Functionalization of Tetrazoles Bearing the Electrochemically Cleavable 1N-(6-Methylpyridyl-2-methyl) Protecting Group.

6-Methylpyridyl-2-methyl protected tetrazoles can be C-H deprotonated using the turbo-Grignard reagent and involved in the reactions with aldehydes and ketones. The protecting group can be cleaved under reductive electrochemical conditions using Pb bronze as a cathode and Zn as a sacrificial anode.

Introduction

Tetrazoles do not exist in nature; however, the tetrazole motif is found in a number of useful compounds with an application in pharmacology,[1] catalysis,[2] and material science.[3] Representative examples of pharmacologically relevant tetrazole derivatives are the antihypertensive drug losartan,[4] antiasthmatic drug tomelukast (LY171883),[5] antibiotic tedizolid,[6] the multidrug resistance efflux pump inhibitor encequidar,[7] and an experimental antitumor agent BMS-317180[8] (Figure ).

Figure 1

Representative examples of pharmacologically relevant tetrazole derivatives.

The importance of tetrazole containing compounds has motivated researchers to develop numerous methods for their synthesis.[9] Among them, C–H functionalization of tetrazoles via metalation is an attractive approach to install substituents at the fifth position. It should be noted, however, that lithiated tetrazoles suffer from low stability due to a rapid retro [2 + 3] cycloaddition forming the cyanamide even at −78 °C.[9a−9c] Organomagnesiun intermediates are considerably more stable (t1/2 = 3 h at −20 °C), which enables the use of routine lab operations for their derivatization.[9c] Recently, we have reported generation organomagnesiun intermediates by C–H deprotonation of 1N-PMB protected tetrazole (1, PG = PMB), which was subsequently subjected to the reaction with electrophiles (Scheme ).[10] To extend the utility of this approach, 1N-pyridyl-2-methyl protected tetrazoles 1a and 1b were investigated as substrates to give C–H functionalization products, which can be deprotected by the electrochemical reduction (Scheme ).

Scheme 1

Functionalization of Tetrazoles Bearing an Electrochemically Cleavable Protecting Group

Results and Discussion

Methylpyridylmethyl protected tetrazole 1a was obtained according to a known method.[11] The 6-methyl analogue 1b was prepared by the alkylation of tetrazole (4) with the bromomethylpyridine derivative 3 (Scheme ). The reaction provided 1N alkylation product 1b as the major isomer together with 2N alkylation product 5, which was separated by chromatography.

Scheme 2

Synthesis of Methylpyridylmethyl Protected Tetrazole 1b

The deprotonation efficiency of substrates 1a and 1b was determined by the deuterium quench of the metalated intermediates generated by the reaction with the turbo-Grignard reagent (Table ).

Table 1

Deprotonation Studies of Pyridyl Protected Tetrazoles 1a and 1b with Turbo-Grignard Reagenta

entry	temp.	time (min)	d-1, yieldb	6, yieldb
1	–60 °C	15	d-1a, ∼40%	6a, trace
2	–60 °C	60	d-1a, ∼60%	6a, trace
3	–60 °C	15	d-1b, 90%	6a, trace
4	–60 °C	30	d-1b, 97%	6b, n.d.
5	–60 °C	60	d-1b, 98%	6b, n.d.
6	0 °Cc	30	d-1b, 55%	6b, ∼30%
7	r.t.c	30	d-1b, 0%	6b, 98%

0.7 mmol of tetrazole and 1.2 equiv of turbo-Grignard reagent at −60 °C for the indicated time; quench with 3 equiv of MeOD, add 3 equiv of AcOH, and warm to r.t.

Yields were calculated on the basis of the weight of the crude material and the reduction of the integral intensity of the 5-CH group in the NMR spectra.

Deprotonation was performed at −60 °C, and then, the reaction was cooled to reach the indicated temperature.

