Methyl 1-(4-fluoro­benz­yl)-1H-indazole-3-carboxyl­ate

Doi, T.; Sakai, T.

doi:10.1107/S2414314623009951

organic compounds

IUCrDATA

ISSN: 2414-3146

Volume 8| Part 11| November 2023| x230995

https://doi.org/10.1107/S2414314623009951

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Methyl 1-(4-fluorobenzyl)-1H-indazole-3-carboxylate

Takahiro Doi ^a ^* and Takayuki Sakai ^a

^aOsaka Institute of Public Health, Division of Hygienic Chemistry, Pharmaceutical Affairs Section, Nakamichi 1-3-3, Higashinari-ku, Osaka, 537-0025, Japan
^*Correspondence e-mail: tdoi@iph.osaka.jp

Edited by M. Zeller, Purdue University, USA (Received 8 August 2023; accepted 16 November 2023; online 23 November 2023)

The title compound, C₁₆H₁₃FN₂O₂, was synthesized by nucleophilic substitution of the indazole N—H hydrogen atom of methyl 1H-indazole-3-carboxylate with 1-(bromomethyl)-4-fluorobenzene. In the crystal, some hydrogen-bond-like interactions are observed.

Keywords: crystal structure; synthetic cannabinoid; intermediate compound.

CCDC reference: 2308333

Structure description

Methyl 1-(4-fluorobenzyl)-1H-indazole-3-carboxylate is an intermediate compound of synthetic cannabinoids, a class of compounds with a high potential for abuse as psychoactive substances, acting as the agonist of the cannabinoid type 1 receptor (Longworth et al., 2017 ; Doi et al., 2018 ; Cannaert et al., 2020 ). The molecule is composed of two planar segments connected at a bond angle of 110.90 (8)° at C6. The indazole ring is nearly coplanar with the ester moiety, suggesting that the ester moiety is conjugated with the aromatic ring. Furthermore, the C3—C14 bond distance is 1.4790 (14) Å, which provides further evidence for the existence of conjugation (Fig. 1). The crystal packing of the title compound is displayed in Fig. 2. At the centre of the crystal, two weak hydrogen-bond-like interactions (C13—H13⋯N2ⁱⁱ and C6—H6A⋯O15ⁱⁱ) are formed between two adjacent molecules related by inversion (Fig. 2) [symmetry operator: (ii) −x, −y + 1, −z + 1]. The hydrogen-donor molecule also acts as acceptor of the same interactions, creating inversion-related dimers. In the extended structure, there are four more non-classical hydrogen-bond-like interactions and a weak C—H⋯π interaction is also observed (Table 1).

Table 1
Hydrogen-bond geometry (Å, °)

Cg is the centroid of the C4/C5/C18–C21 ring.

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
C6—H6A⋯O15ⁱ	0.99	2.67	3.3417 (13)	125
C12—H12⋯O15ⁱⁱ	0.95	2.61	3.2190 (12)	123
C13—H13⋯O15ⁱⁱ	0.95	2.62	3.2339 (12)	123
C13—H13⋯N2ⁱ	0.95	2.62	3.4578 (13)	148
C19—H19⋯F11ⁱⁱⁱ	0.95	2.73	3.3840 (13)	127
C9—H9⋯F11^iv	0.95	2.59	3.2577 (12)	127
C17—H17A⋯Cg^v	0.98	2.95	3.8114 (12)	148
Symmetry codes: (i) ; (ii) ; (iii) $[-x+{\script{1\over 2}}, y-{\script{1\over 2}}, -z+{\script{3\over 2}}]$ ; (iv) ; (v) $[x-{\script{3\over 2}}, -y-{\script{1\over 2}}, z-{\script{3\over 2}}]$ .

Figure 1
Molecular structure of the title compound, with displacement ellipsoids drawn at the 50% probability level.

Figure 2
The crystal packing of the title compound.

