[(2-Chlorophenyl)-(4-fluorophenyl)methylene]-(4-fluorophenyl)amine

Abstract

The formation of a N,1,1-triaryl imine derived from (2-chlorophenyl)-bis-(4-fluorophenyl)methanol is reported. The title compound is formed from a consecutive process which involves a nucleophilic substitution and subsequent Schmidt reaction. A description of the synthesized compound’s NMR spectra is presented and the structure was unambiguously established by X-ray analysis. A Hirshfeld surface analysis is also included, confirming the presence of intermolecular H···F interactions involved in crystal packing.

1. Introduction

A little explored but interesting version of the well-known Schmidt reaction involves the use of tertiary alcohols and azides to give N-substituted imines. In these reactions, a C=N bond is formed from an alkyl/aryl 1,2-migration promoted by azide nucleophilic attack on the electrophilic center derived from tertiary alcohol with subsequent molecular nitrogen loss [1].

This approach has been successfully used in the synthesis of 9-(l-naphthyl)anthracenes [2], alkylpiperidine alkaloids [3], indanones [4], and indolizine derivatives [5,6]. Moreover, this process has found some attractive applications in medicinal chemistry in the preparation of estrogen receptors and tamoxifen analogues [7,8].

Based on the above, and supported by our previous experiences in azide chemistry, we decided to re-investigate this process. In this report, we disclose an unprecedented formation of a N,1,1-triaryl imine containing halogen motifs in a novel version of the Schmidt reaction.

2. Results and Discussion

In the present investigation, (2-chlorophenyl)-bis-(4-fluorophenyl)methanol 2 was the precursor of the titled compound, as depicted in Scheme 1. Compound 2 was prepared from Grignard reaction between commercially available 4-fluorophenylmagnesium bromide and 2-chlorobenzoic acid methyl ester 1.

Following a procedure described by Roy and coworkers for the synthesis of tertiary azides [9], straightforward treatment of alcohol 2 with sodium azide and H₂SO₄ afforded imine 3 as the only reaction product. The identification of this unexpected product was carried out through an analysis of the different NMR spectra. Thus, the ¹H NMR spectrum of compound 3 shows an important doublet of doublets signal at δ 7.72 ppm (J_ab = 8.1 Hz and J_ac = 4.2 Hz) corresponding to hydrogens on C-2 from p-fluorophenyl ring attached to carbonyl group, as well as another doublet of doublets signal at δ 6.75 ppm (J_ab = 7.8 Hz and J_ac = 4.1 Hz) corresponding to hydrogens assigned to C-3 from p-fluorophenyl ring attached to nitrogen atom; see Figure 1. On the other hand, a signal at δ 165.68 ppm is observed in the corresponding ¹³C NMR spectrum (Figure 2) revealing the presence of an imine C=N moiety.

Another interesting fact is observed in the respective ¹⁹F NMR spectrum (Figure 3) that displays two signals located at δ-108.8 and -119.9 ppm associated with 4-substituted phenyl fluorine atoms present in the titled compound which are in different magnetic environments as a consequence of the migration of one of these aryl groups with respect to the starting material.

Another prominent feature found in the mass spectrum of imine 3 is the contribution of chlorine isotopes to the molecular ion m/z 327 [M]⁺ and 329 [M + 2]⁺ in an approximate 3:1 ratio, confirming the presence of the Cl atom, for which there is otherwise no direct evidence (Figure 4). The mass spectrum also shows the base peak at m/z 216, which can be attributed to the cleavage of the FC₆H₄CNC₆H₄–C₆H₄Cl bond to give cation 5 from the iminyl radical cation 4, similar to that described in the literature; see Scheme 2 [10]. Likewise, the appearance of a specific ion registered at m/z 232 can be explained by this fragmentation mechanism.

The imine 3 is a crystalline solid that was obtained from a hexane solution upon slow evaporation over several days which was studied by single-crystal X-ray crystallography, allowing the unequivocal identification of this compound. The crystallographic data and structural refinement parameters of 3 are presented in

Table 1. Crystallographic data for structural analysis of compound 3.

