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DOI: 10.1055/s-0040-1707353
A Catalyst-Free, Temperature-Driven One-Pot Synthesis of 1-Adamantylhydrazine Hydrochloride
The work was supported by the National Institutes of Health (NIH) (NIH/DHHS 1R01Al121364-01A1).
Publication History
Received: 30 June 2020
Accepted after revision: 23 July 2020
Publication Date:
25 August 2020 (online)
Abstract
1-Adamantylhydrazine can be a versatile intermediate for many biologically active compounds as adamantyl possesses a wide spectrum of medicinal properties. Described here is a detailed one-pot synthesis of 1-adamantylhydrazine, carried out on a milligram to gram scale, that steadily delivers a highly stable product used to carry out the synthesis of 1-(adamantan-1-yl)-1H-pyrazol-3-amine for bacterial studies. The reaction employs inexpensive, catalyst free, readily available starting materials. In the synthesis of 1-(adamantan-1-yl)-1H-pyrazol-3-amine, the use of a continuous extraction method allows for complete extraction of the target product into the organic layer and increases the overall percentage yield.
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The polycyclic cage of high symmetry[1] and enhanced lipophilicity[2] of adamantane has been of interest to chemists since its initial discovery in crude oil in 1933. [1] Most importantly, various adamantyl derivatives show a very broad spectrum of medicinal properties such as antiviral,[3] antimicrobial,[4] anticancer,[5] antidiabetic (type 2 diabetes),[6] and many more.[7] Introduction of the adamantyl functionality to medicinal compounds can augment therapeutic effects by increasing the overall effective transportation through biological membranes as a result of enhanced lipophilicity.[8] Adamantyl derivatives are also of importance in material science applications, for instance as calibration for AFM tips.[9] Commonly, adamantane’s tertiary carbon atoms are functionalized via halogenation, which is followed by polar SN1 substitution under electrophilic conditions. Many studies suggest that the positive charge of the 1-adamantyl carbocation can be selectively stabilized with other bridgehead positions by means of second-order hyperconjugations, allowing SN1 substitution.[10] This can be observed in Figure [1a], where an empty ‘p’ orbital of the trivalent carbocation center interacts with the sp3 bridgehead C–H orbitals.[10] Further studies suggested that resonance stabilization, such as in Figure [1b], represents a clear picture of a C–C hyperconjugation effect.[11]


Our laboratory needed an efficient and simple synthetic method for 1-adamantylhydrazine, because it is a mandatory precursor for the synthesis of 1-adamantyl-substituted pyrazolylthioureas with NNSN-motif.[12] This class of novel antibiotics is activated by copper(I) in activated phagosomes[13] and is very effective against Gram-positive bacteria, such as MRSA (methicillin-resistant Staphylococcus aureus).[14] After starting this endeavor, we realized the limited availability of literature describing a feasible methodology. Halogenation of adamantane is typically performed via bromination; however, chlorination and iodation are also possible.[15] [16] Our initial attempts of synthesizing 1-adamantylhydrazine quickly led to the realization that a truly feasible methodology has not been described in the literature prior to this study. Daeniker utilized 1-aminoadamantane as the starting material and performed five subsequent steps via sydnone to obtain 1-adamantylhydrazine.[17] However, this method proved to be lengthy and not (carbon) economic. The highly strained 1,3-dehydroadamantane may undergo SN1 type reactions to highly functionalized adamantane derivatives. In this particular study (Scheme [1]), 1,3-dehydroadamantane (1) was reacted with an excessive amount (10 equiv) of 2-aminoethan-1-ol (2a) and 3-aminopropan-1-ol (2b) at 60–70 °C for 1 hour to obtain O- and N-alkylation products 3a, 3b, 4a, and 4b.[18] Unfortunately, 1,3-dehydroadamantane is expensive and not readily available for purchase.


