Synthesis and selected transformations of 2-unsubstituted 1-(adamantyloxy)imidazole 3-oxides: Straightforward access to non-symmetric 1,3-dialkoxyimidazolium salts

Article abstract of DOI:10.3762/bjoc.15.43

Adamantyloxyamine reacts with formaldehyde to give N-(adamantyloxy)formaldimine as a room-temperature-stable compound that exists in solution in monomeric form. This product was used for reactions with α-hydroxyiminoketones leading to a new class of 2-unsubstituted imidazole 3-oxides bearing the adamantyloxy substituent at N(1). Their reactions with 2,2,4,4-tetramethylcy-clobutane-1,3-dithione or with acetic acid anhydride occurred analogously to those of 1-alkylimidazole 3-oxides to give imidazol-2-thiones and imidazol-2-ones, respectively. Treatment of 1-(adamantyloxy)imidazole 3-oxides with Raney-Ni afforded the corresponding imidazole derivatives without cleavage of the N(1)–O bond. Finally, the O-alkylation reactions of the new imidazole N-oxides with 1-bromopentane or 1-bromododecane open access to diversely substituted, non-symmetric 1,3-dialkoxyimidazolium salts. Adamantyloxyamine reacts with glyoxal and formaldehyde in the presence of hydrobromic acid yielding symmetric 1,3-di(adamantyloxy)-1H-imidazolium bromide in good yield. Deprotonation of the latter with triethylamine in the presence of elemental sulfur allows the in situ generation of the corresponding imidazol-2-ylidene, which traps elemental sulfur yielding a 1,3-dihydro-2H-imidazole-2-thione as the final product.

Full text of DOI:10.3762/bjoc.15.43

Synthesis and selected transformations of 2-unsubstituted
1-(adamantyloxy)imidazole 3-oxides: straightforward access
to non-symmetric 1,3-dialkoxyimidazolium salts
Grzegorz Mlostoń*1, Małgorzata Celeda1, Katarzyna Urbaniak1, Marcin Jasiński1,
Vladyslav Bakhonsky2, Peter R. Schreiner2 and Heinz Heimgartner3
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2019, 15, 497–505.
1Department of Organic and Applied Chemistry, University of Łódź,
Tamka 12, PL-91-403 Łódź, Poland, 2Justus Liebig University,
Institute of Organic Chemistry, Heinrich-Buff-Ring 17, D-35392
Giessen, Germany and 3Department of Chemistry, University of
Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland
doi:10.3762/bjoc.15.43
Received: 08 December 2018
Accepted: 08 February 2019
Published: 19 February 2019
Email:
Associate Editor: J. A. Murphy
Grzegorz Mlostoń* - grzegorz.mloston@chemia.uni.lodz.pl
© 2019 Mlostoń et al.; licensee Beilstein-Institut.
* Corresponding author
License and terms: see end of document.
Keywords:
alkoxyamines; imidazole N-oxides; imidazolium salts; nucleophilic
carbenes; sulfur transfer reaction
Abstract
Adamantyloxyamine reacts with formaldehyde to give N-(adamantyloxy)formaldimine as a room-temperature-stable compound
that exists in solution in monomeric form. This product was used for reactions with α-hydroxyiminoketones leading to a new class
of 2-unsubstituted imidazole 3-oxides bearing the adamantyloxy substituent at N(1). Their reactions with 2,2,4,4-tetramethylcy-
clobutane-1,3-dithione or with acetic acid anhydride occurred analogously to those of 1-alkylimidazole 3-oxides to give imidazol-2-
thiones and imidazol-2-ones, respectively. Treatment of 1-(adamantyloxy)imidazole 3-oxides with Raney-Ni afforded the
corresponding imidazole derivatives without cleavage of the N(1)–O bond. Finally, the O-alkylation reactions of the new imidazole
N-oxides with 1-bromopentane or 1-bromododecane open access to diversely substituted, non-symmetric 1,3-dialkoxyimidazolium
salts. Adamantyloxyamine reacts with glyoxal and formaldehyde in the presence of hydrobromic acid yielding symmetric 1,3-
di(adamantyloxy)-1H-imidazolium bromide in good yield. Deprotonation of the latter with triethylamine in the presence of
elemental sulfur allows the in situ generation of the corresponding imidazol-2-ylidene, which traps elemental sulfur yielding a 1,3-
dihydro-2H-imidazole-2-thione as the final product.
