Copper(II)-Catalyzed Conversion of Aryl/Heteroaryl Boronic Acids, Boronates, and Trifluoroborates into the Corresponding Azides: Substrate Scope and Limitations

Abstract

We report the copper(II)-catalyzed conversion of organoboron compounds into the corresponding azide derivatives. A systematic series of phenylboronic acid derivatives is evaluated to examine the importance of steric and electronic effects of the substituents on reaction yield as well as functional group compatibility. Heterocyclic substrates are also shown to participate in this mild reaction while compounds incorporating B–C(sp³) bonds are unreactive under the reaction conditions. The copper(II)-catalyzed boronic acid–azide coupling reaction is further extended to both boronate esters and potassium organotrifluoroborate salts. The method described herein complements existing procedures for the preparation of aryl azides from the respective amino, triazene, and halide derivatives and we expect that it will greatly facilitate copper- and ruthenium-catalyzed azide–alkyne cycloaddition reactions for the preparation of diversely functionalized 1-aryl- or 1-heteroaryl-1,2,3-triazoles derivatives.

Aryl and heteroaryl azides have emerged as valuable building blocks for the construction of 1,2,3-triazoles in combinatorial drug discovery.^1,2 Traditionally, aryl azides have been prepared from the corresponding amines via diazotization. Moses and co-workers reported an improved diazotization procedure utilizing tert-butyl nitrite and azidotrimethylsilane under mild conditions while Bräse and co-workers described a mild synthesis of aryl azides from aryltriazenes.^3,4 Ma and Zhu demonstrated the synthesis of both aryl and vinyl azides from the respective aryl halides by proline–copper(I)-catalyzed coupling with sodium azide.⁵ Pinhey and co-workers first reported the conversion of arylboronic acids into aryl azides using stoichiometric lead(IV) acetate and mercury(II) acetate to afford intermediate aryl–lead species, which were then reacted with sodium azide in dimethyl sulfoxide.^6,7 In a significant advance, Guo, Liu, and co-workers recently showed that simple arylboronic acids can be elaborated to aryl azides using copper salts at room temperature.⁸ Herein, we disclose our results that examine in much greater detail the substrate scope of this powerful transformation including the influence of ligands, impact of electronics of the substrate on coupling efficiency, functional group compatibility, utilization of boronate esters and organotrifluoroborate salts, and examination of various heterocyclic substrates. Our results demonstrate the broad applicability and identify limitations of the copper(II)-catalyzed boronic acid–azide coupling reaction.

The copper(II)-catalyzed synthesis of aryl azides from arylboronic acids is based on the Chan–Lam coupling of arylboronic acids with N–H containing heteroarenes, anilines, phenols, and amides that employs stoichiometric copper(II) acetate in aprotic solvents and requires a base such as pyridine or triethylamine.^9,10 Since sodium azide is sparingly soluble in most aprotic organic solvents, we examined protic solvents and discovered that in contrast to the Chan–Lam coupling conditions, the azidation of 4-cyanophenylboronic acid (1q) proceeds efficiently in water, methanol, and ethanol (Table 1). Additionally, we found removal of the obligate base (pyridine or triethylamine) in the Chan–Lam coupling improved the yield (Table 1, entries 4 and 7). The ligands 2,2′-bipyridine (Bipy) and 1,10-phenanthroline (Phen) were also evaluated as these have been shown to enhance copper(II)-catalyzed cross-coupling reactions; however, these provided no major benefit in terms of isolated yield or enhancement in the reaction rate (Table 1, entries 5 and 6). If the reaction was conducted under an aerobic atmosphere to reoxidize Cu(0) back to Cu(II), then copper could be used catalytically (Table 1, entry 8). Our standardized reaction conditions involved vigorously stirring a 0.2 M solution of arylboronic acid in methanol with sodium azide (1.5 equiv) and copper(II) acetate (0.1 equiv) at 55 °C for 1–3 hours under air (Table 1, entry 9). The higher temperature used herein allow the reactions to reach completion in 1–3 hours, but the reaction can also be performed at room temperature if the reaction time is extended to 24 hours, which is preferred when working on scales larger than several millimoles.⁸ The reaction was conveniently followed colorimetrically as the dark brown solution turned light green as the reaction reached completion.

Table 1.

Survey of Reaction Conditions^a

Entry	Cu(OAc)2 Solvent (equiv)		Base/ligand (equiv)	Temp (°C)	Time (h)	Yieldb (%)
1	1.0	CH2Cl2	Py (1.0)	25	24	83 ± 0
2	1.0	H2O	Py (1.0)	25	24	66 ± 3
3	1.0	EtOH	Py (1.0)	25	24	92 ± 4
4	1.0	MeOH	Py (1.0)	25	24	80 ± 4
5	1.0	MeOH	Bipy (1.0)	25	24	83 ± 1
6	1.0	MeOH	Phen (1.0)	25	24	95 ± 3
7	1.0	MeOH	none	25	24	94 ± 4
8	0.1	MeOH	none	25	24	77 ± 1
9	0.1	MeOH	none	55	3	98 ± 0.1

^aAll reactions were carried out under air atmosphere using NaN₃ (1.5 equiv), 4-cyanophenylboronic acid (1q, 0.2 M, 1.0 equiv).

^bIsolated yield ± standard deviation from 2–3 independent experiments.

