ISSN 1070-4280, Russian Journal of Organic Chemistry, 2015, Vol. 51, No. 1, pp. 22–25. © Pleiades Publishing, Ltd., 2015. Original Russian Text © R.I. Khusnutdinov, N.A. Shchadneva, L.F. Khisamova, U.M. Dzhemilev, 2015, published in Zhurnal Organicheskoi Khimii, 2015, Vol. 51, No. 1, pp. 29–32.
Synthesis of 3-(1-Aminoethyl)adamantan-1-ol by Hydroxylation of 1-(1-Adamantyl)ethanamine Hydrochloride (Rimantadine) R. I. Khusnutdinov, N. A. Shchadneva, L. F. Khisamova, and U. M. Dzhemilev Institute of Petrochemistry and Catalysis, Russian Academy of Sciences, pr. Oktyabrya 141, Ufa, 450075 Bashkortostan, Russia e-mail:
[email protected] Received December 13, 2013
Abstract—A procedure has been developed for the selective synthesis of 3-(1-aminoethyl)adamantan-1-ol by hydroxylation of 1-(1-adamantyl)ethanamine hydrochloride with the system H2O–CBrCl3 in the presence of W(CO)6 activated by pyridine.
DOI: 10.1134/S1070428015010042 Adamantane derivatives exhibit a broad spectrum of biological activity. The antiviral drug rimantadine [1, 1-(1-adamantyl)ethanamine hydrochloride] is used for the prophylactics and early treatment of influenza [1]. It was found that the presence of a hydroxy group in the adamantane core reduces the toxicity and extends the spectrum of antiviral activity [2, 3]. This tendency is well seen with 3-(1-aminoethyl)adamantan-1-ol (2) as an example, which showed a high activity against herpes viruses. Known methods of synthesis of 3-(1-aminoethyl)adamantan-1-ol include several steps [4–7]. One procedure is based on the oxidation of 1 with a mixture of nitric and sulfuric acids [7], which makes isolation of the target product difficult. We previously [8, 9] found that the system H2O– CBr 4 (CBrCl 3 , CCl 4 )–Mo(CO) 6 ensures selective hydroxylation of adamantane and its derivatives. In this system, the active oxidizing species is hypobromous (or hypochlorous) acid generated in situ from H2O and CBr4, CBrCl3, or CCl4 in the presence of a catalyst. In the present work we continued search for efficient catalysts among Group V–VIII transition metal compounds, which could favor at low concentration
(1–3 mol %) selective oxidation of 1-(1-adamantyl)ethanamine hydrochloride (1) to 3-(1-aminoethyl)adamantan-1-ol (2). Among the examined Ni, Mn, Cu, Pd, Fe, Cr, Co, Mo, and W salts and complexes, tungsten hexacarbonyl W(CO)6 activated by pyridine showed an appreciable catalytic activity in the oxidation of 1 with H2O–CBrCl3 (Scheme 1, Table 1). In this case, the hydroxylation of 1-(1-adamantyl)ethanamine hydrochloride (1) smoothly afforded the desired product, whereas the free base, 1-(1-adamantyl)ethanamine (3) reacted with CBrCl3 and water to produce 1-(3-hydroxyadamantan-1-yl)ethanone (4) (Scheme 2). When CBrCl3 was replaced by CBr4, the reaction direction changed toward the formation of 1-(3-bromoadamantan-1-yl)ethanamine (5). The oxidation of 1 in the presence of W(CO)6 at 130–140°C in 3 h afforded 85–86% of 3-(1-aminoethyl)adamantan-1-ol hydrochloride (2), the conversion of 1 being 90–95%. 1-(3-Bromoadamantan-1-yl)ethanamine (5) formed as by-product was separated from compounds 1 and 2 by column chromatography on silica gel using hexane–methylene chloride (2 : 1) as eluent. The molar ratio W(CO) 6 –AdCH(NH 2 )CH 3– BrCCl3–H2O was (3–5) : 100 : 500 : 4000.