Pyridylmethyl protected tetrazole 1a gave moderate deuterium incorporation at the fifth position according to the NMR spectra of a reaction mixture (Table , entries 1 and 2). A high recovery of tetrazole 1a as well as product deuterated at the CH2 group were observed. Imidazopyridine 6a was isolated from the reaction mixture as a minor impurity resulting from cyanamide 7a, a product of metalated tetrazole decomposition. Considerable improvement in a deuterium quench experiment was observed using methylpyridylmethyl protected tetrazole 1b as a substrate. High deuterium incorporation at the fifth position was observed after deprotonation with turbo-Grignard reagent at −60 °C (Table , entries 3–5). An increase of the temperature after the metalation step led to the formation of imidazopyridine 6b. This formed as a major product if the reaction mixture was warmed to room temperature. Better performance of methylpyridylmethyl protected tetrazole 1b compared to that of substrate 1a can be explained by blocking the relatively acidic C–H at the sixth position of pyridine, which could cause an equilibrium mixture of several metalated species.

Methylpyridylmethyl protected tetrazole 1b, after metalation, was subjected to the reaction with aldehydes 8a–e and ketones 8f–j (Scheme ). The addition of the metalated intermediate to aromatic aldehydes 8a and 8b, aliphatic aldehyde 8c, and heteroaromatic aldehydes 8d and 8e was very productive, providing alcohols 9a–i. The reaction with ketones 8f–j was also successful to give alcohols 9f–9j in moderate to good yields.

Scheme 3

Synthesis of Alcohols 9a–j by the Addition of Tetrazole 1b to Carbonyl Compounds

The pyridylmethyl group has been demonstrated to have electrochemically cleavable protection for thiols,[12,13] carboxylic acids,[14] and alcohols.[13,15] Similar electrochemical conditions were applied for the reductive cleavage of the methylpyridylmethyl group from tetrazole using compound 9a as the model substrate. A range of electrodes and electrolytes was investigated at the fixed current and electric charge (Table ). The best result was achieved using leaded bronze electrode as cathode, sacrificial zinc as anode, and TBA·BF4 (tetrabutylamonium tetrafluoroborate) as electrolyte, providing deprotected tetrazole 10a in good isolated yield (Table , entry 6). A good conversion of the starting material 9a to deprotected tetrazole 10a was also observed using boron-doped diamond (BDD) as cathode and sacrificial zinc as anode (Table , entry 10).

Table 2

Conditions for the Electrochemical Cleavage of the Methylpiridylmethyl Group in Tetrazole 9a

entry	cathode	anode	electrolyte	conversion of 9a to 10a, %a
1	Pb/bronze	Mg	TBABF4	57
2	Pb	Mg	TBABF4	24
4	Pb	Mg	LiClO4	0
5	BDD	Mg	TBABF4	24
6	Pb/bronze	Zn	TBABF4	87 (67)b
7	Pb/bronze	Zn	TBAClO4	42
8	Pb/bronze	Zn	TBAPF6	6
9	Pb	Zn	TBABF4	45
10	BDD	Zn	TBABF4	76 (50)b

Determined by the ratio of 10a and 9a in HPLC of the reaction mixture.

Isolated yield, %.

The best electrochemical conditions found for the substrate 9a deprotection with Pb bronze cathode and the sacrificial Zn anode were applied for the deprotection of tetrazoles 9b–g (Scheme ). The resulting free tetrazoles 10b–g were obtained in fair isolated yields despite high conversion of the starting materials 9b–g. The major loss of the product was due to the very polar nature of tetrazoles 10b–g, which complicated the isolation.

Scheme 4

Electrochemical Deprotection of the Methylpiridylmethyl Group in Tetrazoles 9b–g

The proposed mechanism for the electrochemical cleavage of the 6-methyl-pyridylmethyl group from tetrazole 9 is provided in Scheme in analogy to the cleavage of the O-(4-nitro)benzyl group.[16] The reduction of the pyridylmethyl group at the cathode by sacrificing the Zn anode leads to an anion radical A, which fragments to pyridylmethyl radical B and tetrazole anion [10]−. The pyridyl radical B undergoes further reactions, like hydrogen abstraction, dimerization, oxidation, and/or reduction to give a mixture of byproducts. The formation of pyridylmethyl radical B is supported by the observation of 2,6-lutidine by LC/MS analysis of the crude reaction mixture, which can form by either hydrogen abstraction or a reduction followed by a protonation.