Introduction
Imidazole N-oxides constitute a practically valuable class of located at N(1), C(4), and C(5) is of special interest as so-called
five-membered aromatic N-heterocycles [1-5]. The subclass of ‘nitrone like’ reagents for the synthesis of more complex,
2-unsubstituted imidazole N-oxides 1 with diverse substituents imidazole containing systems (Scheme 1) [6]. These imidazole
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Scheme 1: Synthesis of 2-unsubstituted imidazole N-oxides 1 from α-hydroxyiminoketones 2 and formaldimines 3.
N-oxides are easily accessible via heterocyclization reactions zolium salts resulting from double O-alkylation were isolated
comprising condensation of α-hydroxyiminoketones 2 with [18].
formaldimines 3. The latter are known to exist in monomeric
form in the case of sterically crowded parent amines such as On the other hand, alkoxyamines are known not only as bioac-
1-aminoadamantane or tert-butylamine or, alternatively, as tive compounds [19,20] but also as important initiators of poly-
trimeric hexahydro-1,3,5-triazines 3’ in the case of sterically merization processes that have been extensively studied in the
less crowded amines [7]. In analogy to other azoles and in recent decade [21]. Among alkoxyamines, adamantyloxyamine
contrast to six-membered aromatic N-heterocycles, N-oxides 1 (4) occupies a prominent position, and for that reason it was
cannot be prepared via oxidation of the parent imidazoles by selected for experiments aimed at the preparation of the new
treatment with an oxidizing agent, e.g., with a percarboxylic group of 2-unsubstituted imidazole N-oxides bearing the
acid [6].
adamantyloxy residue at N(1). The goal of the present study
was the synthesis of some representatives of this type and com-
Imidazole N-oxides are versatile substrates for the preparation parison of their properties with those of 1-adamantyl analogues.
of diverse imidazole derivatives and the most characteristic fea-
ture is their 1,3-dipolar reactivity analogous to aldonitrones, Results and Discussion
which enables their conversion via [3 + 2]-cycloadditions with The starting adamantyloxyamine (4) was prepared from
dipolarophiles such as activated ethylenes [8,9], activated 1-bromoadamantane, which in the presence of an equimolar
acetylenes [10,11] or isocyanates [11,12]. The initially formed amount of AgBF4 in boiling dimethoxyethane (DME) reacts
[3 + 2]-cycloadducts undergo spontaneous secondary conver- with N-hydroxyphthalimide to give the O-alkylation product 5
sions leading to re-aromatization of the imidazole ring. The [20] (Scheme 2). The latter was converted to 4, obtained in 86%
same mechanism governs sulfur-transfer reactions with yield, after hydrazinolysis with N2H4.H2O in slight excess. The
cycloaliphatic thioketones yielding the corresponding imida- crude product was reacted with formaldehyde in boiling MeOH,
zole-2-thiones [13]. The isomerization of N-oxides 1 into the and after 1 h, crystalline N-(adamantyloxy)formaldimine (6a)
corresponding imidazol-2-ones can be easily performed by was isolated in 90% yield. The spectroscopic data indicate that
treatment with acetic anhydride at room temperature [14]. An this imine exists in solution in monomeric form exclusively.
important reaction of 1 is the O-alkylation leading to alkoxyimi- Thus, the 1H NMR spectra confirmed this structure by the pres-
dazolium salts, which display in some cases properties of ‘room ence of two doublets located at 6.39 and 7.01 ppm with
temperature ionic liquids’ [15,16]. Finally, straightforward J = 12 Hz, characteristic for the =CH2 group. In addition, the
deoxygenation by treatment with Raney-Ni is also worth men- 13C NMR spectrum showed the absorption of this group at
tioning [17].