Scheme 1. Me
+
CBrCl3 +
W(CO)6, pyridine 140°C, 3 h
H 2O
Me HO
NH2 · HCl 1
NH2 · HCl 2
22
SYNTHESIS OF 3-(1-AMINOETHYL)ADAMANTAN-1-OL
23
Table 1. Oxidation of 1-(1-adamantyl)ethanamine hydrochloride (1) with halomethane–H2O in the presence of different catalysts
Catalyst
Yield, %
Molar ratio catalyst– Temperature, Reaction Conversion Halomethane °C time, h of 1, % 1–halomethane–H2O
2
5
di- and tribromo derivatives
No catalyst
CBrCl3
0 : 100 : 500 : 4000
160
6
020
06
10
04
Ni(acac)2
CBrCl3
1 : 100 : 500 : 4000
160
6
048
16
04
28
Mn(acac)3
CBrCl3
3 : 100 : 500 : 4000
160
6
100
25
11
64
Cu(acac)2
CBrCl3
3 : 100 : 500 : 4000
160
6
048
20
13
15
Pd(acac)2
CBrCl3
3 : 100 : 300 : 4000
160
6
068
28
12
28
Fe(acac)3
CBrCl3
3 : 100 : 100 : 4000
160
6
066
22
08
36
CuBr2
CBrCl3
3 : 100 : 100 : 4000
160
6
078
16
56
06
CoCl2
CBrCl3
3 : 100 : 100 : 4000
140
3
057
20
13
24
CoCl2
CBrCl3
3 : 100 : 100 : 4000
160
5
060
31
17
12
Mo(CO)6
CBrCl3
3 : 100 : 100 : 4000
160
6
081
50
09
22
Mo(CO)6
CBrCl3
3 : 100 : 300 : 4000
140
5
084
76
–
08
Mo(CO)6
CBrCl3
3 : 100 : 500 : 4000
140
5
094
65
8
21
Mo(CO)6–Py
CBrCl3
3 : 100 : 500 : 4000
140
5
100
85
10
05
W(CO)6
CBrCl3
3 : 100 : 100 : 4000
130
6
095
73
12
08
W(CO)6
CBr4
3 : 100 : 100 : 4000
130
3
088
34
26
28
W(CO)6 –Py
CBrCl3
3 : 100 : 500 : 4000
140
3
091
86
05
–
Mn2(CO)10
CBrCl3
3 : 100 : 500 : 4000
140
3
089
54
10
25
Co2(CO)8
CBrCl3
3 : 100 : 500 : 4000
140
3
089
41
12
36
Fe2(CO)9
CBrCl3
3 : 100 : 500 : 4000
140
3
082
60
11
11
Cr(CO)6
CBrCl3
3 : 100 : 500 : 4000
140
3
084
51
16
17
In order to improve the yield of 2 and reaction selectivity we examined the effect of the nature of activating ligands on the reaction course (Table 2). In all cases, pyridine turned out to be the most efficient ligand; in the presence of pyridine, the yield of bromo derivative 5 was minimal (5%). The optimal pyridine–W(CO)6 ratio was estimated at 1 : 1. Increase of the pyridine concentration did not affect the selectivity and the yield of 2, but the isolation procedure was complicated due to poor layer separation, which resulted in reduced yield.
It should be noted that addition of activating ligands favored reduction of the reaction temperature, so that the reactions can be performed in an open system, at 80–85°C (7 h) at a W(CO)6–Py–1–CBrCl3– H2O molar ratio of 3 : 3 : 100 : 1000 : 16000. According to the GLC data, under these conditions the major product was 3-(1-aminoethyl)adamantan-1-ol hydrochloride (2) whose yield was 57% at a conversion of 1 of 74–75%. The by-products (~18–20%) were di- and tribromo(chloro) derivatives of 1, as well as dihydroxy derivatives which were identified by GC/MS.
Scheme 2. Me
+
CBrCl3 +
H 2O
W(CO)6, pyridine 140°C, 3 h
NH2 3
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 51 No. 1 2015
Me HO
O 4
KHUSNUTDINOV et al.
24
Table 2. Oxidation of 1-(1-adamantyl)ethanamine hydrochloride (1) with CBrCl3–H2O in the presence of W(CO)6 and different ligands L [W(CO)6–L–1–CBrCl3–H2O 3 : 3 : 100 : 500 : 4000] Yield, %
Ligand L
Temperature, °C
Reaction time, h
Conversion of 1, %
2
5
di- and tribromo derivatives
N-Hydroxyphthalimide
125
6
95
53
12
30
3-Methylpyridine
140
3
84
50
18
16
4-Methylpyridine
140
3
82
60
12
10
Morpholine
140
2
74
42
10
22
N,N-Dimethylacetamide
140
2
90
53
15
22
Pyridine
130
6
90
78
12
–
Pyridine
140
3
91
86
05
–
Acetonitrile
140
3
90
72
15
03
Triethylamine
140
3
51
45
06
–
Diethylamine
140
3
57
52
07
–
Triphenylphosphine
140
3
65
38
05
14
Triphenyl phosphite
140
3
54
25
09
20
