimers link together through non-classical C–H···O hydrogen bonds to form sheets in the (1 0 1) plane, which stack together through N–H···F hydrogen bonds (Figure 5, Table 3).

In summary, we have been able to record and fully assign the ¹H and ¹³C NMR spectra for compound 3 for the first time. The X-ray structures of two quite different polymorphs have been determined, with only one of them consisting of N–H···O hydrogen-bonded dimers.

3. Experimental

3.1. General Experimental Details

Melting points were recorded on a Reichert hot-stage microscope (Reichert, Vienna, Austria) and are uncorrected. NMR spectra were obtained using a Bruker AV II 400 instrument (Bruker, Billerica, MA, USA). Spectra were run in CDCl₃ or CD₃OD and chemical shifts are reported in ppm to high frequency of the reference and are referenced to internal Me₄Si (δ 0.00) for ¹H, to the solvent signal (δ 77.0 or 49.0) for ¹³C, to external CFCl₃ for ¹⁹F and external BF₃·Et₂O for ¹¹B, and coupling constants are in Hz. NMR spectra were processed using iNMR reader, version 6.3.3 (Mestrelab Research, Santiago de Compostela, Spain). Salicylamide was prepared by heating a mixture of methyl salicylate and aqueous ammonia under reflux for 18 h and filtering off the crystalline product obtained upon cooling [8].

3.2. Synthesis of 2-(Difluoroboryloxy)benzamide 3

A solution of salicylamide (1.37 g, 10 mmol) in diethyl ether (20 mL) was stirred at 0 °C while boron trifluoride diethyl etherate (1.13 mL, 1.42 g, 10 mmol) was added. The mixture was stirred and allowed to warm to RT over 18 h. The resulting precipitate was filtered off to give the product (1.25 g, 68%) as colourless crystals, mp 175–178 °C (lit. [2] 176–178 °C). ¹H NMR (400 MHz, CDCl₃): δ 7.90 (1H, dd, J 8.0, 1.6, 6-H), 7.49 (1H, ddd, J 8.4, 7.2, 1.6, H-4), 6.99 (1H, dd, J 8.4, 0.8, H-3), 6.91 (1H, ddd, J 8.0, 7.2, 0.8, H-5) and 4.18 (2H, br s, NH₂); ¹³C NMR (100 MHz, CDCl₃): δ 174.5 (C=O), 162.2 (O–C=), 137.0 (4-CH), 130.9 (6-CH), 119.6 (5-CH), 117.8 (3-CH) and 111.3 (1-C); ¹⁹F NMR (376 MHz, CDCl₃): δ –145.0; ¹¹B NMR (128 MHz, CDCl₃): δ 3.48; ¹H NMR (400 MHz, CD₃OD): δ 7.85 (1H, ddd, J 8.0, 2.0, 0.4, 6-H), 7.46 (1H, ddd, J 8.4, 7.2, 2.0, H-4), 6.91 (1H, ddd, J 7.2, 1.2, 0.4, H-3) and 6.885 (1H, ddd, J 8.4, 8.0, 1.2, H-5); ¹³C NMR (100 MHz, CD₃OD): δ 173.5 (C=O), 163.1 (O–C=), 136.6 (4-CH), 131.5 (6-CH), 120.1 (5-CH), 118.1 (3-CH) and 113.8 (1-C); ¹⁹F NMR (376 MHz, CD₃OD): δ −154.5; ¹¹B NMR (128 MHz, CD₃OD): δ −1.15.

3.3. X-Ray Structure Determination of 3

X-ray diffraction data for compound 3 (Form A) were collected at 100 K using a Rigaku MM-007HF High Brilliance RA generator/confocal optics with XtaLAB P200 diffractometer (Rigaku Corporation, Tokyo, Japan) [Cu Kα radiation (λ = 1.54187 Å)]. X-ray diffraction data for compound 3 (Form B) were collected at 173 K using a Rigaku FR-X Ultrahigh Brilliance Microfocus RA generator/confocal optics with XtaLAB P200 diffractometer (Rigaku Corporation, Tokyo, Japan) [Mo Kα radiation (λ = 0.71073 Å)]. Data for both forms were collected (using a calculated strategy) and processed (including correction for Lorentz, polarisation and absorption) using CrysAlisPro [9]. The data for Form A was processed as a two-component non-merohedral twin with the second component rotated 179.9770° around [0.00 0.00 1.00] (reciprocal), or [0.35 0.00 0.94] (direct), giving a twin law of [−0.9998 −0.0006 −0.0005 0.0003 −1.0002 0.0002 0.7356 0.0020 1.0002] and a refined twin fraction of 47.0(2)%. Structures were solved by dual-space methods (SHELXT [10]) and refined by full-matrix least-squares against F² (SHELXL-2019/3 [11]). Non-hydrogen atoms were refined anisotropically and hydrogen atoms were refined using a riding model except for the hydrogen atoms on N1, in both structures, which were located from the difference Fourier map and refined isotropically subject to a distance restraint. All calculations were performed using the Olex2 [12] interface. Selected crystallographic data are presented below. CCDC 2,494,454 (Form A) and 2,494,455 (Form B) contain the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via http://www.ccdc.cam.ac.uk/structures.

Form A

Crystal data for C₇H₆BF₂NO₂, M = 184.94 g mol⁻¹, colourless platy-needle, crystal dimensions 0.05 × 0.03 × 0.01 mm, monoclinic, space group P2₁/c (No. 14), a = 11.5161(14), b = 5.0928(4), c = 13.5062(17) Å, β = 108.478(13)°, V = 751.29(16) ų, Z = 4, D_calc = 1.635 g cm⁻³, T = 100 K, Goodness of fit on F² 1.093, 18,479 reflections measured, 2788 unique (R_int = 0.0333), which were used in all calculations. The final R₁ [I > 2σ (I)] was 0.0515 and wR₂ (all data) was 0.1549.

Form B

Crystal data for C₇H₆BF₂NO₂, M = 184.94 g mol⁻¹, colourless prism, crystal dimensions 0.15 × 0.06 × 0.04 mm, monoclinic, space group P2₁/n (No. 14), a = 6.8478(2), b = 5.3517(2), c = 20.9843(7) Å, β = 93.369(3)°, V = 767.69(5) ų, Z = 4, D_calc = 1.600 g cm⁻³, T = 173 K, Goodness of fit on F² 1.052, 13,784 reflections measured, 1913 unique (R_int = 0.0281), which were used in all calculations. The final R₁ [I > 2σ (I)] was 0.0333 and wR₂ (all data) was 0.0899.