Synthesis and crystallization

The synthesis of methyl 1-(4-fluorobenzyl)-1H-indazole-3-carboxylate was described previously (Doi et al., 2018). In a microvial, the resulted compound was dissolved with ethyl acetate at a concentration of 3% (w/v). The microvial was left at room temperature for several months, resulting in the formation of several large rod shape crystals in the vial.

Refinement

Crystal, data collection and refinement details are presented in Table 2.

Table 2
Experimental details

Crystal data
Chemical formula	C₁₆H₁₃FN₂O₂
M_r	284.28
Crystal system, space group	Monoclinic, P2₁/n
Temperature (K)	100
a, b, c (Å)	5.04322 (3), 18.11509 (13), 14.46487 (10)
β (°)	90.4600 (6)
V (Å³)	1321.45 (2)
Z	4
Radiation type	Cu Kα
μ (mm⁻¹)	0.88
Crystal size (mm)	0.32 × 0.13 × 0.12

Data collection
Diffractometer	XtaLAB Synergy, Single source at home/near, HyPix-Arc 100
Absorption correction	Gaussian (CrysAlis PRO; Rigaku OD, 2023 )
T_min, T_max	0.626, 1.000
No. of measured, independent and observed [I > 2σ(I)] reflections	47493, 2732, 2666
R_int	0.035
(sin θ/λ)_max (Å⁻¹)	0.627

Refinement
R[F² > 2σ(F²)], wR(F²), S	0.031, 0.078, 1.03
No. of reflections	2732
No. of parameters	192
H-atom treatment	H-atom parameters constrained
Δρ_max, Δρ_min (e Å⁻³)	0.30, −0.18
Computer programs: CrysAlis PRO (Rigaku OD, 2023), SHELXT2018/2 (Sheldrick, 2015a ), SHELXL2018/3 (Sheldrick, 2015b ), and OLEX2 (Dolomanov et al., 2009 ).

Structural data

CCDC reference: 2308333

Crystal structure: contains datablock I. DOI: https://doi.org/10.1107/S2414314623009951/zl4059sup1.cif

Supporting information file. DOI: https://doi.org/10.1107/S2414314623009951/zl4059Isup3.cml

Structure factors: contains datablock I. DOI: https://doi.org/10.1107/S2414314623009951/zl4059Isup4.hkl

checkCIF report

Computing details top

Methyl 1-(4-fluorobenzyl)-1H-indazole-3-carboxylate top

Crystal data top

C₁₆H₁₃FN₂O₂	F(000) = 592
M_r = 284.28	D_x = 1.429 Mg m⁻³
Monoclinic, P2₁/n	Cu Kα radiation, λ = 1.54184 Å
a = 5.04322 (3) Å	Cell parameters from 29913 reflections
b = 18.11509 (13) Å	θ = 3.9–79.9°
c = 14.46487 (10) Å	µ = 0.88 mm⁻¹
β = 90.4600 (6)°	T = 100 K
V = 1321.45 (2) Å³	Block, clear light colourless
Z = 4	0.32 × 0.13 × 0.12 mm

Data collection top

XtaLAB Synergy, Single source at home/near, HyPix-Arc 100 diffractometer	2732 independent reflections
Radiation source: fine-focus sealed X-ray tube, Enhance (Cu) X-ray Source	2666 reflections with I > 2σ(I)
Graphite monochromator	R_int = 0.035
Detector resolution: 10.0000 pixels mm^-1	θ_max = 75.3°, θ_min = 3.9°
ω scans	h = −6→6
Absorption correction: gaussian (CrysAlisPro; Rigaku OD, 2023)	k = −21→22
T_min = 0.626, T_max = 1.000	l = −18→18
47493 measured reflections

Refinement top

Refinement on F²	Hydrogen site location: inferred from neighbouring sites
Least-squares matrix: full	H-atom parameters constrained
R[F² > 2σ(F²)] = 0.031	w = 1/[σ²(F_o²) + (0.0369P)² + 0.532P] where P = (F_o² + 2F_c²)/3
wR(F²) = 0.078	(Δ/σ)_max = 0.001
S = 1.03	Δρ_max = 0.30 e Å⁻³
2732 reflections	Δρ_min = −0.18 e Å⁻³
192 parameters	Extinction correction: SHELXL-2018/3 (Sheldrick 2018), Fc^*=kFc[1+0.001xFc²λ³/sin(2θ)]^-1/4
0 restraints	Extinction coefficient: 0.0027 (3)
Primary atom site location: dual

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.