136.1 ppm.
Condensations presented in Scheme 1 occur smoothly with Having imine 6a in hands, syntheses of a series of 2-unsubsti-
formaldimines 3 derived from aliphatic amines, but in the case tuted 1-(adamantyloxy)imidazole 3-oxides 7a–e were per-
of primary aromatic amines harsher reaction conditions are re- formed in glacial acetic acid at room temperature. The crude
quired [6]. To date, no synthesis of 1-alkoxyimidazole N-oxides products were transformed into their hydrochlorides by treat-
derived from alkoxyamines (‘hydroxyamine ethers’) has been ment with conc. hydrochloric acid, and subsequent neutraliza-
reported. An alternative approach to these products comprises tion over solid NaHCO3 led to crystalline products (procedure
the alkylation (in most cases methylation) of 1-hydroxyimida- A). Following this procedure, the required N-oxides 7a–e were
zole N-oxides. However, the products of the monomethylation obtained in good to excellent yields (Scheme 3). In addition,
could not be obtained, but symmetric N,N-disubstituted imida- based on the earlier described protocol [7], two imidazole
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Scheme 2: Preparation of adamantyloxyamine (4) and its conversion into N-(adamantyloxy)formaldimine (6a); Ad = 1-adamantyl.
N-oxides 7f and 7g, bearing the adamantan-1-yl moiety at- pectedly, in the case of 7e, the same procedure led to the final,
tached to N(1), were also obtained in high yields starting with crystalline product as a hydrochloride. Apparently, hydrogen
(adamantyl)formaldimine (6b, Scheme 3). In this case, crude bonding in this molecule is strong enough to bind an HCl mole-
products were isolated as hydrochlorides not by treatment with cule, which cannot be removed by treatment with solid
hydrochloric acid but with gaseous hydrogen chloride (proce- NaHCO3 in the methanolic solution under standard conditions.
dure B). Both compounds obtained by this method were fully
characterized and described in an earlier publication [7].
The first question was whether the new imidazole N-oxides 7
can be deoxygenated with Raney-Ni without cleavage of the
N(1)–OAd bond. The test reaction with 7a demonstrated that
the reaction performed in MeOH solution at room temperature
was completed after 2 h, and the main product isolated in 39%
yield was the expected 1-(adamantyloxy)imidazole 8a
(Scheme 4). In the product, the diagnostic HC(2) signal in the
1H NMR spectrum shifts high-field and appears at 7.34 ppm.
Analogously, deoxygenation of N-oxides 7b–d led to the re-
quired imidazoles 8b–d in 66%, 62%, and 39% yield, respec-
tively.
Scheme 4: Deoxygenation of 1-(adamantyloxy)imidazole 3-oxides
7a–d and isomerization of 7b into imidazole-2-one 9.
Scheme 3: Synthesis of 1-(adamantyloxy)imidazole 3-oxides 7a–e
and 1-adamantylimidazole 3-oxides 7f,g in acetic acid at room
temperature.
As pointed out in the introduction, one of the most typical reac-
In all cases the 1H NMR spectra of new products confirmed the tions of 2-unsubstituted imidazole N-oxides is their isomeriza-
structures 7a–d by the presence of the diagnostic HC(2) signal tion to imidazol-2-ones. In many reported cases, this transfor-
between 8.76 and 7.93 ppm. In the 13C NMR spectra, absorp- mation can be performed by treatment with acetic anhydride,
tions of the three imidazole C-atoms were found between 120 heating in a high boiling solvent or photolytically [6]. In a test
and 130 ppm. In addition, the signals of OC(1) of the adamantyl experiment with 7b, the reaction with Ac2O in CHCl3 solution
skeleton appeared in a narrow range at 89.0–86.9 ppm. Unex- at room temperature overnight led to a crystalline product iden-
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tified as the expected imidazole-2-one 9 in 36% yield philic carbenes (imidazol-2-ylidenes). For example, deproton-
(Scheme 4). In that case, the 1H NMR singlet located at ation of 1,3-diadamantylimidazolium chloride led to the first
11.02 ppm belongs to HN(3). The 13C NMR spectrum con- stable imidazol-2-ylidene (the so-called ‘Arduengo carbene’)
firmed the structure of 9 by the signal of the C(2)=O group [24,25]. Alkylation of 2-unsubstituted imidazole N-oxides is a
found at 153.0 ppm. The corresponding band in the IR spec- known procedure for the preparation of alkoxyimidazolium
trum appeared at 1702 cm−1as the strongest absorption.