A systematic series of para-substituted phenylboronic acids was initially examined to explore the influence of electron-donating and -withdrawing substituents on coupling efficiency (Table 2). Remarkably, all compounds underwent coupling providing 40–98% yields of the corresponding aryl azides. While coupling efficiency did not correlate with electron-donating ability as measured by the Hammett substituent constant σ_p, ¹¹ we observed that arylboronic acids with strongly electron-withdrawing groups reacted more slowly, requiring three hours to reach completion and compounds with electron-donating groups, such as methoxy, were complete within one hour. In the case of volatile azides, such as phenyl azide (2e), 1-azido-4-fluorobenzene (2g), and 1-azido-4-(trifluoromethyl)benzene (2p), low isolated yields were obtained, therefore these were isolated as the corresponding triazole derivatives 3e, 3g, and 3p, respectively, by reacting the azides with methyl propiolate at room temperature. Overall, the results highlight the functional group compatibility of this reaction. The impact of sterics was examined with 2-(pivaloylamino)phenylboronic acid (1v) that provided 2v in 94% yield while biphenyl-2- (1u), -3- (1t), and -4-boronic acid (1c) provided 2u, 2t, and 2c, respectively, in yields ranging from 40–50% illustrating the relative lack of sensitivity to sterics (Table 2).

Table 2.

Scope of the Copper(II)-Catalyzed Azidation of Arylboronic Acids

Entry	R	σpa	Product	Yieldb (%)
1	4-OMe	−0.27	2a	78 ± 5
2	4-OPh	−0.03	2b	92 ± 8
3	4-Ph	−0.01	2c	50 ± 1
4	4-CH2OH	0	2d	98 ± 1
5	H	0	3e	64c
6	4-SMe	0	2f	97 ± 1
7	4-F	+0.06	3g	68c
8	4-I	+0.18	2h	63 ± 2
9	4-Cl	+0.23	2i	73 ± 4
10	4-Br	+0.23	2j	68 ± 6
11	4-CONH2	+0.36	2k	84 ± 3
12	4-CHO	+0.42	2l	81 ± 4
13	4-CO2H	+0.45	2m	89 ± 3
14	4-CO2Me	+0.45	2n	99 ± 0
15	4-COMe	+0.50	2o	81 ± 3
16	4-CF3	+0.54	3p	68c
17	4-CN	+0.66	2q	98 ± 1
18	4-SO2Me	+0.72	2r	86 ± 3
19	4-NO2	+0.78	2s	85 ± 1
20	3-Ph	–d	2t	46 ± 1
21	2-Ph	–d	2u	40 ± 2
22	2-NHCOt-Bu	–d	2v	94 ± 2

^aHammett substituent constants.¹¹

^bIsolated yield ± standard deviation from 2–3 independent experiments.

^cDue to volatility, the crude azides were not isolated, but reacted in situ with methyl propiolate to afford the corresponding triazoles 3. The isolated yields are for the corresponding triazole products. See experimental section for details.

^dNot applicable.

Next, arylboronic acid pinacol esters were evaluated. 4-Cyanophenylboronic acid pinacol ester (4q) furnished azide 2q in 81% yield (Table 3, entry 1), while 2q was obtained in 98% yield from the corresponding boronic acid derivative 1q (Table 2, entry 17). The successful coupling of amino- and dimethylamino-substituted phenylboronic acid pinacol esters 4w and 4x to afford azides 2w and 2x further highlights the functional group compatibility of this reaction (Table 3). Examination of heterocyclic substrates revealed some limitations to this reaction as 4-azidopyrazole 2y and 5-azidoindole 2z were isolated in only modest yields.

Table 3.

Scope of the Copper(II)-Catalyzed Azidation of Boronic Acid Pinacol Esters

Entry	R	Product	Yielda (%)
1		2q	81 ± 3
2		2w	94 ± 1
3		2x	83 ± 1
4		2y	29 ± 5
5		2z	51 ± 1

^aIsolated yield ± standard deviation from 2–3 independent experiments.

Heterocyclic boronic acids were also examined including pyridine, pyrimidine, quinoline, and isoquinoline 5a–d and the corresponding azides 6a–d were isolated in yields ranging from 34–42% (Table 4). Finally, several substrates containing B–C(sp³) bonds were examined including cyclopropyl 5e, cyclohexyl 5f, and benzyl 5g; however, no coupling was observed with any of these substrates demonstrating the limitations of the current method, which is restricted to substrates with B–C(sp²) bonds.

Table 4.

Scope of the Copper(II)-Catalyzed Azidation of Heteroaryl- and Alkylboronic Acids

Entry	R	Product	Yielda (%)
1		6a	42 ± 1
2		6b	40 ± 8
3		6c	34 ± 4
4		6d	40 ± 6
5		6e	0
6		6f	0
7		6g	0

^aIsolated yield ± standard deviation from 2–3 independent experiments.

Potassium organotrifluoroborate salts have emerged as attractive reagents in organic synthesis due to their increased chemical stability, excellent reactivity, and improved physicochemical properties.¹² Therefore we examined whether this valuable class of organoboron reagents would participate in the copper(II)-catalyzed cross-coupling reaction with sodium azide. A subset of the aryltrifluoroborates (Table 5) was selected in order to directly compare the results with the corresponding boronic derivatives from Table 1. The aryltrifluoroborates were competent substrates, but provided lower yields of the azides in all cases and were slightly less reactive than the respective arylboronic acids.

Table 5.