Refinement. All the H atoms were included using a riding model starting from calculated positions (aromatic C—H = 0.95 Å, methylene C—H = 0.99 Å, and alkyl C—H = 1.00 Å). The U_iso(H) values were fixed at 1.2 times the equivalent U_eq value of the parent C atoms (1.5 times for the methyl group).

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å²) top

	x	y	z	U_iso*/U_eq
F11	0.20188 (14)	0.51087 (4)	0.93308 (4)	0.03075 (18)
O16	0.11216 (15)	0.25606 (4)	0.38007 (5)	0.02287 (18)
O15	0.03249 (15)	0.37833 (4)	0.38349 (5)	0.02512 (19)
N1	0.65913 (16)	0.38193 (5)	0.56604 (6)	0.01720 (19)
N2	0.45483 (16)	0.39395 (5)	0.50783 (6)	0.01800 (19)
C5	0.71051 (19)	0.30814 (5)	0.57692 (7)	0.0168 (2)
C4	0.52753 (19)	0.27022 (5)	0.52017 (7)	0.0170 (2)
C3	0.37458 (19)	0.32774 (5)	0.47872 (7)	0.0172 (2)
C7	0.63589 (19)	0.46374 (5)	0.70088 (7)	0.0180 (2)
C6	0.7843 (2)	0.44440 (6)	0.61369 (7)	0.0194 (2)
H6A	0.786848	0.487719	0.571991	0.023*
H6B	0.970040	0.431674	0.629647	0.023*
C12	0.2762 (2)	0.52949 (6)	0.77426 (7)	0.0201 (2)
H12	0.131495	0.562982	0.771153	0.024*
C13	0.4240 (2)	0.51310 (5)	0.69631 (7)	0.0191 (2)
H13	0.380134	0.535846	0.639021	0.023*
C14	0.1556 (2)	0.32536 (6)	0.41015 (7)	0.0185 (2)
C18	0.5330 (2)	0.19243 (6)	0.51774 (7)	0.0200 (2)
H18	0.411852	0.165588	0.480012	0.024*
C21	0.9019 (2)	0.27162 (6)	0.63117 (7)	0.0198 (2)
H21	1.025145	0.297972	0.668632	0.024*
C10	0.3461 (2)	0.49563 (6)	0.85637 (7)	0.0212 (2)
C20	0.9017 (2)	0.19570 (6)	0.62728 (8)	0.0226 (2)
H20	1.028026	0.168985	0.663067	0.027*
C8	0.7006 (2)	0.43131 (6)	0.78554 (7)	0.0219 (2)
H8	0.845925	0.398046	0.789401	0.026*
C19	0.7187 (2)	0.15640 (6)	0.57148 (8)	0.0225 (2)
H19	0.723970	0.103984	0.571045	0.027*
C9	0.5551 (2)	0.44705 (6)	0.86433 (7)	0.0242 (2)
H9	0.598636	0.424934	0.922035	0.029*
C17	−0.0982 (2)	0.24943 (6)	0.31188 (8)	0.0250 (2)
H17A	−0.046710	0.275111	0.255159	0.038*
H17B	−0.260822	0.271534	0.336094	0.038*
H17C	−0.129430	0.197143	0.298222	0.038*

