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Synthesis 2009(6): 909-912  
DOI: 10.1055/s-0028-1087979
PAPER
© Georg Thieme Verlag Stuttgart ˙ New York

Synthetic Routes to Aminotriamantanes, Topological Analogues of the Neuroprotector Memantine®

Andrey A. Fokin*a,b, Anika Merzb, Natalie A. Fokinab, Hartmut Schwertfegerb, Shenggao L. Liuc, Jeremy E. P. Dahlc, Robert K. M. Carlsonc, Peter R. Schreiner*b
a Department of Organic Chemistry, Kiev Polytechnic Institute, pr. Pobedy 37, 03056 Kiev, Ukraine
b Institute of Organic Chemistry, Justus-Liebig University, Heinrich-Buff-Ring 58, 35392 Giessen, Germany
c MolecularDiamond Technologies, Chevron Technology Ventures, 100 Chevron Way, Richmond, CA 94802, USA
Fax: +49(641)9934309; e-Mail: aaf@xtf.ntu-kpi.kiev.ua; e-Mail: prs@org.chemie.uni-giessen.de;

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Publication History

Received 22 September 2008
Publication Date:
02 March 2009 (online)

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Abstract

The amino derivatives of diamantane and triamantane, representing close topological analogues of the neuroprotective drug Memantine®, were prepared via amination of the respective carboxylic acids or alcohols.

Key words

amines - diols - drugs - hydrocarbons - medicinal chemistry

Adamantane amino derivatives play an outstanding role in the treatment of influenza and a wide spectrum of diseases of the central nervous system. However, many recent studies have shown an increase in resistance of common viruses toward adamantane-containing drugs such as amantadine and rimantadine. [²] These findings have prompted a number of studies on the preparation of the amino derivatives of other cage compounds. [³] [4]

Fortunately, Memantine” [1-amino-3,5-dimethyladamantane; 1] is still the most effective drug for combating Alzheimer’s disease and it was recently considered to be the ‘new hope’ in the development of N-methyl-d-aspartate-receptor antagonists. [5] Memantine” also shows pronounced antiparkinsonian activity. The key mechanistic feature in the mechanism of action involves blocking of the NMDA-receptor channel, where 1 displays a moderate binding affinity due to its size and hydrophobicity. [5] Further development of this class of neuroprotectors should build on these two key features of the Memantine” molecule­.

A number of higher adamantane analogues, i.e., diamondoids (nanodiamonds), were recently isolated from crude oil, [6] and triamantane, [121]-, [1(2)3]-, [123]tetramantanes, [1(2,3)4]pentamantane and [12312]hexamantane (cyclohexamantane), are now available in preparative quantities. [7] [8] Recently, we developed a variety of methods for the selective preparation of functional derivatives of these hydrocarbons involving selective C-H substitutions as well as functional group exchanges. [¹] [9-¹5] The diamondoid derivatives have already shown some remarkable properties such as negative electron affinity and highly effective self-assembly. [¹6] [¹7]

Herein, we report the preparation of hitherto unknown amino triamantanes that are geometrically and electronically related to Memantine”    allowing variations in the topological and spatial characteristics of these potential neurodrugs. The computed geometries of 1, as well as 2-amino- (2), 3-amino- (3), 4-amino-(4) and 9-amino tri­amantane (5), show that all these molecules have a common maximum dimension of around 5.6 Å (Figure  [¹] ). For comparison, we also prepared 1- and 4-amino diamantane (6 and 7, vide infra) as higher homologues of amantadine (1-amino adamantane), as well as diamantane diamines (8 and 9). [¹8] [¹9] [²³]

Figure 1 The key spatial dimensions of Memantine”    (1), 2-amino- (2), 3-amino- (3), 4-amino- (4), and 9-amino triamantane (5) computed at the B3LYP/6-31+G(d) level of theory

For the preparation of the amino derivatives we utilized two alternative procedures shown in Scheme  [¹] : (a) the reaction of the respective carboxylic acids with diphenylphosphoryl azide [²0] followed by hydrolysis (method A) and (b) acid-catalyzed exchange of the hydroxyl group of the respective diamondoid alcohol with chloroacetonitrile followed by cleavage of the chloroacetamide thus formed [²¹] (method B).