salts [16], and the alkylation of N-oxides of type 7 should lead
to 1,3-dialkoxyimidazolium salts, which form a little-known
Thermal isomerization of 7b was also tested. However, boiling class of imidazole derivatives. The method reported earlier for
in bromobenzene for 15 min resulted in decomposition of the their synthesis comprises the two-fold alkylation (methylation
starting material, and in this case, the expected imidazole-2-one with Me2SO4 or benzylation using benzyl bromide) of some
9 could not be detected in the crude reaction mixture.
1-hydroxyimidazole 3-oxides leading to symmetric 1,3-
dialkoxyimidazolium salts [18]. In a recent publication, howev-
Sulfur-transfer reactions offer an attractive approach to imida- er, sequential alkylation of 1-hydroxyimidazole 3-oxide using
zole-2-thiones starting with 2-unsubstituted imidazole N-oxides two different alkyl halides (R1X and R2X; R1, R2 = Me, Et,
[13]. The importance of this procedure is reflected in the multi- n-Bu, or allyl) as alkylating agents, leading to non-symmetric
step reactions applied for the preparation of some bioactive 1,3-dialkoxyimidazolium salts, was also reported [26].
imidazole derivatives [22,23]. However, the preparation of
imidazole-2-thiones with N-alkoxy groups, starting with the In the present study, imidazole N-oxides 7 bearing either an
corresponding 2-unsubstituted imidazole 3-oxides, has not yet adamantyloxy or adamantyl moiety at N(1) were smoothly alky-
been reported. It turned out that the imidazole N-oxide 7b can lated with 1-bromopentane (12a) or 1-bromododecane (12b) in
smoothly be converted into 1-(adamantyloxy)imidazole-2- CHCl3 at room temperature. In the case of 7a and 7b, both reac-
thione 10b in the presence of 2,2,4,4-tetramethylcyclobutane- tions were completed after 24 h and a crystalline product was
1,3-dithione (11a) as the sulfur-donating reagent. The reaction isolated in each case. The NMR spectra confirmed the expected
was carried out in CH2Cl2 at room temperature, and after 1 h, structure of 1-adamantyloxy-3-alkoxyimidazolium bromides
the desired product 10b was isolated in 55% yield (Scheme 5); 13a and 13b, respectively (Scheme 6). In the 1H NMR spectra
its structure was confirmed spectroscopically. For example, in of both compounds, the most characteristic signal of HC(2) was
the 1H NMR spectrum a singlet located at 12.15 ppm was attri- shifted significantly to lower field and appeared at 11.46 and
buted to the HN(3) unit. Moreover, the 13C NMR spectrum 12.12 ppm, respectively. In the 13C NMR spectra of 13a, two
revealed the C=S absorption at 159.6 ppm. Analogous transfor- signals at 83.9 and 91.5 ppm were attributed to CH2–O and
mations were achieved with 7a and 7c,d. A plausible explana- C–O of the pentyloxy and adamantyloxy residues.
tion of the sulfur-transfer mechanism via the intermediate
[3 + 2]-cycloadduct A is presented in Scheme 5. The elimi- In order to compare the course of the alkylation reactions of 7a
nated monothione 11b enters an analogous reaction with the and 7b with those of the structurally analogous 1-adamantylimi-
starting imidazole N-oxide 7, leading to a second molecule of dazole 3-oxides 7f and 7g, the latter were treated with 12a or
10 and 2,2,4,4-tetramethylcyclobutane-1,3-dione.