In 1968, the synthesis of 1-adamantylhydrazine and its derivatives was patented by Thomas and Shetty; the authors reacted a halogenated adamantane with anhydrous hydrazine under a continuously supplied inert atmosphere and sustained heating.[19] An important drawback of this patent is that the compounds were identified by means of their melting points only. When we reproduced the original procedure, drawbacks were encountered such as the necessity of using anhydrous hydrogen chloride and inefficient drying methods. Most importantly, we always obtained mixtures of the target compounds and multiple byproducts.
Here we report modifications of the original synthetic procedures by Thomas and Shetty, which were designed to obtain a significantly higher yield of 1-adamantylhydrazine (Scheme [2]), which was used to subsequently synthesize the target 1-(1-adamantyl)pyrazol-3-amine as shown in Scheme [3].




1-Bromoadamantane (purity 99%) and hydrazine monohydrate (purity 98%) were purchased from Alfa Aesar. 2-Chloroacrylonitrile (99%, stabilized) was purchased from Acros Organics. Diethyl ether 99%, ethyl acetate (Certified ACS), potassium carbonate (anhydrous) 99%, sodium bicarbonate (Powder/Certified ACS), and hydrochloric acid (12.1 N, certified ACS Plus) were purchased from Fisher Scientific International, Inc., and used as received without further purifications. In-house distilled water was used as the solvent for the pyrazole cyclization reaction. 1H (400, 600 MHz) and 13C (100, 151 MHz) spectra were obtained by using Bruker-Ascend NMR spectrometers. Mass spectra were obtained on a Waters Acquity UPLC TQD spectrometer. The UPLC column was CORTECS C18, 90 Å, 2.7 μm reversed phase. Melting points were acquired by using a Mel-Temp 1001D instrument.
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1-Adamantylhydrazine hydrochloride
[CAS Reg. No. 16782-39-1]
Since 1-bromoadamantane is moisture-sensitive, light-sensitive, and air-sensitive, it was flushed with argon gas before measuring and then added to a reaction vessel. If the reaction continues for a prolonged period, it is necessary to cover the reaction vessel with a light-blocking material such as aluminum foil. Ivory-colored (literature states white to yellow[19]) 1-bromoadamantane (5 g, 23.24 mmol) was weighed on weighing paper and transferred to a 500 mL, one-necked, round-bottom flask with a magnetic stirring bar by using a powder funnel. Then the round-bottom flask was charged with an excess amount of hydrazine monohydrate (50 mL, 51.6 g, 1.03 mol), which acted as the solvent and reactant. 1-Bromoadamantane did not dissolve in hydrazine at this point (Figure [2a]) and a dispersion occurred in the reaction vessel. It is noteworthy that vigorous stirring was not required as it pushed the solid 1-bromoadamantane above the solvent level. Therefore, moderate stirring was crucial to keep all the solids within the solvent. The round-bottom flask was connected to a coiled reflux condenser which was connected to continuous water flow. A mineral oil bath was utilized to reflux the reaction mixture at 125–135 °C. Inside the reaction vessel, the temperature was set to 110 °C. The reflux temperature was crucial, because if the reaction mixture refluxed below 100 °C, it delivered both the product and unreacted 1-bromoadamantyl. The mixture was kept at that temperature for 8–12 hours. During reflux, 1-bromoadamantane completely dissolved in hydrazine monohydrate and the reaction mixture eventually consisted of a very clear light-yellow colored solution, as shown in Figure [2b]. TLC was performed (EtOAc/hexane 1:1). Spots were visualized with phosphomolybdic acid (PMA), as 1-bromoadamantane is not visible under the short wavelength of UV. The starting material 1-bromoadamantane created a dark spot on the light green background (Rf = 0.90), whereas the product spot was not significantly visible as a dark spot, which indirectly confirmed the formation of at least one new product.