Crystal Data	3
Empirical formula	C19H12ClF2N
Formula weight	327.75
Temperature (K)	100(2)
Radiation type	Mo Kα
Crystal system	Monoclinic
Space group	P21/c
Unit cell dimensions (Å, °)
a	14.9045(11)
b	18.2310(14)
c	11.9976(9)
α	90
β	108.2613(13)
γ	90
Volume (Å3)	3095.9(4)
Z	8
Density (calculated, Mg/m3)	1.406
Absorption coefficient μ (mm−1)	0.265
F(000)	1344
Crystal size (mm3)	0.571 × 0.496 × 0.390
Θ range (deg)	2.108 to 27.445
Index ranges	−19 ≤ h ≤ 19, −23 ≤ k ≤ 23, −15 ≤ l ≤ 15
Reflections collected	31,893
Independent reflections	5902 [R(int) = 0.0365]
Data/restraints/parameters	7074/1336/607
Goodness-of-fit on F2	1.068
Final R indices [I > 2sigma(I)]	R1 = 0.0554, wR2 = 0.1081
R indices (all data)	R1 = 0.0444, wR2 = 0.1021
Largest diff. peak and hole (e Å−3)	0.461, −0.361

, and the crystal structure of compound 3 is shown in Figure 5. The characteristic imine bond angles are present in this molecule in agreement with the literature [11]. In this case, molecule 3 displays angles N(1)-C(1)-C(8) and C(1)-N(1)-C(14) of 118.42° and 121.11°, respectively; see

Table 2. Selected bond distances (Å) and bond angles (deg) for compound 3.

Bond	Distance (Å)	Bond	Angle (°)
N(1)-C(1)	1.276(2)	N(1)-C(1)-C(8)	118.42(15)
N(1)-C(14)	1.423(2)	N(1)-C(1)-C(2)	122.22(18)
C(3)-Cl(1)	1.737(2)	C(8)-C(1)-C(2)	119.19(17)
F(1)-C(11)	1.3645(19)	C(1)-N(1)-C(14)	121.11(15)
F(2)-C(17)	1.360(2)	F(1)-C11(3)-C(10)	118.69(15)

.

Worthy of mention are the C-H···F interactions found in imine 3. In this regard, distances C7-H···F3 = 2.495 Å, C5-H···F2 = 2.620 Å, C5-H···F4 = 2.660 Å and C24-H···F2 = 2.660 Å are detected, and particularly, two important interactions with distances C29-H···F4 = 2.341 Å and C10-H···F1 = 2.655 Å are involved in the formation of cyclic structures, as seen in Figure 6. In addition, intermolecular bond distances C38-H···N = 2.708 Å, F2···Cl2 = 3.038 Å and F4···Cl1 = 2.846 Å also denote important interactions involved in this crystal structure.

Besides the D–H···A interactions, some anion/π-like interactions are recognized in imine 3 and registered in

Table 3. Hydrogen bond geometry (Å, °).

D–H···A	d(D–H)	d(H···A)	d(D···A)	∠D–H···A	Symmetry Operation
C29–H29···F4	0.95	2.34	3.190(2)	148.6	−x, −y, −z + 1
C32–H32···F1	0.95	2.57	3.403(2)	145.8	x, −y − 1/2, z − 1/2
C35A–H35A···F3A	0.95	2.43	3.320(13)	155	−x + 1, −y + 1, −z + 1
C31–H31···Cg7	0.95	2.84	3.7134(3)	153	−x + 1, −y, −z + 1
C24A–H24A···Cg9	0.95	2.9	3.7947(3)	157	x − 1, −y − 1/2, z − 3/2
C3–Cl1···Cg8	1.737(2)	3.9700(3)	4.7062(4)	104.14(1)	x, −y − 1/2, z − 3/2
C30–F4···Cg8	1.362(2)	3.6476(3)	4.1689(3)	102.92(1)	−x + 1, y − 1/2, −z + 3/2

. Important distances of both fluorine F4 and chlorine Cl1 atoms to the computed Cg8 centroid of the phenyl ring appended to the nitrogen atom, Cg8···F4 = 3.6476(3) Å and Cg8···Cl1 = 3.9700(3) Å, are observed and illustrated in Figure 7. Weaker π-π stacking interactions are detected and presented in

Table 4. π-π stacking interactions in imine 3.

Cg(I)–Cg(J)	Cg–Cg (Å) a	Symmetry Operation
Cg3···Cg7	4.1009(3)	x, −y − 1/2, z−1/2
Cg5···Cg7	4.2046(3)	x, −y − 1/2, z−1/2
Cg6···Cg8	4.3525(3)	x, −y − 1/2, z−1/2
Cg1···Cg2	4.3802(3)	x, −y − 1/2, z−1/2
Cg2···Cg4	4.5044(3)	x, −y − 1/2, z−1/2
Cg8···Cg9	4.5669(4)	x, −y − 1/2, z−1/2
Cg2i···Cg5ii	4.9103(4)	x, −y − 1/2, z−3/2
Cg2i···Cg4ii	4.9214(4)	x, −y − 1/2, z−3/2

^a Distance between ring centroids.