Atomic displacement parameters (Å²) top

	U¹¹	U²²	U³³	U¹²	U¹³	U²³
F11	0.0376 (4)	0.0365 (4)	0.0183 (3)	0.0086 (3)	0.0041 (3)	−0.0015 (3)
O16	0.0232 (4)	0.0211 (4)	0.0241 (4)	0.0026 (3)	−0.0085 (3)	−0.0028 (3)
O15	0.0253 (4)	0.0218 (4)	0.0281 (4)	0.0045 (3)	−0.0065 (3)	0.0027 (3)
N1	0.0187 (4)	0.0158 (4)	0.0171 (4)	0.0004 (3)	−0.0013 (3)	0.0006 (3)
N2	0.0189 (4)	0.0187 (4)	0.0163 (4)	0.0013 (3)	−0.0001 (3)	0.0014 (3)
C5	0.0170 (4)	0.0165 (5)	0.0171 (5)	0.0003 (4)	0.0025 (4)	0.0006 (4)
C4	0.0160 (4)	0.0183 (5)	0.0168 (5)	0.0005 (4)	0.0012 (4)	0.0009 (4)
C3	0.0179 (5)	0.0169 (5)	0.0168 (5)	0.0008 (4)	0.0009 (4)	0.0009 (4)
C7	0.0190 (5)	0.0151 (5)	0.0199 (5)	−0.0037 (4)	−0.0022 (4)	−0.0014 (4)
C6	0.0202 (5)	0.0165 (5)	0.0216 (5)	−0.0027 (4)	−0.0004 (4)	−0.0010 (4)
C12	0.0209 (5)	0.0168 (5)	0.0224 (5)	0.0009 (4)	−0.0028 (4)	−0.0008 (4)
C13	0.0218 (5)	0.0166 (5)	0.0189 (5)	−0.0022 (4)	−0.0039 (4)	0.0018 (4)
C14	0.0184 (5)	0.0197 (5)	0.0172 (5)	0.0009 (4)	0.0011 (4)	0.0013 (4)
C18	0.0195 (5)	0.0174 (5)	0.0230 (5)	−0.0009 (4)	−0.0001 (4)	−0.0004 (4)
C21	0.0180 (5)	0.0216 (5)	0.0199 (5)	0.0007 (4)	−0.0015 (4)	0.0005 (4)
C10	0.0255 (5)	0.0208 (5)	0.0173 (5)	−0.0008 (4)	0.0003 (4)	−0.0034 (4)
C20	0.0202 (5)	0.0221 (5)	0.0255 (5)	0.0043 (4)	−0.0018 (4)	0.0042 (4)
C8	0.0236 (5)	0.0187 (5)	0.0235 (5)	0.0032 (4)	−0.0043 (4)	−0.0007 (4)
C19	0.0227 (5)	0.0162 (5)	0.0287 (5)	0.0019 (4)	0.0007 (4)	0.0019 (4)
C9	0.0315 (6)	0.0231 (5)	0.0179 (5)	0.0023 (4)	−0.0053 (4)	0.0019 (4)
C17	0.0231 (5)	0.0284 (6)	0.0234 (5)	0.0017 (4)	−0.0082 (4)	−0.0035 (4)

Geometric parameters (Å, º) top

F11—C10	1.3601 (12)	C12—H12	0.9500
O16—C14	1.3459 (13)	C12—C13	1.3887 (15)
O16—C17	1.4477 (12)	C12—C10	1.3801 (15)
O15—C14	1.2047 (13)	C13—H13	0.9500
N1—N2	1.3432 (12)	C18—H18	0.9500
N1—C5	1.3704 (13)	C18—C19	1.3767 (15)
N1—C6	1.4653 (13)	C21—H21	0.9500
N2—C3	1.3329 (13)	C21—C20	1.3765 (15)
C5—C4	1.4090 (14)	C10—C9	1.3770 (15)
C5—C21	1.4046 (14)	C20—H20	0.9500
C4—C3	1.4259 (13)	C20—C19	1.4135 (15)
C4—C18	1.4098 (14)	C8—H8	0.9500
C3—C14	1.4790 (14)	C8—C9	1.3900 (15)
C7—C6	1.5129 (14)	C19—H19	0.9500
C7—C13	1.3943 (14)	C9—H9	0.9500
C7—C8	1.3946 (14)	C17—H17A	0.9800
C6—H6A	0.9900	C17—H17B	0.9800
C6—H6B	0.9900	C17—H17C	0.9800