The reaction mixture was cooled to room temperature, followed by the addition of 45% (w/w) aq KOH solution (50 mL). When the mixture cooled, the clear solution turned cloudy due to the adamantyl product featuring low solubility in hydrazine monohydrate. Further addition of 45% (w/w) aq KOH solution (125 mL) facilitated the separation of excessive hydrazine from the crude 1-adamantylhydrazine.[19] At this point, the previously cloudy reaction mixture turned into an opaque dispersion. It was transferred to a separatory funnel and extracted with Et2O (3 × 50 mL). Due to the hydrophobic adamantyl moiety, the product could be found in the organic layer (Et2O). The organic layer was dried over anhydrous sodium sulfate. Note that the original literature stated using anhydrous magnesium sulfate.[19] Upon the addition of anhydrous sodium sulfate, the product solution turned clear. The product solution was then concentrated under vacuum to approximately a quarter of the solvent volume. Then the concentrated reaction mixture was charged with concentrated hydrochloric acid (3–5 mL), lowering the pH to 2.0, to obtain the 1-adamantylhydrazine chloride salt, which is more stable than 1-adamantylhydrazine. Upon the addition of hydrochloric acid, a white solid product crashed out of the Et2O solution, as shown in Figure [3a]. The solid product was isolated via gravity-driven filtration and dried under high vacuum (Figure [3b]). Original literature stated to conduct recrystallization of this white solid using 2-propanol. Although this purification step was reproduced, it led to considerable loss of product due to solubility of the reaction product in 2-propanol.[19] Without recrystallization, the yield was >88% (4.13 g) of 1-adamantylhydrazine hydrochloride. After recrystallization, it was diminished to ~53%. It should be noted that the reaction product was pure according to NMR and TLC characterization before and after recrystallization from 2-propanol.


NMR samples were prepared for 1-adamantylhydrazine hydrochloride in DMSO-d 6. The product was also analyzed by means of UPLC-MS, which clearly indicated the presence of 1-adamantylhydrazine with a molecular peak of 166.14 mass units. The melting point observed (216–220 °C) did not fit with the literature value (250–253 °C[19]). However, as stated above, the original literature only utilized melting point analysis for product characterization.[19]
Mp 216–220 °C.
IR: 2891 (w,s), 2709 (w,s), 2549 (m,b), 1480 (m,s), 1085 (m,s) cm–1.
1H NMR (400 MHz, DMSO-d 6): δ = 2.11 (s, 3 H), 1.78 (s, 6 H), 1.59 (m, 6 H).
13C NMR (101 MHz, DMSO-d 6): δ = 45.72, 37.05, 35.88, 30.50, 28.65.
MS: m/z = 167.15 [M + 1].
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1-(Adamantan-1-yl)-1H-pyrazol-3-amine (Scheme [3])
[CAS Reg. No. 128315-61-7]
A previously published protocol was used for the synthesis of the desired adamantyl-substituted heterocyclic product with slight modifications to the workup process.[20] 2-Chloroacrylonitrile (202.4 mg, 2.31 mmol) was measured into a 150 mL round-bottom flask and dispersed with distilled water (5 mL). Separately, K2CO3 (168 mg, 1.21 mmol) and NaHCO3 (204 mg, 2.48 mmol) were dissolved in distilled water (5–7 mL) and mixed, followed by the addition to the 2-chloroacrylonitrile solution. Then 1-adamantylhydrazine hydrochloride salt (2.31 mmol, 466.0 mg) was dissolved in distilled water (15 mL) and transferred to the original mixture, which was stirred continuously overnight. According to the original protocol, the product was meant to be extracted with EtOAc (3×). However, from previous experience, it was both convenient and effective to perform a continuous extraction (Figure [4]) to collect the desired product from the aqueous layer, as pyrazole derivatives tend to show considerable hydrophilic behavior. Finally, the organic layer was dried under vacuum and purified via flash column chromatography (EtOAc/hexane 5:95 to 25:75); this gave a thick dark orange oil-like liquid.
Yield: 216 mg (43%).