Scope of the Copper(II)-Catalyzed Azidation of Organofluoroborate Salts

Entry	R	Product	Yield (%)
1		2a	70
2		2d	40
3		2f	67
4		2i	46
5		2m	75
6		2o	73

The Chan–Lam coupling of arylboronic acids with azides as first disclosed by Guo, Liu, and co-workers represents a powerful and more environmentally friendly method for the preparation of various aryl and heteroaryl azides.⁸ Another major advantage of this method is the compatibility with the conditions for the copper(I)-catalyzed azide–alkyne cycloaddition (CuAAC) reaction, thus enabling one to sequentially perform both reactions in the same vessel.^13,14 Notably, the Chan–Lam coupling is a copper(II) catalytic cycle while the CuAAC reaction requires a copper(I) cycle. At the completion of the copper(II)–boronic acid–azide coupling, the addition of an alkyne and a reducing agent (aqueous solution of sodium ascorbate) results in a facile CuAAC reaction. The product azides in general are nonpolar and can be easily purified by filtration through a short silica gel column to remove all inorganic salts and potentially unreacted organoboron substrates. In almost all cases, except for heterocyclic compounds, the reaction as monitored by thin-layer chromatography resulted in complete consumption of the polar organoboranes followed by the formation of the more nonpolar aryl azide with no observed byproducts. The mass balance for compounds that resulted in less than 90% yield is likely due to losses obtained during purification of these volatile low molecular weight (MW < 150) azide derivatives. While we primarily investigated the coupling of arylboronic acids with sodium azide using catalytic copper(II) salts, the stoichiometric version may be preferred in common parallel synthesis reactors due to lack of turnover of the air headspace. Additionally, stoichiometric copper is more desirable for volatile organic azides as reaction can be done in a sealed flask.

The proposed catalytic cycle for the Chan–Lam coupling of organoboranes with the azide ion is shown in Scheme 1 and consists of an initial transmetalation to afford a R–Cu(II) intermediate. In the second step, the azide anion coordinates to the R–Cu(II) complex providing R–Cu(II)–N₃ that subsequently undergoes reductive elimination to afford the organic azide and Cu(0). Oxidation of Cu(0) to Cu(II) by molecular oxygen completes the catalytic cycle. The successful copper-catalyzed coupling of aryl iodides with sodium azide as reported by Zhu and Ma, demonstrated that aryl–Cu(II)–azido complexes could undergo reductive elimination and immediately suggested the viability of the Chan–Lam coupling with the azide anion.⁵ Reoxidation of Cu(0) to Cu(II) is slow and can be rate-limiting if the reaction vessel is sealed. Alternatively, it is plausible that oxidation of the aryl–Cu(II)–azido complex to a Cu(III) species would serve to promote reductive elimination to afford the product aryl azide and a Cu(I) species, which could be rapidly oxidized to Cu(II). This mechanism has been proposed for the Chan–Lam coupling.¹⁵ Furthermore, the first Cu(III) intermediate, which was identified from conjugate addition to an enone, has been recently spectroscopically characterized.¹⁶

Scheme 1.

Proposed catalytic cycle for Chan–Lam coupling of boronic acids with the azide anion

In closing, it is important to note the excellent functional group tolerance of aryl azides and boronic acids. Thus, 1-azido-2-bromobenzene has been reported to successfully participate in Suzuki cross-coupling with arylboronic acids.¹⁷ In an even more impressive example, Ham, Molander, and co-workers demonstrated the chemoselective azidation of bromo- and iodoaryltrifluoroborates to form (azidoaryl)trifluoroborates employing catalytic copper(I) bromide followed by Suzuki cross-coupling of these bifunctional molecules.¹⁸ The use of a copper(I) salt by these authors led to azidation of the halogen while the use of copper(II) salts reported herein results in the azidation of the trifluoroborate moiety. These complimentary reaction outcomes highlight the critical role of the copper oxidation state.

All commercial reagents (Sigma-Aldrich, Acros, Boron Molecular) were used as provided. Flash chromatography was performed with an ISCO Combiflash Companion^® purification system with pre-packed 4 g silica gel cartridges with the indicated solvent system. ¹H and ¹³C NMR spectra were recorded on a Varian 600 MHz spectrometer. Chemical shifts are reported in ppm from an internal standard of residual methanol (δ = 3.31 ppm for ¹H NMR and δ = 49.1 ppm for ¹³C NMR). Proton chemical data are reported as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet), coupling constant, integration. FT-IR spectra were obtained on a Nicolet Protégé 460 ESP spectrometer. The presence of an azido group was confirmed by a characteristic strong infrared absorption at 2100–2150 cm⁻¹. High-resolution mass spectra were acquired on an Agilent TOF II TOF/MS instrument equipped with either an ESI or APCI interface. Azides that failed to ionize under ESI or APCI conditions were treated with Ph₃P in THF at 55 °C for 2 h to form the corresponding iminophosphoranes (R–N=PPh₃), which were subsequently characterized by HRMS. Melting points were measured on an electrothermal Mel-Temp manual melting point apparatus and are uncorrected. CAUTION: Organic azides are potentially explosive substances and the proposed synthesis employing elevated temperature should only be run on scales less than 1 mmol.

Azide Synthesis; General Procedure

To the boronic acid (1.0 mmol, 1.0 equiv), pinacol boronate (1.0 mmol, 1.0 equiv), or potassium organotrifluoroborate salt (1.0 mmol, 1.0 equiv) in MeOH (5 mL) were added NaN₃ (1.5 mmol, 1.5 equiv) and Cu(OAc)₂ (0.1 mmol, 0.1 equiv). The soln was vigorously stirred in an 8-mL round-bottom vial at 55 °C under air. The mixture was concentrated onto Celite and purification by flash chromatography (prepacked silica cartridges) afforded the title compounds.

1-Azido-4-methoxybenzene (2a)

Following the general procedure using 4-methoxyphenylboronic acid (1a) or potassium trifluoro(4-methoxyphenyl)borate (7a) for 3 h and chromatography (10% EtOAc–hexane) afforded 2a (110 mg, 74% from 1a; 105 mg, 70% from 7a) as a yellow oil; R_f = 0.6 (hexane–EtOAc, 9:1).

IR: 2109 cm⁻¹.