Scheme 5

Proposed Mechanism for Electrochemical Cleavage of the Methylpyridylmethyl Group

Conclusions

6-Methylpyridyl-2-methyl protected tetrazoles can be C–H deprotonated using the turbo-Grignard reagent and involved in the reactions with aldehydes and ketones. The protecting group can be cleaved in reductive electrochemical conditions using Pb bronze as a cathode and Zn as a sacrificial anode. This expands the utility of tetrazole functionalization via C–H deprotonation, particularly for the cases where selective protecting group cleavage should be achieved. To our knowledge, this is the first example for the protection of tetrazole with an electrochemically cleavable protecting group.

Experimental Section

General Information

Commercially available reagents were used without further purification. All air- or moisture-sensitive reactions were carried out under an argon atmosphere using oven-dried glassware. Flash chromatography was carried out using Merck Kieselgel 60 (230–400 mesh). Thin layer chromatography was performed on silica gel and was visualized by staining with KMnO4. NMR spectra were recorded on a Varian Mercury spectrometer (400 MHz) and a Bruker Fourier spectrometer (300 MHz) with chemical shift values (δ) in ppm relative to TMS using the residual chloroform signal as an internal standard. Elemental analyses were performed using a Carlo-Erba EA1108 Elemental Analyzer. HRMS spectra were obtained using a Q-TOF micro high resolution mass spectrometer with ESI (ESI+/ESI−).

Synthesis of Starting Materials

1H-Tetrazole (4)

4 (11.4 g, 73%) was synthesized according to a literature procedure.[17]

2-(Bromomethyl)-6-methylpyridine (3)

3 (13.1 g, 68%) was synthesized according to a known method.[18]

2-(1H-Tetrazol-1-ylmethyl)pyridine (1a)

1a was synthesized according to a known method.[11]

2-Methyl-6-(1H-tetrazol-1-ylmethyl)pyridine (1b)

A mixture of 1H-tetrazole (4) (2.9 g, 1.2 equiv), dry THF (150 mL), and 2-(bromomethyl)-6-methylpyridine (3) (6.5 g, 1 equiv) was cooled at 0 °C. Triethylamine (19.47 mL, 2.5 equiv) was added, and the mixture was left stirring overnight. Brine (450 mL) was added to quench the reaction, and the mixture was transferred to a separatory funnel and then extracted with ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated by a rotary evaporator. Concentration of the extract gave two isomers 1b and 5, which were separated by column chromatography on silica gel. The desired isomer 1b was obtained in high purity (>96%) as an off-white solid.

General Protocol for the Reaction of Tetrazole 1b with Electrophiles

The tetrazole (1b, 1.1. equiv) was dissolved in THF (0.12 M) and cooled to −60 °C. An isopropyl magnesium chloride–lithium chloride complex (1.2 equiv) was added dropwise and, after 30 min, at the same temperature, the corresponding electrophile (1 equiv), dissolved in THF (0.7 M), was added dropwise. The reaction mixture was slowly left to reach room temperature and stirring continued for 24–72 h. NH4Cl was added to quench the reaction; the aqueous phase was extracted with EtOAc (3×), and the combined organics were washed with brine, dried, and evaporated. The crude was purified with column chromatography on silica.

General Protocol for Electrolytic Removal of the 6-Methyl-pyridylmethyl Protecting Group

A single cell with leaded bronze as a cathode and zinc as an anode was charged with 0.28–0.3 mmol of the corresponding tetrazole 9 and supporting electrolyte TBABF4 (1 equiv) under an inert atmosphere. Dry MeCN (7.5 mL) was added, and the reaction was started by applying constant current (15 mA, total charge of 2.5 F/mol). After the end of the reaction, AcOH (1 equiv) was added and the mixture was diluted with EtOAc and water. The aqueous phase was extracted with EtOAc, and the combined organics were washed with 1 N aqueous HCl and brine, dried, and evaporated; product 10 was purified by column chromatography eluted with a mixture of petroleum ether/ethyl acetae/acetic acid (1:1:0.04).

Characterization of the Products

2-(1H-Tetrazol-1-ylmethyl)pyridine (1a)

1a, 1.2 g, 76%. 1H NMR (400 MHz, CDCl3) δ 8.87 (s, 1H, −CH−), 8.58 (ddd, J = 4.8, 1.9, 1.0 Hz, 1H, Ar), 7.73 (td, J = 7.7, 1.8 Hz, 1H, Ar), 7.36–7.26 (m, 2H, Ar), 5.71 (s, 2H, −CH2−). 13C NMR (101 MHz, CDCl3) δ 152.46, 150.13, 143.11, 137.59, 123.95, 122.74, 53.30.