IR: 3318.16 (w,b), 2904 (m, s), 2849 (m,s), 1683 (w,s), 1542 (w.s), 743 (m,s) cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.47 (d, J = 14.3 Hz, 1 H), 6.36 (d, J = 14.3 Hz, 1 H), 6.06 (s, 1 H), 2.23 (m, 3 H), 1.77 (m, 6 H), 1.28 (s, 6 H).
13C NMR (101 MHz, CDCl3): δ = 160.39, 146.58, 106.20, 42.73, 40.20, 36.32, 29.55.


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Supporting Information
- Supporting Information for this article is available online at https://doi-org.accesdistant.sorbonne-universite.fr/10.1055/s-0040-1707353.
- Supporting Information
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References
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- 2 Stella V, Borchardt R, Hageman M, Oliyai R, Maag H, Tilley J. Prodrugs: Challenges and Rewards, Part 1. Springer; New York: 2007
- 3 Davies WL, Grunert RR, Haff RF, McGahen JW, Neumayer EM, Paulshock M, Watts JC, Wood TR, Hermann EC, Hoffmann CE. Science 1964; 144: 862
- 4 Khaziev R, Shtyrlin N, Pavelyev R, Nigmatullin R, Gabbasova R, Grishaev D, Shtro A, Galochkina A, Nikolaeva Y, Vinogradova T, Manicheva O, Dogonadze M, Gnezdilov O, Sokolovich E, Yablonskiy P, Balakin K, Shtyrlin Y. Lett. Drug Des. Discov. 2019; 1360
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- 8 Shvekhgeimer M.-GA. Russ. Chem. Rev. 1996; 65: 555
- 9 Li Q, Jin C, Petukhov PA, Rukavishnikov AV, Zaikova TO, Phadke A, LaMunyon DH, Lee MD, Keana JF. W. J. Org. Chem. 2004; 69: 1010
- 10 Olah GA, Surya Prakash GK, Shih JG, Krishnamurthy VV, Mateescu GD, Liang G, Sipos G, Buss V, Gund TM, Ragué Schleyer PV. J. Am. Chem. Soc. 1985; 107: 2764
- 11 Sunko D, Hiršl-Starčević S, Pollack S, Hehre W. J. Am. Chem. Soc. 1979; 101: 6163
- 12 Haeili M, Moore C, Davis CJ. C, Cochran JB, Shah S, Shrestha TB, Zhang Y, Bossmann SH, Benjamin WH, Kutsch O, Wolschendorf F. Antimicrob. Agents Chemother. 2014; 58: 3727
- 13 Wolschendorf F, Ackart D, Shrestha TB, Hascall-Dove L, Nolan S, Lamichhane G, Wang Y, Bossmann SH, Basaraba RJ, Niederweis M. Proc. Natl. Acad. Sci. U. S. A. 2011; 108: 1621
- 14 Dalecki AG, Malalasekera AP, Schaaf K, Kutsch O, Bossmann SH, Wolschendorf F. Metallomics 2016; 8: 412
- 15 Wanka L, Iqbal K, Schreiner PR. Chem. Rev. 2013; 113: 3516
- 16 Ohno M, Ishizaki K, Eguchi S. J. Org. Chem. 1988; 53: 1285
- 17 Daeniker HU. Helv. Chim. Acta 1967; 50: 2008
- 18 Butov GM, Mokhov VM. Russ. J. Org. Chem. 2018; 54: 1760
- 19
Thomas T,
Shetty B.