¹H NMR (600 MHz, CD₃OD): δ = 3.76 (s, 3 H), 6.92 (d, J = 9.0 Hz, 2 H), 6.96 (d, J = 9.0 Hz, 2 H).

¹³C NMR (150 MHz, CD₃OD): δ = 56.1, 116.4, 121.1, 133.7, 158.8.

HRMS (ESI+) (iminophosphorane adduct): m/z [M − N₂ + PPh₃ + H]⁺ calcd for C₂₅H₂₂NOP: 384.1512; found: 384.1535.

1-Azido-4-phenoxybenzene (2b)

Following the general procedure using 4-phenoxyphenylboronic acid (1b) for 3 h and chromatography (hexane) afforded 2b (182 mg, 86%) as a brown oil: R_f = 0.2 (hexane).

IR: 2123 cm⁻¹.

¹H NMR (600 MHz, CD₃OD): δ = 6.92–6.97 (m, 6 H), 7.06 (t, J = 7.2 Hz, 1 H), 7.27–7.30 (m, 2 H).

¹³C NMR (150 MHz, CD₃OD): δ = 119.7, 121.4, 124.3, 124.5, 130.9, 136.4, 155.9, 158.7.

HRMS (ESI+) (iminophosphorane adduct): m/z [M − N₂ + PPh₃ + H]⁺ calcd for C₃₀H₂₄NOP: 446.1668; found: 446.1707.

4-Azidobiphenyl (2c)

Following the general procedure using biphenyl-4-ylboronic acid (1c) for 3 h and chromatography (hexane) afforded 2c (100 mg, 51%) as a yellow solid; mp 62–64 °C; R_f = 0.3 (hexane).

IR: 2115 cm⁻¹.

¹H NMR (600 MHz, CD₃OD): δ = 7.12 (d, J = 7.8 Hz, 2 H), 7.32 (t, J = 7.2 Hz, 1 H), 7.41 (t, J = 7.2 Hz, 2 H), 7.58 (d, J = 7.8 Hz, 2 H), 7.63 (d, J = 7.8 Hz, 2 H).

¹³C NMR (150 MHz, CD₃OD): δ = 120.6, 127.9, 128.5, 129.6, 130.1, 139.5, 140.7, 141.5.

HRMS (ESI+) (iminophosphorane adduct): m/z [M − N₂ + PPh₃ + H]⁺ calcd for C₃₀H₂₄NP: 430.1719; found: 430.1756.

1-Azido-4-(hydroxymethyl)benzene (2d)

Following the general procedure using 4-(hydroxymethyl)phenylboronic acid (1d) or potassium trifluoro[4-(hydroxymethyl)phenyl]borate (7d) for 3 h and chromatography (Et₂O) afforded 2d (148 mg, 99% from 1d; 60 mg, 40% from 7d) as a yellow oil; R_f = 0.3 (hexane–EtOAc, 7:3).

IR: 2107 cm⁻¹.

¹H NMR (600 MHz, CD₃OD): δ = 4.57 (s, 2 H), 7.03 (d, J = 8.4 Hz, 2 H), 7.37 (d, J = 8.4 Hz, 2 H).

¹³C NMR (150 MHz, CD₃OD): δ = 64.7, 120.0, 129.6, 139.9, 140.5.

HRMS (ESI+) (iminophosphorane adduct): m/z [M − N₂ + PPh₃ + H]⁺ calcd for C₂₅H₂₂NOP: 384.1512; found: 384.1512.

Methyl 1-Phenyl-1H-1,2,3-triazole-4-carboxylate (3e)

Following the general procedure using phenylboronic acid (1e) for 1.5 h afforded crude 2e. Methyl propiolate (3.0 equiv) and sodium ascorbate (0.1 equiv) were added and the mixture was stirred at r.t. overnight. Chromatography (30% EtOAc–hexane) afforded 3e (130 mg, 64%) as a white solid; mp 178–182 °C; R_f = 0.3 (hexane–EtOAc, 7:3).

¹H NMR (600 MHz, CD₃OD): δ = 3.96 (s, 3 H), 7.53 (t, J = 7.8 Hz, 1 H), 7.60 (t, J = 7.8 Hz, 2 H), 7.89 (d, J = 7.8 Hz, 2 H), 9.11 (s, 1 H).

¹³C NMR (150 MHz, CD₃OD): δ = 52.8, 122.0, 127.9, 129.9, 131.2, 138.0, 141.4, 161.1.

HRMS (ESI+): m/z [M + H]⁺ calcd for C₁₀H₁₀N₃O₂: 204.0768; found: 204.0790.

1-Azido-4-(methylthio)benzene (2f)

Following the general procedure using 4-(methylthio)boronic acid (1f) or potassium trifluoro[4-(methylthio)phenyl]borate (7f) for 3 h and chromatography (Et₂O) afforded 2f (162 mg, 98% from 1f; 110 mg, 67% from 7f) as a yellow oil; R_f = 0.6 (hexane–EtOAc, 9:1).

IR: 2115 cm⁻¹.

¹H NMR (600 MHz, CD₃OD): δ = 2.45 (s, 3 H), 6.98 (d, J = 8.4 Hz, 2 H), 7.28 (d, J = 8.4 Hz, 2 H).

¹³C NMR (150 MHz, CD₃OD): δ = 16.4, 120.6, 129.6, 136.6, 138.6.

HRMS (ESI+) (iminophosphorane adduct): m/z [M − N₂ + PPh₃ + H]⁺ calcd for C₂₅H₂₂NPS: 400.1283; found: 400.1296.