C14—O16—C17	114.47 (8)	O15—C14—O16	123.86 (9)
N2—N1—C5	111.93 (8)	O15—C14—C3	124.86 (9)
N2—N1—C6	119.68 (8)	C4—C18—H18	120.9
C5—N1—C6	128.23 (8)	C19—C18—C4	118.24 (9)
C3—N2—N1	106.36 (8)	C19—C18—H18	120.9
N1—C5—C4	106.64 (8)	C5—C21—H21	121.7
N1—C5—C21	130.70 (9)	C20—C21—C5	116.59 (10)
C21—C5—C4	122.66 (9)	C20—C21—H21	121.7
C5—C4—C3	103.78 (8)	F11—C10—C12	118.50 (9)
C5—C4—C18	119.27 (9)	F11—C10—C9	118.41 (9)
C18—C4—C3	136.95 (9)	C9—C10—C12	123.09 (10)
N2—C3—C4	111.28 (9)	C21—C20—H20	119.1
N2—C3—C14	117.47 (9)	C21—C20—C19	121.78 (10)
C4—C3—C14	131.23 (9)	C19—C20—H20	119.1
C13—C7—C6	119.54 (9)	C7—C8—H8	119.6
C13—C7—C8	119.06 (9)	C9—C8—C7	120.80 (10)
C8—C7—C6	121.36 (9)	C9—C8—H8	119.6
N1—C6—C7	110.90 (8)	C18—C19—C20	121.45 (10)
N1—C6—H6A	109.5	C18—C19—H19	119.3
N1—C6—H6B	109.5	C20—C19—H19	119.3
C7—C6—H6A	109.5	C10—C9—C8	118.12 (10)
C7—C6—H6B	109.5	C10—C9—H9	120.9
H6A—C6—H6B	108.0	C8—C9—H9	120.9
C13—C12—H12	121.0	O16—C17—H17A	109.5
C10—C12—H12	121.0	O16—C17—H17B	109.5
C10—C12—C13	117.95 (9)	O16—C17—H17C	109.5
C7—C13—H13	119.5	H17A—C17—H17B	109.5
C12—C13—C7	120.97 (9)	H17A—C17—H17C	109.5
C12—C13—H13	119.5	H17B—C17—H17C	109.5
O16—C14—C3	111.28 (8)

Hydrogen-bond geometry (Å, º) top

Cg is the centroid of the C4/C5/C18–C21 ring.

D—H···A	D—H	H···A	D···A	D—H···A
C6—H6A···O15ⁱ	0.99	2.67	3.3417 (13)	125
C12—H12···O15ⁱⁱ	0.95	2.61	3.2190 (12)	123
C13—H13···O15ⁱⁱ	0.95	2.62	3.2339 (12)	123
C13—H13···N2ⁱ	0.95	2.62	3.4578 (13)	148
C19—H19···F11ⁱⁱⁱ	0.95	2.73	3.3840 (13)	127
C9—H9···F11^iv	0.95	2.59	3.2577 (12)	127
C17—H17A···Cg^v	0.98	2.95	3.8114 (12)	148

Symmetry codes: (i) −x+1, −y+1, −z+1; (ii) −x, −y+1, −z+1; (iii) −x+1/2, y−1/2, −z+3/2; (iv) −x+1, −y+1, −z+2; (v) x−3/2, −y−1/2, z−3/2.

Acknowledgements

The authors would like to sincerely thank Dr Takashi Sato (Rigaku Corporation) for his helpful and fundamental instructions and advice on the measurement, analysis, and interpretation of the results.

Funding information

Funding for this research was provided by: JSPS KAKENHI (grant No. 18K19719 to T. Doi; grant No. 22K10521 to T. Doi, T. Sakai).

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