. For example, an intermolecular Cg3···Cg7 interaction with a distance of 4.1009(3) Å (symmetry code x, −y−1/2, z−1/2) is formed between the two centroids of the 4-flurophenyl rings that are gathered at the carbonyl carbon. In this context, steric and electron repulsions probably dominate the intramolecular structure, and edge–face π-π interactions appear to be of significant importance to the crystal structure, for example, the edge-face distance (<3.2 Å) between the imine–aryl surface, suggesting that these interactions are likely more directive of the packing than the halogen–π interactions.

Moreover, the aromatic rings in compound 3 are not parallel and have dihedral angles ranging from 60° to 73° according to

Table 5. Dihedral angles (°) formed by aromatic rings in imine 3.

	Ring	Dihedral Angle (°)
	A/B	72.97
	A/C	60.86
	B/C	73.40

. This arrangement between the rings reduces π-π stacking interactions, which is an important factor contributing to the shape of the molecule. The set of all the interactions described above determines the crystal packing, as shown in Figure 8.

The aforementioned intermolecular interactions were clearly visualized using Hirshfeld surface analysis, which has gained currency as a quick, visually friendly tool for observing this kind of interaction caused by intermolecular contacts on a crystal [12]. A general projection of the Hirshfeld surfaces for imine 3, mapped over d_norm, d_i, d_e, shape index and curvedness, is charted in Figure 9.

In this instance, the Hirshfeld surfaces plotted over d_norm are particularly useful. These graphics represent the normalized contact distances based on the contact distance of the nearest atom that is inside to outside the surface on a fixed color scale, where the red spots symbolize the shortest contacts and negative d_norm values [13]. As expected, the closest, high-intensity contacts, denoted by red spots, are located on halogen atoms that experiment with these distinctive C–H···Cl / C–H···F interactions, as seen in Figure 10.

Another important aspect to consider in the analysis of Hirshfeld surfaces is the fingerprint plots, projected in Figure 11 and defined as those graphical representations that allow the visualization of intermolecular interactions in the crystal through a 2D histogram obtained from the calculation of both d_i and d_e distances for each point on the Hirshfeld surface [14,15]. For compound 3, the largest contribution to the overall crystal packing is from H···H interactions, 42.5%. Another important contribution to the Hirshfeld surface is F···H/H···F interaction (15.3%), which appears in the middle of the scattered points in the 2D fingerprint plot, similar to other fluorinated compounds [16]. Smaller percentage interactions are as follows: Cl···H/H···Cl (4.9%), N···H/H···H (2.2%), F···F (2.1%), Cl···F/F···Cl (2.1%), C···F/F···C (1.4%), C···Cl/Cl···C (0.9%), C···C (0.7%), C···N/N···C (0.6%), and Cl···Cl (0.2%). These features indicate that van der Waals interactions and hydrogen bonding play the major roles in the crystal packing.

A plausible reaction mechanism is illustrated in Scheme 3. O-protonated alcohol 7 is formed from alcohol 2 and substituted by azide ion to generate trityl azide 8, which undergoes an aryl group 1,2-migration followed by molecular nitrogen loss to afford imine 3.

To the best of our knowledge, this is the first example of a fluoroaryl group 1,2-migration resulting from a nucleophilic azide substitution with a concomitant molecular nitrogen loss in a Schmidt-type reaction under acidic conditions. This fact is a stimulus for future and deeper investigations.

3. Materials and Methods

The starting materials were purchased from Aldrich Chemical Co. (Milwakee, WI, USA) and were used without further purification. The solvents were distilled before use. Silica plates of 0.20 mm thickness were used for thin layer chromatography. Melting points were determined with a Krüss Optronic melting point apparatus,( A.KRÜSS Optronic GmbH, Hamburg, Germany) and they were uncorrected. ¹H and ¹³C NMR spectra were recorded using a Bruker Avance 300-MHz (Bruker, Billerica, MA, USA); the chemical shifts (δ) are given in ppm relative to TMS as an internal standard (0.00). For analytical purposes, the mass spectra were recorded on a Shimadzu GCMS-QP2010 Plus (Shimadzu, Kyoto, Japan) in the EI mode, 70 eV, and 200 °C via direct inlet probe. Only the molecular and parent ions (m/z) are reported. IR spectra were recorded on a Bruker Tensor 27 (Bruker, Billerica, MA, USA) (Compounds spectroscopic data are in Supplementary Materials).