Scheme 1 The two alternative approaches used for the preparation of diamondoid amino derivatives

As starting compounds for method A we used the diamondoid carboxylic acids prepared as described previously through the carboxylation of the respective diamondoid derivatives. [²²] Method B, applied to the readily available alcohols, [¹²] gave mono- (6 and 7) as well as diamines (8 and 9) [²³] [¹8] in high preparative yields with complete conservation of the substitution pattern (Figure  [²] ). The X-ray crystal structures of intermediate chloroacetamides 14 and 16 are shown in Figure  [³] . These routes offer a convenient alternative to the existing synthetic approach to amino diamantanes based on the reaction of the respective bromo-derivatives with nitrogen trichloride [²4] or through the Ritter reaction, which gives hydrolytically stable acet­amides. [²5] It is also safer and operationally superior to the method of Davis and Nissan (starting from the bromides utilizing a large excess of TMSN3 and SnCl2) because it does not involve potentially hazardous (and expensive) chemicals. [²6]

Figure 2 The structures and preparative yields of compounds 2-17

Figure 3 The X-ray crystal structures and crystal packing of chloro­acetamides 14 and 16 [²7]

As we described previously, [¹²] all possible tertiary hydroxy derivatives form through the nitroxylation/hydrolysis of triamantane. Method B gave the 2-, 3-, 4-, and 9- amino triamantanes (2-5) via the cleavage of the respective chloroacetamides (11-13) in high preparative yields (Figure  [²] ). The only exception is the most sterically hindered acetamide 10, which gave amine 2 in very low yield.

In summary, we have obtained a number of diamondoid amines in good yields from their respective acids and alcohols. Testing of the neurophysiological activities of these structural analogues of Memantine”   is currently underway­.

NMR: Bruker Avance II spectrometers operating at 400.130 and 200.13 MHz (¹H NMR) and 100.613 and 50.32 MHz (¹³C NMR) and an Avance II spectrometer at 600.130 MHz (¹H NMR) and 150.903 MHz (¹³C NMR); internal standard = Me4Si. GC-MS: HP5890 GC instrument with an H5971A mass-selective detector; HP GC-MS capillary column 50 m 0.2 mm, Ultra 1, silicone, 80-205 ˚C. All compounds showed adequate IR and DEPT ¹³C NMR spectra.

Method A; General Procedure

A mixture of the chosen diamondoid carboxylic acid (1 mmol), Et3N (0.14 mL, 1 mmol) and diphenylphosphoryl azide (275 mg, 1 mmol; Acros) and t-BuOH (2 mL) was stirred for 12 h, quenched with aq NaHCO3, extracted with CHCl3, and dried over Na2SO4. The residue after evaporation was dissolved in MeOH and stored in a flow of anhydrous HCl. Evaporation of MeOH, washing of the resulting hydrochloride with Et2O, neutralization with 10% NaOH, extraction with Et2O, and drying over Na2SO4, gave the pure amines 6 and 7, whose spectral data were identical to those of standard samples. [²²] [²4]

Method B; General Procedure

A solution of the respective diamondoid alcohol (1 mmol) in a mixture of AcOH (1.7 mL, 30 mmol), ClCH2CN (0.4 mL, 6.3 mmol) and concd H2SO4 (0.5 mL, 9.4 mmol) was stirred at r.t. for 20 h. The reaction mixture was poured onto ice and extracted with CHCl3. Evaporation of the extracts gave the chloroacetamide, which was dissolved in a mixture of EtOH (0.8 mL, 13.7 mmol), thiourea (20 mg, 0.26 mmol) and AcOH (0.3 mL, 5.2 mmol) and heated at 95 ˚C for 20 h. The mixture was neutralized with 10% NaOH, extracted with CHCl3, and dried over Na2SO4. Evaporation gave amines 2-5, which were purified through their hydrochlorides as described in Method A.

2-Aminotriamantane (2)

Colorless solid; mp 236-239 ˚C.