12b under the same conditions. Remarkably, these alkylations
occurred more slowly and their completion was established only
Imidazolium salts are of special importance as they are widely after 3 d leading to 1-adamantyl-3-alkoxyimidazolium bro-
used as ionic liquids or precursors of imidazole-based nucleo- mides 13d–g. These results indicate that the 1-adamantyloxy
Scheme 5: Conversions of imidazole 3-oxides 7a–d into 1-(adamantyloxy)imidazole-2-thiones 10a–d via sulfur transfer reaction.
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Scheme 6: Syntheses of the non-symmetric 1,3-dialkoxyimidazolium bromides 13a–c and 1-alkyl-3-alkoxyimidazolium bromides 13d–g.
substituent enhances the nucleophilicity of the N-oxides and the zoles have already been reported [31], similar reactions with
alkylation requires shorter reaction times.
heterocyclic N-oxides have not been published yet. For that
reason, in the final part of the study, a preliminary experiment
In extension of this study, the alkylation of 1-adamantyloxy- aimed at the O-adamantylation of imidazole N-oxide 7a was
4,5-diphenylimidazole (8b) with 12b was also attempted under carried out under typical conditions (CHCl3 solution, rt) using
the same conditions. In that case, however, the expected 1-bromoadamantane as an alkylating agent. However, forma-
N-alkylation did not occur at room temperature and even after tion of the expected 1,3-bis(adamantyloxy)imidazolium salt was
2 d the starting materials were found unchanged in the reaction not observed neither in the absence nor in the presence of
mixture. On the other hand, the attempted N-alkylation of 8b AgBF4. Based on this observation, 1-bromoadamantane was
upon MW irradiation led to the formation of a mixture of replaced by adamantan-1-yl trifluoroacetate (Scheme 7). Unex-
starting materials and some unidentified decomposition prod- pectedly, this test experiment, performed with 7a at room
ucts.
temperature, led after 24 h not to the expected, symmetric 1,3-
di(adamantyloxy)imidazolium salt 13h but to the trifluoro-
Due to the great importance of both carbocyclic and hetero- acetate of the starting material, i.e., compound 14, formed side
cyclic systems functionalized with the adamantyl group [27], by side with adamantan-1-ol. Apparently, the initially formed
different types of adamantylation reactions (C-, N-, or 13h underwent spontaneous hydrolysis in the presence of air
O-adamantylation) attract attention, and typically 1,3-dehy- moisture, leading to the mixture of both isolated products.
droadamantane [28] or 1-haloadamantanes [29] are applied as
alkylating reagents. Adamantan-1-yl carboxylates are also Finally, in extension of the study focused on the preparation of
known as efficient adamantylating reagents [30]. In spite of the new, symmetric 1,3-dialkoxyimidazolium salts, the synthesis of
fact that adamantylations of some benzimidazoles and imida- 1,3-di(adamantyloxy)imidazolium salt, starting with glyoxal
Scheme 7: Attempted O-adamantylation of imidazole N-oxide 7a with adamantan-1-yl trifluoroacetate and subsequent hydrolysis of the initially
formed imidazolium salt 13h.
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hydrate, adamantyloxyamine (4) and formaldehyde, using these chemistry. The acetic acid anhydride assisted isomerization
reagents in a ratio 1:2:1, in the presence of hydrobromic acid reaction of a new N-oxide leads to the corresponding imidazol-
was attempted. The reaction performed overnight in acetic acid 2-one. However, the attempted thermal isomerization of a
at room temperature led to the expected imidazolium bromide 1-(adamantyloxy)imidazole N-oxide resulted in decomposition
15 in 41% yield (Scheme 8). Its structure was confirmed by of the starting material. The alkylation experiments performed
spectroscopic data; for example, in the 1H NMR spectrum the with 1-bromopentane and 1-bromododecane showed that
characteristic singlets of H(2) and H(4)/H(5) appeared at 11.90 1-(adamantyloxy)imidazole 3-oxides are more reactive than
and 7.68 ppm, respectively, and the ratio of the intensities was their 1-adamantanyl analogues, and the corresponding 1,3-
1:2. On the other hand, the 13C NMR revealed the absorptions dialkoxyimidazolium bromides were obtained in high yields.
of C(2) and C(4)/C(5) at 137.0 and 120.2 ppm, respectively.