For the X-ray diffraction studies, crystals of compound 3 were obtained by slow evaporation of a dilute hexane solution, and the reflections were acquired with a Bruker APEX DUO diffractometer (Bruker, Billerica, MA, USA) equipped with an Apex II CCD detector, Mo Kα radiation (λ = 0.71073 Å) at 100 K. Frames were collected using omega scans and integrated with SAINT and multi-scan absorption correction (SADABS) was applied [17]. The structure was solved by direct methods (SHELXS-97) [18]; missing atoms were found by difference-Fourier synthesis and refined on F2 by a full-matrix least-squares procedure using anisotropic dis-placement parameters using SHELXL [19] using the ShelXle GUI [20]. The hydrogen atoms of the C–H bonds were placed in idealized positions. The molecular graphics were prepared using Mercury [21] and POV-Ray [22]. Crystallographic data for the structure reported in this paper have been deposited with the Cambridge Crystallographic Data Centre, CCDC No. 2371061 for compound 3. Copies of available materials can be obtained free of charge on application to the Director, CCDC, 12 Union Road, Cambridge CB2 IEZ, UK (facsimile: (44) 01223 336033); e-mail: [email protected]

The Hirshfeld surface mapped with d_norm and fingerprint plots were performed with Crystal Explorer 21.5 program [23]. The 2D fingerprint plots were used for visualizing, exploring, and quantifying intermolecular interactions.

Synthesis of [(2-Chlorophenyl)-(4-fluorophenyl)methylene]-(4-fluorophenyl)amine 3

Safety Notes. Azides are thermally and photochemically labile and some organic azides can rapidly decompose with heat to release large amounts of nitrogen. In addition, some other azides present impact sensitivity being often potentially explosive, especially low-molecular-weight azides [24,25]. CAUTION! Although we did not have any incidents in handling them, it is known that organic azides and azide-rich compounds can be HIGHLY explosive. Decomposition of organic azides can be also catalyzed by certain transition metal species and by strong acids or during concentration under reduced pressure [26]. Along with the appropriate personal protective gear, procedures should be carried out in a well-ventilated hood behind a safety shield. All workers should be thoroughly trained in the use of azides before undertaking experiments.

H₂SO₄ (0.4 mL, 0.732 g, 7.47 mmol) was added dropwise to a suspension of NaN₃ (0.455 g, 7 mmol) in toluene (7 mL) at room temperature over a 10 min period. The mixture was stirred at room temperature for 15 min. A solution of (2-chlorophenyl)-bis-(4-fluoro-phenyl)-methanol (0.365 g, 1.0 mmol) in toluene (7 mL) was added dropwise at 0° to pH = 10. The product was extracted with AcOEt (3× 15 mL), the organic layers were joined and dried over Na₂SO₄, the solvent was removed under reduced pressure and the product was purified by column chromatography (SiO₂, hexane/AcOEt 95:5) affording [(2-Chlorophenyl)-(4-fluorophenyl)methylene]-(4-fluorophenyl)amine 3 as a white solid (0.308 g, 87 %), m.p. 115 °C. ¹H NMR (300 MHz, CDCl₃) δ 7.76–7.66 (m, 2H), 7.34 (t,d, 1H), 7.29–7.15 (m, 2H), 7.13–6.98 (m, 3H), 6.87–6.69 (m, 4H); ¹³C NMR (75 MHz, CDCl₃) δ 165.70, 165.13, 163.69, 160.50–158.57, 146.36, 135.48, 134.09, 132.34, 130.71, 130.64, 130.16, 130.11, 129.64, 126.71, 121.71, 121.65, 115.64, 115.46, 115.28, 115.11; ¹⁹F NMR (282.4 MHz, CDCl₃) δ-108.79, −119.75; IR (ATR, cm⁻¹): 2926, 1732, 1672, 1597, 1504, 1229; MS [EI+] m/z (%): 329 [M + 2]⁺, (20), 327 [M]⁺, (60), 234, 232 [M-C₆H₄F]⁺ (30), 216 [M-C₆H₄Cl]⁺ (100); Anal. Calcd. for C₁₉H₁₂ClF₂N (%): C, 69.63; H, 3.69; N, 4.17; found: C, 69.59; H, 3.78; N, 4.28.

4. Conclusions

The title compound was obtained from a halogenated triphenylmethyl alcohol and sodium azide via the Schmidt reaction approach, which promises widespread applications in the synthesis of imines.