Methyl 1-(4-Fluorophenyl)-1H-1,2,3-triazole-4-carboxylate (3g)

Following the general procedure using 4-fluorophenylboronic acid (1g) for 1.5 h afforded crude 2g. Methyl propiolate (3.0 equiv) and sodium ascorbate (0.1 equiv) were added and the mixture was stirred at r.t. overnight. Chromatography (20% EtOAc–hexane) afforded 3g (148 mg, 67%) as a yellow solid; mp 185–188 °C; R_f = 0.4 (hexane–EtOAc, 7:3).

¹H NMR (600 MHz, CD₃OD): δ = 3.96 (s, 3 H), 7.35 (d, J = 8.4 Hz, 2 H), 7.93 (d, J = 8.4 Hz, 2 H), 9.10 (s, 1 H).

¹³C NMR (150 MHz, CD₃OD): δ = 52.8, 117.9 (d, ²J_C-F = 24 Hz), 124.4 (d, ³J_C-F = 8.9 Hz), 128.2, 136.8, 141.5, 162.4, 164.5 (d, ¹J_C-F = 247 Hz).

HRMS (ESI+): m/z [M + H]⁺ calcd for C₁₀H₉FN₃O₂: 222.0673; found: 222.0675.

1-Azido-4-iodobenzene (2h)

Following the general procedure using 4-iodophenylboronic acid (1h) for 3 h and chromatography (hexane) afforded 2h (157 mg, 64%) as a yellow oil; R_f = 0.8 (hexane–EtOAc, 8:2).

IR: 2125 cm⁻¹.

¹H NMR (600 MHz, CD₃OD): δ = 6.87 (d, J = 7.2 Hz, 2 H), 7.70 (d, J = 7.2 Hz, 2 H).

¹³C NMR (150 MHz, CD₃OD): δ = 89.0, 122.3, 140.2, 141.7.

HRMS (ESI+) (iminophosphorane adduct): m/z [M − N₂ + PPh₃ + H]⁺ calcd for C₂₄H₁₉INP: 480.0373; found: 480.0417.

1-Azido-4-chlorobenzene (2i)

Following the general procedure using 4-chlorophenylboronic acid (1i) or potassium 4-chlorophenyltrifluoroborate (7i) for 3 h and chromatography (Et₂O) afforded 2i (117 mg, 76% from 1i; 70 mg, 46% from 7i) as a brown oil; R_f = 0.7 (hexane–EtOAc, 9:1).

IR: 2106 cm⁻¹.

¹H NMR (600 MHz, CD₃OD): δ = 7.04 (d, J = 8.4 Hz, 2 H), 7.37 (d, J = 8.4 Hz, 2 H).

¹³C NMR (150 MHz, CD₃OD): δ = 89.0, 122.3, 140.2, 141.7.

HRMS (ESI+) (iminophosphorane adduct): m/z [M − N₂ + PPh₃ + H]⁺ calcd for C₂₄H₁₉ClNP: 388.1016; found: 388.1024.

1-Azido-4-bromobenzene (2j)

Following the general procedure using 4-bromophenylboronic acid (1j) for 3 h and chromatography (Et₂O) afforded 2j (143 mg, 72%) as a yellow oil; R_f = 0.7 (hexane–EtOAc, 9:1).

IR: 2108 cm⁻¹.

¹H NMR (600 MHz, CD₃OD): δ = 6.99 (d, J = 8.4 Hz, 2 H), 7.51 (d, J = 8.4 Hz, 2 H).

¹³C NMR (150 MHz, CD₃OD): δ = 118.8, 122.0, 134.0, 141.0.

HRMS (ESI+) (iminophosphorane adduct): m/z [M − N₂ + PPh₃ + H]⁺ calcd for C₂₄H₁₉BrNP: 432.0511; found: 432.0533.

4-Azidobenzamide (2k)

Following the general procedure using 4-carbamoylphenylboronic acid (1k) for 3 h and chromatography (70% EtOAc–hexane) afforded 2k (131 mg, 81%) as a white amorphous solid; mp 167–169 °C; R_f = 0.2 (hexanes–EtOAc, 6:4).

IR: 2097 cm⁻¹.

¹H NMR (600 MHz, CD₃OD): δ = 7.14 (d, J = 8.4 Hz, 2 H), 7.90 (d, J = 8.4 Hz, 2 H).

¹³C NMR (150 MHz, CD₃OD): δ = 120.0, 130.7, 131.6, 145.3, 171.8.

HRMS (ESI+) (iminophosphorane adduct): m/z [M − N₂ + PPh₃ + H]⁺ calcd for C₂₅H₂₁N₂OP: 397.1464; found: 397.1479.

4-Azidobenzaldehyde (2l)

Following the general procedure using 4-formylphenylboronic acid (1l) for 3 h and chromatography (5% EtOAc–hexane) afforded 2l (124 mg, 84%) as a brown oil; R_f = 0.3 (hexane–EtOAc, 9:1).

IR: 2115 cm⁻¹.

¹H NMR (600 MHz, CD₃OD): δ = 7.22 (d, J = 8.4 Hz, 2 H), 7.91 (d, J = 8.4 Hz, 2 H), 9.90 (s, 1 H).

¹³C NMR (150 MHz, CD₃OD): δ = 120.7, 132.7, 134.9, 147.9, 192.7.

HRMS (ESI+) (iminophosphorane adduct): m/z [M − N₂ + PPh₃ + H]⁺ calcd for C₂₅H₂₀NOP: 382.1355; found: 382.1393.

4-Azidobenzoic Acid (2m)

Following the general procedure using 4-carboxyphenylboronic acid (1m) or potassium 4-carboxyphenyltrifluoroborate (7m) for 3 h. The mixture was treated with 1 M HCl (10 mL) and extracted with EtOAc (3 × 20 mL). The combined extracts were washed with sat. aq NaCl, dried (Na₂SO₄), and concentrated in vacuo. Recrystallization of the crude mixture (EtOAc, 10 mL) afforded 2m (150 mg, 92% from 1m; 121 mg, 75% from 7m) as a yellow solid; mp 109–115 °C; R_f = 0.3 (hexanes–EtOAc, 7:3).