¹H NMR (400 MHz, CD3OD): δ = 2.15-2.10 (m, 2 H), 1.90-1.87 (m, 2 H), 1.86-1.81 (m, 2 H), 1.81-1.71 (m, 7 H), 1.70-1.64 (m, 4 H), 1.56-1.51 (m, 4 H), 1.08-1.04 (m, 2 H).

¹³C NMR (100 MHz, CD3OD): δ = 56.0 (C), 50.5 (CH), 44.2 (CH), 40.1 (CH2), 39.9 (CH), 39.8 (CH), 39.6 (CH2), 39.3 (CH2), 38.2 (C), 33.5 (CH2), 28.9 (CH).

MS (EI): m/z (%) = 255, 239, 238 (100), 197, 167, 129, 128.

HRMS: m/z calcd for C18H25N: 255.1987; found: 255.1968.

3-Aminotriamantane (3)

Colorless solid; mp 206-210 ˚C.

¹H NMR (400 MHz, CDCl3): δ = 2.06-1.93 (m, 3 H), 1.85-1.78 (m, 1 H), 1.77-1.70 (m, 2 H), 1.68-1.50 (m, 9 H), 1.47-1.30 (m, 6 H), 1.28-1.15 (m, 4 H).

¹³C NMR (100 MHz, CDCl3): δ = 52.8 (CH), 51.1 (C), 46.7 (CH2), 46.1 (CH), 45.1 (CH2), 44.7 (CH2), 41.5 (CH), 39.1 (CH), 37.9 (CH2), 37.7 (CH2), 37.6 (CH2), 37.5 (CH), 34.9 (C), 34.8 (CH), 33.2 (CH2), 32.1 (CH), 29.7 (CH), 27.6 (CH).

MS (EI): m/z (%) = 255, 239, 238 (100), 167, 128.

HRMS: m/z calcd for C18H25N: 255.1987; found: 255.1992.

4-Aminotriamantane (4)

Colorless solid; mp 207-209 ˚C.

¹H NMR (400 MHz, CDCl3): δ = 2.09-2.01 (m, 2 H), 1.85-1.75 (m, 3 H), 1.72-1.65 (m, 6 H), 1.60-1.55 (m, 2 H), 1.51-1.37 (m, 8 H), 1.31-1.26 (m, 2 H), 1.25-1.21 (m, 2 H).

¹³C NMR (100 MHz, CDCl3): δ = 49.2 (C), 48.4 (CH), 47.1 (CH2), 45.5 (CH2), 44.8 (CH2), 44.1 (CH), 39.3 (CH), 37.9 (CH), 37.5 (CH2), 32.9 (C), 32.7 (CH2), 27.6 (CH), 27.3 (CH).

MS (EI): m/z (%) = 255, 238 (100), 181, 167, 142, 130, 129, 91.

HRMS: m/z calcd for C18H25N: 255.1987; found: 55.1933.

9-Aminotriamantane (5)

Colorless solid; mp 193-194 ˚C.

¹H NMR (400 MHz, CDCl3): δ = 1.83-1.79 (m, 1 H), 1.78-1.74 (m, 2 H), 1.73-1.59 (m, 9 H), 1.58-1.43 (m, 7 H), 1.36-1.31 (m, 2 H), 1.29-1.25 (m, 2 H), 1.14-1.09 (m, 2 H).

¹³C NMR (100 MHz, CDCl3): δ = 53.7 (CH2), 47.3 (C), 46.3 (CH2), 44.7 (CH), 44.0 (CH2), 38.6 (CH), 37.8 (CH2), 37.7 (CH2), 37.5 (CH), 34.9 (CH), 34.8 (C), 34.0 (CH), 27.3 (CH).

MS (EI): m/z (%) = 255 (100), 240, 239, 197, 183, 144, 106, 91.

HRMS: m/z calcd for C18H25N: 255.1987; found: 255.1989.

N -Chloroacetyltriamantane-2-amine (10)

Colorless solid; mp 164-166 ˚C.

¹H NMR (400 MHz, CDCl3): δ = 6.67 (br s, 1 H), 4.00 (s, 2 H), 2.67-2.61 (m, 2 H), 1.91-1.54 (m, 17 H), 1.49-1.42 (m, 2 H), 1.15-1.08 (m, 2 H).