Attempted adamantylation of a 1-(adamantyloxy)imidazole
3-oxide with 1-bromoadamantane or adamantan-1-yl trifluoro-
Unfortunately, attempted syntheses of analogous, symmetric acetate was unsuccessful. Nevertheless, the corresponding sym-
1,3-dialkoxyimidazolium bromides, derived from diacetyl or metric 1,3-di(adamantyloxy)imidazolium bromide was ob-
1,2-diphenylethane-1,2-dione, using the same protocol, were tained in the reaction of adamantyloxyamine with glyoxal,
unsuccessful.
formaldehyde and hydrobromic acid. By treatment with triethyl-
amine, it was deprotonated and formed the corresponding
Nucleophilic carbenes are known to undergo conversion into imidazol-2-ylidene, which reacts with elemental sulfur yielding
imidazole-2-thiones by trapping of elemental sulfur [26,32]. the expected 1,3-dihydro-2H-imidazole-2-thione. Thus, the
Treatment of the symmetric imidazolium salt 15 with triethyl- elaborated protocols provide straightforward access to diverse
amine in pyridine solution in the presence of elemental sulfur 1-(adamantyloxy)imidazole 3-oxides as well as to 1,3-dialkoxy-
led to the 1,3-dihydro-2H-imidazole-2-thione 17 isolated in imidazolium salts, which are attractive substrates for syntheses
83% yield (Scheme 8). In the 1H NMR spectrum, two equiva- of other imidazole derivatives, including a new group of
lent HC(4) and HC(5) atoms appeared at 6.69 ppm, and in the 1-alkoxy and 1,3-dialkoxyimidazol-2-ylidenes. In all described
13C NMR spectrum, the C(4) and C(5) atoms gave only one cases, it is of interest to probe the influence of the alkoxy
signal localized at 114.6 ppm. Apparently, deprotonation of the residues on the stability and reactivity of the hitherto unknown
imidazolium cation results in the formation of the nucleophilic nucleophilic carbenes bearing this groups at N(1) and/or N(3)
imidazol-2-ylidene 16, which in situ reacts with elemental atoms.
sulfur dissolved in pyridine solution yielding the symmetrically
substituted 1,3-dihydro-2H-imidazole-2-thione 17.
In addition, it is worth mentioning that 1,3-dibenzyl-4,5-
dimethylimidazolium chloride as well as its 2-methyl-substi-
tuted analogue are well known imidazole alkaloids, which
Conclusion
The present study demonstrates that the heterocyclization reac- found wide application in some regions as food-stuff and
tion with α-hydroxyiminoketones and formaldimines leading to medical supply [33]. The method described in the present study
2-unsubstituted imidazole 3-oxides can efficiently be per- opens a straightforward access to their benzyloxy analogues,
formed with N-(adamantyloxy)formaldimine, and 2-unsubsti- potentially bioactive compounds, which have not been known
tuted 1-(adamantyloxy)imidazole 3-oxides were obtained in yet.
high yields. In general, they react similarly to their 1-alkyl ana-
logues and undergo deoxygenation without removal of the Experimental
adamantyloxy fragment. The sulfur transfer reactions provide General information: Solvents and chemicals were purchased
access to the new group of 1-(adamantyloxy)imidazole-2- and used as received without further purification. Products were
thiones, which potentially are of interest for medicinal purified by standard column chromatography on silica gel
Scheme 8: Synthesis of the symmetric 1,3-di(adamantyloxy)imidazolium bromide (15) and its transformation to 1,3-dihydro-2H-imidazol-2-thione 17
via the intermediate imidazol-2-ylidene 16.