(Pennwalt Corporation, Philadelphia, PA, USA) US3719710A, 1973
- 20 Ji N, Meredith E, Liu D, Adams CM, Artman GD, Jendza KC, Ma F, Mainolfi N, Powers JJ, Zhang C. Tetrahedron Lett. 2010; 51: 6799
-
References
- 1 Fort RC. Adamantane: The Chemistry of Diamond Molecules. In Studies in Organic Chemistry, Vol. 5. Marcel Dekker; New York: 1976
- 2 Stella V, Borchardt R, Hageman M, Oliyai R, Maag H, Tilley J. Prodrugs: Challenges and Rewards, Part 1. Springer; New York: 2007
- 3 Davies WL, Grunert RR, Haff RF, McGahen JW, Neumayer EM, Paulshock M, Watts JC, Wood TR, Hermann EC, Hoffmann CE. Science 1964; 144: 862
- 4 Khaziev R, Shtyrlin N, Pavelyev R, Nigmatullin R, Gabbasova R, Grishaev D, Shtro A, Galochkina A, Nikolaeva Y, Vinogradova T, Manicheva O, Dogonadze M, Gnezdilov O, Sokolovich E, Yablonskiy P, Balakin K, Shtyrlin Y. Lett. Drug Des. Discov. 2019; 1360
- 5 Kukushkin ME, Skvortsov DA, Kalinina MA, Tafeenko VA, Burmistrov VV, Butov GM, Zyk NV, Majouga AG, Beloglazkina EK. Beilstein Arch. 2019; 2019143
- 6 Augeri DJ, Robl JA, Betebenner DA, Magnin DR, Khanna A, Robertson JG, Wang A, Simpkins LM, Taunk P, Huang Q, Han S.-P, Abboa-Offei B, Cap M, Xin L, Tao L, Tozzo E, Welzel GE, Egan DM, Marcinkeviciene J, Chang SY, Biller SA, Kirby MS, Parker RA, Hamann LG. J. Med. Chem. 2005; 48: 5025
- 7 Lamoureux G, Artavia G. Curr. Med. Chem. 2010; 17: 2967
- 8 Shvekhgeimer M.-GA. Russ. Chem. Rev. 1996; 65: 555
- 9 Li Q, Jin C, Petukhov PA, Rukavishnikov AV, Zaikova TO, Phadke A, LaMunyon DH, Lee MD, Keana JF. W. J. Org. Chem. 2004; 69: 1010
- 10 Olah GA, Surya Prakash GK, Shih JG, Krishnamurthy VV, Mateescu GD, Liang G, Sipos G, Buss V, Gund TM, Ragué Schleyer PV. J. Am. Chem. Soc. 1985; 107: 2764
- 11 Sunko D, Hiršl-Starčević S, Pollack S, Hehre W. J. Am. Chem. Soc. 1979; 101: 6163
- 12 Haeili M, Moore C, Davis CJ. C, Cochran JB, Shah S, Shrestha TB, Zhang Y, Bossmann SH, Benjamin WH, Kutsch O, Wolschendorf F. Antimicrob. Agents Chemother. 2014; 58: 3727
- 13 Wolschendorf F, Ackart D, Shrestha TB, Hascall-Dove L, Nolan S, Lamichhane G, Wang Y, Bossmann SH, Basaraba RJ, Niederweis M. Proc. Natl. Acad. Sci. U. S. A. 2011; 108: 1621
- 14 Dalecki AG, Malalasekera AP, Schaaf K, Kutsch O, Bossmann SH, Wolschendorf F. Metallomics 2016; 8: 412
- 15 Wanka L, Iqbal K, Schreiner PR. Chem. Rev. 2013; 113: 3516
- 16 Ohno M, Ishizaki K, Eguchi S. J. Org. Chem. 1988; 53: 1285
- 17 Daeniker HU. Helv. Chim. Acta 1967; 50: 2008
- 18 Butov GM, Mokhov VM. Russ. J. Org. Chem. 2018; 54: 1760
- 19
Thomas T,
Shetty B.
(Pennwalt Corporation, Philadelphia, PA, USA) US3719710A, 1973
- 20 Ji N, Meredith E, Liu D, Adams CM, Artman GD, Jendza KC, Ma F, Mainolfi N, Powers JJ, Zhang C. Tetrahedron Lett. 2010; 51: 6799