¹³C NMR (100 MHz, CDCl3): δ = 163.9 (C=O), 60.9 (C-N), 49.2 (CH), 43.4 (CH2), 39.5 (CH2), 39.7 (CH2), 38.3 (CH2), 38.1 (CH), 37.6 (CH), 36.7 (CH), 35.6 (C), 32.7 (CH2), 27.0 (CH).

MS (EI): m/z (%) = 331, 239, 238 (100), 197, 167, 129, 128, 91.

HRMS: m/z calcd for C20H26ClNO: 331.1703; found: 331.1668.

N -Chloroacetyltriamantane-3-amine (11)

Colorless solid; mp 146-147 ˚C.

¹H NMR (400 MHz, CDCl3): δ = 6.31 (br s, 1 H), 3.94 (s, 2 H), 2.16-2.11 (m, 1 H), 2.08-2.04 (m, 2 H), 2.03-1.97 (m, 1 H), 1.94-1.80 (m, 5 H), 1.77-1.56 (m, 8 H), 1.47-1.40 (m, 2 H), 1.38-1.28 (m, 3 H), 1.25-1.19 (m, 1 H).

¹³C NMR (100 MHz, CDCl3): δ = 164.3 (C=O), 57. 2 (C-N), 47.9 (CH), 46.1 (CH), 44.6 (CH2), 44.4 (CH2), 43.1 (CH2), 41.1 (CH2), 38.8 (CH), 37.6 (CH2), 37.5 (CH2), 37.4 (CH), 37.0 (CH2), 36.8 (CH), 34.9 (C), 34.2 (CH), 33.2 (CH2), 32.4 (CH), 29.1 (CH), 27.4 (CH).

MS (EI): m/z (%) = 331, 295, 282, 239, 238 (100), 167, 129, 128, 91.

HRMS: m/z calcd for C20H26ClNO: 331.1703; found: 331.1697.

N -Chloroacetyltriamantane-4-amine (12)

Colorless solid; mp 147-149 ˚C.

¹H NMR (400 MHz, CDCl3): δ = 6.36 (br s, 1 H), 3.96 (s, 2 H), 2.19-2.13 (m, 2 H), 2.03-1.98 (m, 2 H), 1.96-1.88 (m, 2 H), 1.86-1.79 (m, 3 H), 1.78-1.74 (m, 2 H), 1.74-1.60 (m, 6 H), 1.54-1.45 (m, 2 H), 1.33-1.25 (m, 4 H).

¹³C NMR (100 MHz, CDCl3): δ = 164.4 (C=O), 47.7 (CH), 45.2 (CH2), 44.6 (CH2), 43.1 (CH2), 41.4 (CH2), 39.4 (CH), 37.5 (CH), 37.3 (C), 37.2 (CH), 37.0 (CH2), 33.2 (C), 32.8 (CH2), 27.4 (CH), 26.8 (CH).

MS (EI): m/z (%) = 331, 282, 239, 238 (100), 167, 142, 129, 85, 84, 83.

HRMS: m/z calcd for C20H26ClNO: 331.1703; found: 331.1720.

N -Chloroacetyltriamantane-9-amine (13)

Colorless solid; mp 128-131 ˚C.

¹H NMR (400 MHz, CDCl3): δ = 6.20 (br s, 1 H), 3.90 (s, 2 H), 2.00-1.91 (m, 4 H), 1.86-1.79 (m, 3 H), 1.74-1.56 (m, 12 H), 1.48-1.43 (m, 2 H), 1.33-1.29 (m, 2 H).

¹³C NMR (100 MHz, CDCl3): δ = 164.7 (C), 52.4 (C), 48.4 (CH2), 45.6 (CH), 44.7 (CH2), 42.9 (CH2), 41.6 (CH2), 39.1 (CH), 37.9 (CH), 37.6 (CH2), 37.4 (CH2), 34.8 (CH), 34.7 (C), 34.0 (CH), 37.1 (CH).

MS (EI): m/z (%) = 331, 296, 282, 256, 239, 238 (100), 167, 142, 91.

HRMS: m/z calcd for C20H26ClNO: 331.1703; found: 331.1684.

N -Chloroacetyldiamantane-4-amine (14)

Colorless solid; mp 166 ˚C.