1b, off-white solid (2.55 g, 42%), mp 53–55 °C. 1H NMR (300 MHz, CDCl3) δ 8.87 (s, 1H, −CH−), 7.59 (t, J = 7.7 Hz, 1H, Ar), 7.10 (dd, J = 17.0, 7.7 Hz, 2H, Ar), 5.64 (s, 2H, −CH2−), 2.51 (s, 3H, −CH3). 13C NMR (101 MHz, CDCl3) δ 159.40, 151.78, 143.15, 137.78, 123.66, 119.75, 53.52, 24.46. Element. Anal. for C8H9N5: N, 39.98; C, 54.85; H, 5.18. Found: N, 39.99; C, 54.85; H, 5.11. HR-MS (ESI-TOF) m/z: Calcd for C8H9N5Na 198.0756; Found [M + Na]+ 198.0758.

4-(Methoxyphenyl)(1-((6-methylpyridin-2-yl)methyl)-1H-tetrazol-5-yl)methanol (9a)

9a, white solid (83%), mp 91–95 °C. 1H NMR (400 MHz, CDCl3) δ 7.60 (t, J = 7.7 Hz, 1H, pyr.), 7.28 (dd, J = 8.9, 0.8 Hz, 1H, Ar), 7.19 (d, J = 7.1 Hz, 1H, pyr.), 7.11 (d, J = 7.8 Hz, 1H, pyr.), 6.82 (d, J = 8.8 Hz, 2H, Ar), 6.38 (s, 1H, −CH–OH), 5.45 (d, J = 14.8 Hz, 1H, −CH2−), 5.34 (d, J = 14.8 Hz, 1H, −CH2−), 3.73 (s, 3H, −OCH3), 2.44 (s, 3H, −CH3). 13C NMR (101 MHz, CDCl3) δ 159.55, 158.87, 156.90, 151.36, 138.83, 131.38, 127.21, 124.26, 120.87, 114.13, 66.12, 55.33, 52.14, 23.54. HR-MS (ESI-TOF) m/z: Calcd for C16H17N5O2Na 334.1280; Found [M + Na]+ 334.1279.

(4-Bromophenyl)(1-((6-methylpyridin-2-yl)methyl)-1H-tetrazol-5-yl)methanol (9b)

9b, light green solid (75%), mp 131–135 °C. 1H NMR (400 MHz, chloroform-d) δ 7.71 (t, J = 7.7 Hz, 1H, pyr.), 7.51 (d, J = 8.5 Hz, 2H, Ar), 7.37 (d, J = 7.9 Hz, 2H, Ar), 7.31 (d, J = 7.6 Hz, 1H, pyr.), 7.22 (d, J = 7.8 Hz, 1H, pyr.), 6.46 (s, 1H, −CH–OH), 5.58 (d, J = 14.8 Hz, 1H, −CH2−), 5.45 (d, J = 14.8 Hz, 1H, −CH2−), 2.53 (s, 3H, −CH3). 13C NMR (101 MHz, CDCl3) δ 158.90, 156.34, 151.09, 139.00, 138.39, 131.85, 127.77, 124.43, 122.41, 120.99, 65.92, 52.19, 23.51. HR-MS (ESI-TOF) m/z: Calcd for C15H15BrN5O 360.0460; Found [M + H]+ 360.0470.

1-(1-((6-Methylpyridin-2-yl)methyl)-1H-tetrazol-5-yl)pentan-1-ol (9c)

9c, white solid (77%), mp 105–108 °C. 1H NMR (400 MHz, chloroform-d) δ 7.68 (t, J = 7.7 Hz, 1H, pyr.), 7.33 (d, J = 7.6 Hz, 1H, pyr.), 7.18 (d, J = 7.8 Hz, 1H, pyr.), 7.06 (sb, 1H, −OH), 5.80 (d, J = 14.6 Hz, 1H, −CH2−), 5.68 (d, J = 14.6 Hz, 1H, −CH2−), 5.18 (dd, J = 7.9, 5.2 Hz, 1H, −CH–OH), 2.50 (s, 3H, −CH3), 2.21–1.94 (m, 2H, −CH2−), 1.60–1.35 (m, 4H, −CH2–CH2−), 0.92 (t, J = 7.2 Hz, 3H, −CH3). 13C NMR (101 MHz, CDCl3) δ 158.86, 157.26, 151.66, 138.78, 124.21, 121.01, 64.90, 52.27, 35.58, 27.44, 23.73, 22.47, 14.00. HR-MS (ESI-TOF) m/z: Calcd for C13H20N5O 262.1668; Found [M + H]+ 262.1667.