Thus, tungsten hexacarbonyl activated by pyridine is an efficient catalyst for the selective synthesis of 3-(1-aminoethyl)adamantan-1-ol hydrochloride (2) by hydroxylation of 1-(1-adamantyl)ethanamine hydrochloride (1) with the system H2O–CBrCl3. EXPERIMENTAL The IR spectra were recorded in KBr or mineral oil on a Bruker Vertex 79V spectrometer. The 1H and 13 C NMR spectra were measured on a Bruker Avance400 spectrometer at 400.13 and 100.62 MHz, respecttively, using CDCl3 as solvent and tetramethylsilane as reference. The mass spectra were obtained on a Shimadzu GCMS-QP2010Plus instrument (SPB-5 capillary column, 30 m × 0.25 mm; carrier gas helium; oven temperature programming from 40 to 300°C at a rate of 8 deg/min; injector temperature 280°C; ion source temperature 200°C; electron impact, 70 eV). The elemental compositions were determined on a Carlo Erba 1106 analyzer. The progress of reactions was monitored, the purity of the isolated compounds was checked, and the product composition was determined, by GLC on a Khrom-5 chromatograph (1.2 m × 3-mm column packed with 5% of SE-30 on Chromaton N-AW-HMDS; oven temperature programming from 50 to 280°C at a rate of 8 deg/min; carrier gas helium); adamantan-1-ol was used as internal stan-
dard; the calibration factor for 3-(1-aminoethyl)adamantan-1-ol (2) was 3.92. The reagents used had a purity of no less than 99%. 1-(1-Adamantyl)ethanamine hydrochloride (1), bromotrichloromethane, and W(CO)6 were commercial products (from Acros Organics). Commercial N-hydroxylphthalimide, 3-methylpyridine, 4-methylpyridine, morpholine, N,N-dimethylacetamide, pyridine, acetonitrile, triethylamine, diethylamine, triphenylphosphine, and triphenyl phosphite were preliminarily purified by distillation or recrystallization according to the procedures described in [10]. The reactions were carried out in a 20-mL glass ampule or a 17-mL stainless-steel high-pressure micro reactor which was charged under argon with 0.3 mmol of W(CO)6, 10 mmol of 1-(1-adamantyl)ethanamine hydrochloride (1), 50 mmol of bromotrichloromethane, and 550 mmol of water. The reactor was hermetically closed (the ampule was sealed) and heated for 3 h at 140°C under stirring. When the reaction was complete, the reactor (ampule) was cooled to room temperature, and the mixture was dissolved in hexane and washed with methylene chloride where the major product is soluble. 3-(1-Aminoethyl)adamantan-1-ol hydrochloride (2). Yield 86%, mp 323–324°C. IR spectrum: ν 2500–3500 cm–1 (NH, OH). 1H NMR spectrum, δ, ppm: 1.57 m (2H, 2-H), 1.51 m (6H, 6-H, 8-H, 9-H),
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 51 No. 1 2015
SYNTHESIS OF 3-(1-AMINOETHYL)ADAMANTAN-1-OL
2.27 m (2H, 5-H, 7-H), 1.61–1.76 m (4H, 8-H, 10-H), 1.24 (2H, 4-H, 10-H), 1.24 d (3H, CH3, J = 6.8 Hz), 3.09 q (1H, CH, J = 6.8 Hz), 7.20 s (3H, NH 3+ ). 13 C NMR spectrum (free base, mp 110–112°C), δ C, ppm: 16.56 (CH3), 28.32 (C5, C7), 35.61 (C6), 36.69 (C4), 36.88 (C9), 44.80 (C8, C10), 45.74 (C3), 55.54 (CHNH2), 66.42 (C1). 1-(3-Hydroxyadamantan-1-yl)ethanone (4). Yield 78%, mp 86–87°C (from hexane); published data [6]: mp 89–91°C (from EtOAc–hexane). IR spectrum, ν, cm–1: 3395 (OH), 1680 (C=O). 13C NMR spectrum, δC, ppm: 24.59 (CH3), 30.16 (C5, C7), 35.02 (C6), 37.03 (C8, C10), 44.23 (C4, C9), 45.63 (C2), 49.90 (C1), 68.29 (C3), 212.74 (C=O). Mass spectrum, m/z (Irel, %): 194 (7) [M]+, 152 (9), 151 (100), 133 (7), 109 (7), 107 (19), 95 (36), 93 (48), 91 (7), 81 (11), 79 (8), 77 (9), 67 (11), 65 (7), 59 (9), 55 (9), 43 (38), 41 (12), 39 (9), 29 (7). Found, %: C 74.05; H 9.29. C12H18O2. Calculated, %: C 74.19; H 9.34. M 194.270 1-(3-Bromoadamantan-1-yl)ethanamine (5). Yield 64%. 13C NMR spectrum, δC, ppm: 17.44 (CH3), 32.36 (C3, C8), 32.6 (C5), 34.95 (C10), 39.3 (C4), 48.85 (C2, C7), 49.77 (C6), 52.97 (C11), 61.05 (C1). Found, %: C 55.52; H 8.08; N 5.17. C12H21BrN. Calculated, %: C 73.48; H 10.71; N 6.95. This study was performed under financial support by the President of the Russian Federation (program for support of young scientists and post-graduate students engaged in advanced research and developments in the priority fields of modernization of the Russian economics for 2013–2015, project no. SP-4810.2013.4).
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