IR: 2110 cm⁻¹.

¹H NMR (600 MHz, CD₃OD): δ = 7.15 (d, J = 9.0 Hz, 2 H), 8.04 (d, J = 9.0 Hz, 2 H).

¹³C NMR (150 MHz, CD₃OD): δ = 120.1, 128.9, 132.8, 146.4, 169.2.

HRMS (ESI–): m/z [M – H]⁻ calcd for C₇H₄N₃O₂: 162.0309; found: 162.0323.

Methyl 4-Azidobenzoate (2n)

Following the general procedure using 4-(methoxycarbonyl)phenylboronic acid (1n) for 3 h and chromatography (10% EtOAc–hexane) afforded 2n (175 mg, 99%) as a yellow oil; R_f = 0.7 (hexane–EtOAc, 7:3).

IR: 2117 cm⁻¹.

¹H NMR (600 MHz, CD₃OD): δ = 3.89 (s, 3 H), 7.16 (d, J = 8.4 Hz, 2 H), 8.03 (d, J = 8.4 Hz, 2 H).

¹³C NMR (150 MHz, CD₃OD): δ = 52.8, 120.2, 128.2, 132.6, 146.6, 167.9.

HRMS (ESI+) (iminophosphorane adduct): m/z [M − N₂ + PPh₃ + H]⁺ calcd for C₂₆H₂₂NO₂P: 412.1461; found: 412.1477.

4′-Azidoacetophenone (2o)

Following the general procedure using 4-acetylphenylboronic acid (1o) or potassium 4-acetylphenyltrifluoroborate (7o) for 3 h and chromatography (10% EtOAc–hexane) afforded 2o (134 mg, 83% from 1o; 117 mg, 73% from 7o) as a brown solid; mp 40–45 °C; R_f = 0.3 (hexane–EtOAc, 9:1).

IR: 2128 cm⁻¹.

¹H NMR (600 MHz, CD₃OD): δ = 2.55 (s, 3 H), 7.12 (d, J = 8.4 Hz, 2 H), 7.98 (d, J = 8.4 Hz, 2 H).

¹³C NMR (150 MHz, CD₃OD): δ = 26.6, 120.1, 131.6, 135.1, 146.6, 198.9.

HRMS (ESI+) (iminophosphorane adduct): m/z [M − N₂ + PPh₃ + H]⁺ calcd for C₂₆H₂₂NOP: 396.1512; found: 396.1552.

Methyl 1-[4-(Trifluoromethyl)phenyl]-1H-1,2,3-triazole-4-carboxylate (3p)

Following the general procedure using 4-(trifluoromethyl)phenylboronic acid (1p) for 3 h afforded crude 2p. Methyl propiolate (3.0 equiv) and sodium ascorbate (0.1 equiv) were added and the mixture was stirred at r.t. overnight. Chromatography (20% EtOAc–hexane) afforded 3p (184 mg, 68%) as a yellow solid; mp 193–196 °C; R_f = 0.3 (hexane–EtOAc, 7:3).

¹H NMR (600 MHz, CD₃OD): δ = 3.97 (s, 3 H), 7.94 (d, J = 8.4 Hz, 2 H), 8.15 (d, J = 8.4 Hz, 2 H), 9.27 (s, 1 H).

¹³C NMR (150 MHz, CD₃OD): δ = 52.8, 122.4, 128.2, 128.3 (q, ³J_C-F = 4.8 Hz), 132.4 (d, ²J_C-F = 33.0 Hz), 140.7, 141.7, 162.2; CF₃ signal not observed.

HRMS (ESI+): m/z [M + H]⁺ calcd for C₁₁H₉F₃N₃O₂: 272.0641; found: 272.0647.

4-Azidobenzonitrile (2q)

Following the general procedure using 4-cyanophenylboronic acid (1q) or 4-cyanophenylboronic acid pinacol ester (4q) for 3 h and chromatography (Et₂O) afforded 2q (141 mg, 98% from 1q; 118 mg, 82% from 4q) as a light brown solid; mp 56–59 °C; R_f = 0.4 (hexane–EtOAc, 9:1).

IR: 2112 cm⁻¹.

¹H NMR (600 MHz, CD₃OD): δ = 7.23 (d, J = 8.4 Hz, 2 H), 7.74 (d, J = 8.4 Hz, 2 H).

¹³C NMR (150 MHz, CD₃OD): δ = 109.3, 119.5, 121.2, 135.2, 146.8.

HRMS (ESI+) (iminophosphorane adduct): m/z [M − N₂ + PPh₃ + H]⁺ calcd for C₂₅H₁₉N₂P: 379.1359; found: 379.1370.

1-Azido-4-(methylsulfonyl)benzene (2r)

Following the general procedure using 4-(methylsulfonyl)phenylboronic acid (1r) for 3 h and chromatography (10% EtOAc–hexane) afford 2r (166 mg, 84%) as a brown oil; R_f = 0.2 (hexane–EtOAc, 7:3).

IR: 2132 cm⁻¹.

¹H NMR (600 MHz, CD₃OD): δ = 3.11 (s, 3 H), 7.29 (d, J = 8.4 Hz, 2 H), 7.95 (d, J = 8.4 Hz, 2 H).

¹³C NMR (150 MHz, CD₃OD): δ = 44.5, 120.9, 130.6, 138.2, 147.4.

HRMS (ESI+) (iminophosphorane adduct) : m/z [M − N₂ + PPh₃ + H]⁺ calcd for C₂₅H₂₂NO₂PS: 432.1182; found: 432.1184.