(1-((6-Methylpyridin-2-yl)methyl)-1H-tetrazol-5-yl)(thiophen-3-yl)methanol (9d)

9d, subwhite solid (85%), mp 76–80 °C. 1H NMR (400 MHz, CDCl3) δ 7.97 (sb, 1H, −OH) 7.62 (t, J = 7.7 Hz, 1H, pyr.), 7.32 (dt, J = 2.7, 1.3 Hz, 1H, thioph.), 7.28 (dd, J = 5.0, 3.1 Hz, 1H, thioph.), 7.20 (d, J = 7.6 Hz, 1H, pyr.), 7.13 (d, J = 7.8 Hz, 1H, pyr.), 6.97 (dd, J = 5.0, 1.3 Hz, 1H, thioph.), 6.47 (d, J = 1.2 Hz, 1H, −CH–OH), 5.55 (d, J = 14.8 Hz, 1H, −CH2−), 5.41 (d, J = 14.8 Hz, 1H, −CH2−), 2.43 (s, 3H, −CH3). 13C NMR (101 MHz, CDCl3) δ 158.79, 156.24, 151.33, 140.75, 138.80, 126.98, 125.65, 124.22, 122.31, 120.82, 63.80, 52.24, 23.52. HR-MS (ESI-TOF) m/z: Calcd for C13H14N5OS 288.0919; Found [M + H]+ 288.0909.

Furan-3-yl(1-((6-methylpyridin-2-yl)methyl)-1H-tetrazol-5-yl)methanol (9e)

9e, light brown solid (79%), mp 71–75 °C. 1H NMR (400 MHz, CDCl3) δ 7.69 (t, J = 7.7 Hz, 1H, pyr.), 7.52 (q, J = 1.2 Hz, 1H, furan), 7.42 (t, J = 1.8 Hz, 1H, furan), 7.31 (d, J = 7.6 Hz, 1H, pyr.), 7.18 (d, J = 7.8 Hz, 1H, pyr.), 6.40 (d, J = 1.3 Hz, 2H, furan), 5.64 (s, 2H, −CH2−), 2.48 (s, 3H, −CH3). 13C NMR (101 MHz, CDCl3) δ 158.92, 156.00, 151.31, 143.92, 140.23, 138.90, 125.18, 124.35, 121.02, 108.84, 61.01, 52.32, 23.54. HR-MS (ESI-TOF) m/z: Calcd for C13H14N5O2 272.1147; Found [M + H]+ 272.1151.

1-(1-((6-Methylpyridin-2-yl)methyl)-1H-tetrazol-5-yl)-1-phenylethan-1-ol (9f)

9f, yellow crystalline (86%), mp 106–109 °C. 1H NMR (400 MHz, CDCl3) δ 7.64 (t, J = 7.7 Hz, 1H, pyr.), 7.48–7.41 (m, 2H, Ar), 7.37–7.25 (m, 3H, Ar), 7.21 (d, J = 7.6 Hz, 1H, pyr.), 7.15 (d, J = 7.8 Hz, 1H, pyr.), 5.38 (d, J = 14.8 Hz, 1H, −CH2−), 5.12 (d, J = 14.8 Hz, 1H, −CH2−), 2.51 (s, 3H, −CH3), 2.16 (s, 3H, −CH3). 13C NMR (101 MHz, CDCl3) δ 159.48, 158.60, 151.44, 144.76, 138.93, 128.69, 127.85, 124.80, 124.23, 120.92, 71.11, 52.21, 31.99, 23.38. HR-MS (ESI-TOF) m/z: Calcd for C16H18N5O 296.1511; Found [M + H]+ 296.1516.