¹H NMR (400 MHz, CDCl3): δ = 6.24 (br s, 1 H), 3.95 (s, 2 H), 2.04-1.99 (m, 6 H), 1.93 (br s, 3 H), 1.85-1.74 (m, 10 H).

¹³C NMR (100 MHz, CDCl3): δ = 164.8 (C=O), 51.3 (C), 43.0 (CH2), 41.8 (CH2), 38.5 (CH), 37.3 (CH2), 36.4 (CH), 25.5 (CH).

HRMS: m/z calcd for C16H22ClNO: 279.1390; found: 279.1391.

Anal. Calcd for C16H22ClNO: C, 68.68; H, 7.93; N, 5.01. Found: C, 68.48; H, 7.85; N, 4.79.

Bis( N -chloroacetyl)diamantane-4,9-diamine (15)

Colorless solid; mp 292-293 ˚C (dec.).

¹H NMR (400 MHz, DMSO-d 6): δ = 7.69 (s, 2 H), 3.95 (s, 4 H), 1.91 (s, 12 H), 1.82 (s, 6 H).

¹³C NMR (100 MHz, DMSO-d 6): δ = 165.0 (C=O), 49.7 (C), 43.4 (CH2), 40.3 (CH2), 36.9 (CH).

HRMS: m/z calcd for C18H24Cl2N2O2: 370.1215; found: 370.1190.

N -Chloroacetyldiamantane-1-amine (16)

Colorless solid; mp 125 ˚C.

¹H NMR (400 MHz, CDCl3): δ = 6.40 (br s, 1 H), 3.99 (s, 2 H), 2.25 (s, 2 H), 2.10-1.91 (m, 7 H), 1.83-1.62 (m, 8 H), 1.59-1.50 (m, 2 H).

¹³C NMR (100 MHz, CDCl3): δ = 164.3 (C=O), 56.6 (C), 43.1 (CH2), 41.2 (CH2), 39.0 (CH), 38.7 (CH), 38.0 (CH2), 37.2 (CH2), 36.9 (CH), 32.7 (CH2), 28.5 (CH), 24.9 (CH).

HRMS: m/z calcd for C16H22ClNO: 279.1390; found: 279.1391.

Anal. Calcd for C16H22ClNO: C, 68.68; H, 7.93; N, 5.01. Found: C, 68.62; H, 7.96; N, 4.97.

Bis( N -chloroacetyl)diamantane-1,6-diamine (17)

Colorless solid; mp 313 ˚C (dec.).

¹H NMR (400 MHz, DMSO-d 6): δ = 7.60 (s, 2 H), 4.01 (s, 4 H), 2.36 (br s, 4 H), 1.99-1.81 (m, 10 H), 1.40-1.31 (m, 4 H).

¹³C NMR (100 MHz, DMSO-d 6): δ = 164.9 (C=O), 54.8 (C), 43.5 (CH2), 41.0 (CH2), 39.0 (CH), 31.4 (CH2), 27.1 (CH).

HRMS: m/z calcd for C18H24Cl2N2O2: 370.1215; found: 370.1185.

Acknowledgment

This work was supported by the Fonds der Chemischen Industrie, the Ukrainian Basic Research Foundation, and MolecularDiamond Technologies, Chevron Technology Ventures. We are thankful to M. Serafin and C. Würtele for X-ray structure analyses.

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The structures have been deposited in the Cambridge Crystallographic Data Centre and can be retrieved using the following numbers: CCDC 701883 (14) and 701884 (16).

27

The structures have been deposited in the Cambridge Crystallographic Data Centre and can be retrieved using the following numbers: CCDC 701883 (14) and 701884 (16).

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Figure 1 The key spatial dimensions of Memantine”    (1), 2-amino- (2), 3-amino- (3), 4-amino- (4), and 9-amino triamantane (5) computed at the B3LYP/6-31+G(d) level of theory

Scheme 1 The two alternative approaches used for the preparation of diamondoid amino derivatives

Figure 2 The structures and preparative yields of compounds 2-17

Figure 3 The X-ray crystal structures and crystal packing of chloro­acetamides 14 and 16 [²7]