1-Azido-4-nitrobenzene (2s)

Following the general procedure using 4-nitrophenylboronic acid (1s) for 3 h and chromatography (Et₂O) afforded 2s (140 mg, 85%) as a yellow solid; mp 63–66 °C; R_f = 0.4 (hexane–EtOAc, 9:1).

IR: 2128 cm⁻¹.

¹H NMR (600 MHz, CD₃OD): δ = 7.27 (d, J = 8.4 Hz, 2 H), 8.28 (d, J = 8.4 Hz, 2 H).

¹³C NMR (150 MHz, CD₃OD): δ = 120.9, 126.7, 146.2, 148.6.

HRMS (ESI+) (iminophosphorane adduct): m/z [M − N₂ + PPh₃ + H]⁺ calcd for C₂₄H₁₉N₂O₂P: 399.1257; found: 399.1251.

3-Azidobiphenyl (2t)

Following the general procedure using biphenyl-3-ylboronic acid (1t) for 3 h and chromatography (hexane) afforded 2t (90 mg, 46%) as a colorless oil; R_f = 0.4 (hexane).

IR: 2101 cm⁻¹.

¹H NMR (600 MHz, CD₃OD): δ = 6.98 (d, J = 7.2 Hz, 1 H), 7.16 (s, 1 H), 7.30–7.34 (m, 2 H), 7.37 (m, 3 H), 7.52 (d, J = 8.4 Hz, 2 H).

¹³C NMR (150 MHz, CD₃OD): δ = 118.5, 118.8, 124.8, 128.1, 128.9, 130.0, 131.4, 141.4, 141.9, 144.4.

HRMS (ESI+) (iminophosphorane adduct): m/z [M − N₂ + PPh₃ + H]⁺ calcd for C₃₀H₂₄NP: 430.1719; found: 430.1757.

2-Azidobiphenyl (2u)

Following the general procedure using biphenyl-2-ylboronic acid (1u) for 3 h and chromatography (hexane) afforded 2u (80 mg, 41%) as a colorless oil; R_f = 0.3 (hexane).

IR: 2107 cm⁻¹.

¹H NMR (600 MHz, CD₃OD): δ = 7.19 (t, J = 7.8 Hz, 1 H), 7.26 (d, J = 7.8 Hz, 1 H), 7.29–7.32 (m, 2 H), 7.36–7.39 (m, 5 H).

¹³C NMR (150 MHz, CD₃OD): δ = 120.1, 126.2, 128.5, 129.1, 130.0, 130.6, 132.3, 135.3, 138.4, 139.7.

HRMS (ESI+) (iminophosphorane adduct): m/z [M − N₂ + PPh₃ + H]⁺ calcd for C₃₀H₂₄NP: 430.1719; found: 430.1713.

1-Azido-N-pivaloylaniline (2v)

Following the general procedure using 2-(pivaloylamino)phenylboronic acid (1v) for 3 h and chromatography (5% EtOAc–hexane) afforded 2v (207 mg, 95%) as a yellow oil; R_f = 0.5 (hexane–EtOAc, 9:1).

IR: 2129 cm⁻¹.

¹H NMR (600 MHz, CD₃OD): δ = 1.31 (s, 9 H), 7.11 (t, J = 7.8 Hz, 1 H), 7.17 (overlapping d, J = 7.8 Hz, 1 H), 7.19 (overlapping t, J = 7.8 Hz, 1 H), 7.79 (d, J = 7.8 Hz, 1 H).

¹³C NMR (150 MHz, CD₃OD): δ = 27.9, 40.7, 119.6, 126.2, 126.3, 127.2, 130.5, 133.2, 179.5.

HRMS (ESI+) (iminophosphorane adduct): m/z [M − N₂ + PPh₃ + H]⁺ calcd for C₂₉H₂₉N₂OP: 453.2090; found: 453.2116.

4-Azidoaniline (2w)

Following the general procedure using 4-aminophenylboronic acid pinacol ester (4w) for 24 h and chromatography (10% EtOAc–hexane) afforded 2w (127 mg, 95%) as a brown oil; R_f = 0.3 (hexanes–EtOAc, 9:1).

IR: 2108 cm⁻¹.

¹H NMR (600 MHz, CD₃OD): δ = 6.73 (d, J = 8.4 Hz, 2 H), 6.80 (d, J = 8.4 Hz, 2 H).

¹³C NMR (150 MHz, CD₃OD): δ = 117.8, 120.8, 130.9, 146.6.

HRMS (ESI+) (iminophosphorane adduct): m/z [M − N₂ + PPh₃ + H]⁺ calcd for C₂₄H₂₁N₂P: 369.1515; found: 369.1528.

4-Azido-N,N-dimethylaniline (2x)

Following the general procedure using 4-(dimethylamino)phenylboronic acid pinacol ester (4x) for 24 h and chromatography (15% EtOAc–hexane) afforded 2x (130 mg, 80%) as a yellow solid; mp 35–39 °C; R_f = 0.3 (hexanes–EtOAc, 7:3).

IR: 2087 cm⁻¹.

¹H NMR (600 MHz, CD₃OD): δ = 2.88 (s, 6 H), 6.77 (d, J = 9.0 Hz, 2 H), 6.89 (d, J = 9.0 Hz, 2 H).

¹³C NMR (150 MHz, CD₃OD): δ = 41.3, 115.4, 120.7, 129.9, 150.1.

HRMS (ESI+) (iminophosphorane adduct): m/z [M − N₂ + PPh₃ + H]⁺ calcd for C₂₆H₂₅N₂P: 397.1828; found: 397.1796.