(1-((6-Methylpyridin-2-yl)methyl)-1H-tetrazol-5-yl)diphenyl Methanol (9g)

9g, subyellow solid (47%), mp 108–112 °C. 1H NMR (400 MHz, CDCl3) δ 7.66 (t, J = 7.7 Hz, 1H, pyr.), 7.47–7.41 (m, 4H, Ar), 7.38–7.26 (m, 7H, Ar(6H) + pyr.(1H)), 7.12 (d, J = 7.8 Hz, 1H, pyr.), 5.72 (s, 2H, −CH2−), 2.31 (s, 3H, −CH3). 13C NMR (101 MHz, CDCl3) δ 159.04, 158.58, 151.64, 144.28, 139.09, 128.17, 127.96, 127.11, 124.33, 121.17, 76.65, 52.97, 23.16. HR-MS (ESI-TOF) m/z: Calcd for C21H20N5O 358.1668; Found [M + H]+ 358.1666.

9-(1-((6-Methylpyridin-2-yl)methyl)-1H-tetrazol-5-yl)-9H-fluoren-9-ol (9h)

9h, yellow solid (65%), mp 165–170 °C. 1H NMR (400 MHz, CDCl3) δ 8.33 (s, 1H, −OH), 7.72–7.64 (m, 3H, pyr.(1H) + Ar(2H)), 7.40 (ddd, J = 7.5, 6.9, 1.7 Hz, 2H, Ar), 7.33–7.16 (m, 6H. pyr.(2H) + Ar(4H)), 5.98 (s, 2H, −CH2−), 2.58 (s, 3H, −CH3). 13C NMR (101 MHz, CDCl3) δ 158.54, 157.81, 151.94, 146.88, 139.84, 138.89, 130.00, 128.44, 124.25, 124.11, 120.78, 120.75, 79.37, 53.03, 23.85. HR-MS (ESI-TOF) m/z: Calcd for C21H18N5O 356.1511; Found [M + H]+ 356.1508.

1-(1-((6-Methylpyridin-2-yl)methyl)-1H-tetrazol-5-yl)cyclohex-2-en-1-ol (9i)

9i, beige solid (80%), mp 92–95 °C. 1H NMR (400 MHz, CDCl3) δ 7.67 (t, J = 7.7 Hz, 1H, pyr.), 7.44 (sb, 1H, −OH), 7.29 (d, J = 7.6 Hz, 1H, pyr.), 7.17 (d, J = 7.8 Hz, 1H, pyr.), 6.03 (dt, J = 9.9, 3.7 Hz, 1H, −CH=CH−), 5.95 (d, J = 14.5 Hz, 1H, −CH2−), 5.85 (d, J = 14.5 Hz, 1H, −CH2−), 5.79 (dd, J = 10.0, 1.0 Hz, 1H, −CH=CH−), 2.51 (s, 3H, −CH3), 2.27 (ddd, J = 13.2, 10.3, 3.6 Hz, 1H, −CH2−), 2.18 (dddd, J = 9.3, 5.7, 3.3, 2.2 Hz, 2H, −CH2−), 2.10 (dddd, J = 13.3, 7.2, 3.2, 1.1 Hz, 1H, −CH2−), 2.01–1.83 (m, 2H, −CH2−). 13C NMR (101 MHz, CDCl3) δ 160.01, 158.61, 152.27, 138.70, 131.13, 129.20, 124.05, 120.93, 68.58, 53.11, 37.21, 24.62, 23.79, 18.08. HR-MS (ESI-TOF) m/z: Calcd for C14H17N5O 272.1511; Found [M + H]+ 272.1513.