4-Azido-1-(tert-butoxycarbonyl)-1H-pyrazole (2y)

Following the general procedure using 1-(tert-butoxycarbonyl)-1H-pyrazole-4-boronic acid pinacol ester (2y) for 1 h and chromatography (15% EtOAc–hexane) afforded 2y (50 mg, 24%) as a yellow oil; R_f = 0.2 (hexane–EtOAc, 9:1).

IR: 2119 cm⁻¹.

¹H NMR (600 MHz, CD₃OD): δ = 1.64 (s, 9 H), 7.73 (s, 1 H), 8.10 (s, 1 H).

¹³C NMR (150 MHz, CD₃OD): δ = 26.8, 86.3, 91.3, 120.6, 136.8, 147.1.

HRMS (ESI+) (iminophosphorane adduct): m/z [M − N₂ + PPh₃ + H]⁺ calcd for C₂₆H₂₆N₃O₂P: 444.1835; found: 444.1880.

5-Azido-1-(tert-butoxycarbonyl)-1H-indole (2z)

Following the general procedure using 1-(tert-butoxycarbonyl)-1H-indole-5-boronic acid pinacol ester (1z) for 24 h and chromatography (10% EtOAc–hexane) afforded 2z (135 mg, 52%) as a brown oil; R_f = 0.7 (hexane–EtOAc, 8:2).

IR: 2111 cm⁻¹.

¹H NMR (600 MHz, CD₃OD): δ = 1.67 (s, 9 H), 6.59 (d, J = 4.2 Hz, 1 H), 6.99 (dd, J = 8.4, 2.4 Hz, 1 H), 7.25 (d, J = 2.4 Hz, 1 H), 7.64 (d, J = 4.2 Hz, 1 H), 8.11 (d, J = 8.4 Hz, 1 H).

¹³C NMR (150 MHz, CD₃OD): δ = 28.5, 85.2, 108.0, 111.7, 116.6, 117.2, 128.3, 133.2, 134.1, 136.2, 150.8.

HRMS (ESI+) (iminophosphorane adduct): m/z [M − N₂ + PPh₃ + H]⁺ calcd for C₃₁H₂₉N₂O₂P: 493.2039; found: 493.2007.

4-Azidopyridine (6a)

Following the general procedure using pyridin-4-ylboronic acid (5a) for 24 h and chromatography (30% EtOAc–hexane) afforded 6a (41 mg, 34%); as a yellow oil R_f = 0.2 (hexanes–EtOAc, 7:3).

IR: 2112 cm⁻¹.

¹H NMR (600 MHz, CD₃OD): δ = 7.14 (d, J = 5.4 Hz, 2 H), 8.47 (br s, 2 H).

¹³C NMR (150 MHz, CD₃OD): δ = 115.9, 151.5, 151.6.

HRMS (ESI+): m/z [M + H]⁺ calcd for C₅H₅N₄: 121.0509; found: 121.0509.

5-Azidopyrimidine (6b)

Following the general procedure using pyrimidin-5-ylboronic acid (5b) for 24 h and chromatography (30% EtOAc–hexane) afforded 6b (44 mg, 36%) as a white solid; mp 52–57 °C; R_f = 0.3 (hexane–EtOAc, 7:3).

IR: 2110 cm⁻¹.

¹H NMR (600 MHz, CD₃OD): δ = 8.60 (s, 2 H), 8.92 (s, 1 H).

¹³C NMR (150 MHz, CD₃OD): δ = 138.4, 149.1, 155.3.

HRMS (ESI+): m/z [M + H]⁺ calcd for C₄H₄N₅: 122.0461; found: 122.0475.

8-Azidoquinoline (6c)

Following the general procedure using quinolin-8-ylboronic acid (5c) for 24 h and chromatography (15% EtOAc–hexane) afforded 6c (60 mg, 35%) as a white solid; mp 54–57 °C; R_f = 0.1 (hexane–EtOAc, 9:1).

IR: 2120 cm⁻¹.

¹H NMR (600 MHz, CD₃OD): δ = 6.98 (d, J = 7.8 Hz, 1 H), 7.15 (d, J = 8.4 Hz, 1 H), 7.32 (t, J = 7.8 Hz, 1 H), 7.40 (dd, J = 8.4, 4.2 Hz, 1 H), 8.14 (d, J = 8.4 Hz, 1 H), 8.70 (d, J = 4.2 Hz, 1 H).

¹³C NMR (150 MHz, CD₃OD): δ = 111.8, 117.0, 122.5, 128.7, 130.5, 137.6, 139.6, 145.8, 148.5.

HRMS (ESI+): m/z [M + H]⁺ calcd for C₉H₇N₄: 171.0665; found: 171.0677.

4-Azidoisoquinoline (6d)

Following the general procedure using isoquinolin-4-ylboronic acid (5d) for 24 h and chromatography (10% EtOAc–hexane) afforded 6d (73 mg, 43%) as a white solid; mp 54–56 °C; R_f = 0.2 (hexane–EtOAc, 9:1).

IR: 2123 cm⁻¹.

¹H NMR (600 MHz, CD₃OD): δ = 7.75 (t, J = 7.8 Hz, 1 H), 7.83 (t, J = 7.8 Hz, 1 H), 8.09 (overlapping d, J = 9.0 Hz, 1 H), 8.10 (overlapping d, J = 8.4 Hz, 1 H), 8.39 (s, 1 H), 9.04 (s, 1 H).

¹³C NMR (150 MHz, CD₃OD): δ = 122.6, 128.8, 130.0, 130.3, 130.5, 132.5 (2 C), 134.5, 149.8.

HRMS (ESI+): m/z [M + H]⁺ calcd for C₉H₇N₄: 171.0665; found: 171.0682.