4-Methyl-2-(1-((6-methylpyridin-2-yl)methyl)-1H-tetrazol-5-yl)pentan-2-ol (9j)

9j, thick yellow oil (56%). 1H NMR (400 MHz, chloroform-d) δ 7.69 (t, J = 7.7 Hz, 1H, pyr.), 7.35 (d, J = 7.5 Hz, 1H, pyr.), 7.18 (d, J = 7.8 Hz, 1H, pyr.), 5.99 (d, J = 14.2 Hz, 1H, −CH2−), 5.82 (d, J = 14.3 Hz, 1H, −CH2−), 2.52 (s, 3H, −CH3), 2.05 (dd, J = 14.2, 6.7 Hz, 1H, −CH2−), 1.95 (dd, J = 14.2, 5.5 Hz, 1H, −CH2−), 1.86–1.75 (m, 1H, −CH−), 1.72 (s, 3H, −CH3), 0.98 (d, J = 6.7 Hz, 3H, −CH3), 0.73 (d, J = 6.7 Hz, 3H, −CH3). 13C NMR (101 MHz, CDCl3) δ 160.53, 158.50, 152.28, 138.93, 124.22, 121.35, 72.49, 52.93, 51.62, 31.57, 24.61, 24.41, 23.68, 23.63. HR-MS (ESI-TOF) m/z: Calcd for C14H22N5O 276.1824; Found [M + H]+ 276.1834.

(4-Methoxyphenyl)(1H-tetrazol-5-yl)methanol (10a)

10a, 67%. 1H NMR (300 MHz, CD3OD) δ 7.35 (d, J = 8.7 Hz, 2H, Ar), 6.92 (d, J = 8.7 Hz, 2H, Ar), 6.10 (s, 1H, −CH–OH), 3.77 (s, 3H, −OCH3).[10]

(4-Bromophenyl)(1H-tetrazol-5-yl)methanol (10b)

10b, 65%. 1H NMR (300 MHz, CD3OD) δ 7.54 (d, J = 8.5 Hz, 2H, Ar), 7.39 (d, J = 8.4 Hz, 2H, Ar), 6.14 (s, 1H, −CH–OH).[10]

1-(1H-Tetrazol-5-yl)pentan-1-ol (10c)

10c, 68%. 1H NMR (300 MHz, CD3OD) δ 5.04 (t, J = 6.5 Hz, 1H, −CH–OH), 2.00–1.77 (m, 2H, −CH2−), 1.38 (dd, J = 7.4, 3.9 Hz, 4H, −CH2–CH2−), 1.09–0.81 (m, 3H, −CH3).[11]

Furan-3-yl(1H-tetrazol-5-yl)methanol (10d)

10d, white amorphous solid (68%). 1H NMR (400 MHz, CD3OD) δ 7.58 (s, 1H, −C=CH–O−), 7.49 (t, J = 1.9 Hz, 1H, =CH–O−), 6.45 (t, J = 1.9 Hz, 1H, C–CH=), 6.14 (s, 1H, −CH–OH). 13C NMR (101 MHz, CD3OD) δ 159.10, 143.68, 140.15, 125.50, 108.37, 60.22. HR-MS (ESI-TOF) m/z: Calcd for C6H6N4O2 165.0413; Found [M – H]− 165.0417.

9-(1H-Tetrazol-5-yl)-9H-fluoren-9-ol (10e)

10e, 71%. 1H NMR (400 MHz, CD3OD) δ 7.79 (dd, J = 7.6, 0.9 Hz, 2H), 7.49–7.39 (m, 4H), 7.32 (td, J = 7.5, 1.1 Hz, 2H).[10]

1-Phenyl-1-(1H-tetrazol-5-yl)ethan-1-ol (10f)

10f, white solid (70%), mp 142–146 °C. 1H NMR (400 MHz, MeOD) δ 7.51 (d, J = 7.2 Hz, 2H), 7.33 (t, J = 7.5 Hz, 2H), 7.25 (t, J = 7.3 Hz, 1H), 2.02 (s, 3H, −CH3). 13C NMR (101 MHz, CD3OD) δ 164.03, 145.86, 129.40, 128.72, 125.99, 72.19, 30.08. HR-MS (ESI-TOF) m/z: Calcd for C9H10N4O 189.0776; Found [M – H]− 189.0780.

Diphenyl(1H-tetrazol-5-yl)methanol (10g)

10g, white solid (64%), mp 146–150 °C. 1H NMR (400 MHz, CD3OD) δ 7.43–7.37 (m, 4H), 7.37–7.28 (m, 6H). 13C NMR (101 MHz, CD3OD) δ 163.45, 145.20, 129.15, 129.09, 128.27, 77.81. HR-MS (ESI-TOF) m/z: Calcd for C14H12N4O 251.0933; Found [M – H]− 251.0943.