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(230–400 mesh, Merck). Unless stated otherwise, yields refer ucts obtained thereby were dried over freshly prepared molecu-
to analytically pure samples. NMR spectra were recorded lar sieves 4 Å to give hydrate-free samples.
with a Bruker Avance III 600 MHz instrument (1H NMR:
600 MHz; 13C NMR: 151 MHz). Chemical shifts are reported 1-Adamantyloxy-4,5-dimethylimidazole 3-oxide (7a): Yield:
relative to solvent residual peaks (1H NMR: δ = 7.26 ppm 204 mg (78%). Pale yellow crystals; mp 104–106 °C; 1H NMR
[CHCl3]; 13C NMR: δ = 77.0 ppm [CDCl3]). IR spectra were δ 1.60, 1.69 (AB-system, JH,H = 12.0 Hz, 6H, 3CH2(ad)), 1.85
registered with a FTIR NEXUS spectrometer (as film or KBr (pseudo d, JH,H = 2.6 Hz, 6H, 3CH2(ad)), 2.16, 2.19 (2s, 6H,
pellets). Melting points were determined in capillaries with a 2CH3), 2.27 (brs, 3H, 3CH(ad)), 7.83 (s, 1H, HC(2)) ppm;
Stuart SMP30 apparatus with automatic temperature monitor- 13C NMR δ 7.13, 8.47 (2CH3), 30.9 (3CH(ad)), 35.6, 40.7
ing.
(6CH2(ad)), 86.9 (Cq(ad)-O), 120.9, 122.9, 123.6 (2C=, HC(2))
ppm; IR υ: 2909 (s), 2853 (m), 1523 (m), 1448 (m), 1355 (s),
Starting materials: Adamantyloxyamine (4) was prepared 1189 (m), 1082 (m), 1047 (vs), 963 (m), 881 (s), 738 (m),
following a modified published procedure [20]. For the first 574 (s) cm−1; anal. calcd for C15H22N2O2 (262.35): C, 68.67;
step, the O-adamantylation of N-hydroxyphthalimide, the H, 8.45; N, 10.68; found: C, 68.52; H, 8.56; N, 10.51.
recommended diethyl ether as a solvent was replaced by 1,2-
dimethoxyethane. Methylideneadamantylamine (6b) was pre- Deoxygenation of imidazole N-oxides 7a–d – general proce-
pared by treatment of 1-aminoadamantane, isolated from com- dure: A portion of freshly prepared Raney-Ni suspended in
mercial 1-aminoadamantane hydrochloride after neutralization MeOH was added in excess to the stirred solution of 1 mmol of
of its aqueous solution with diluted sodium hydroxide solution, an imidazole N-oxide 7 dissolved in MeOH (ca. 1 mL). The
with paraformaldehyde [34]. 1-(Adamantan-1-yl)-4,5- solution was stirred magnetically for 1–2 h at rt. The progress of
dimethylimidazole N-oxide (7f) and 1-(adamantan-1-yl)-4,5- the deoxygenation was monitored by TLC. As soon as the
diphenylimidazole N-oxide (7g) were obtained as crystalline starting material disappeared, the suspension was filtered and
materials following a published protocol (method B) [7]. the filtrate was evaporated. The obtained material was tritu-
α-Hydroxyiminoketones 2a,c–e were prepared based on the rated with petroleum ether and filtered off yielding analytically
earlier described procedure via nitrosylation of the correspond- pure samples.
ing ketones or β-ketoamides with isoamyl nitrate [35] or, as in
the case of 2b, by oximation of 1,2-diphenylethane-1,2-dione 1-Adamantyloxy-4,5-dimethyl-1H-imidazole (8a): Yield:
[36]. 2,2,4,4-Tetramethylcyclobutane-1,3-dithione (11a) was 96 mg (39%). Colorless crystals; mp 47–50 °C; 1H NMR δ
prepared from the dimethylketene dimer (2,2,4,4-tetramethylcy- 1.60, 1.67 (AB-system, JH,H = 12.4 Hz, 6H, 3CH2(ad)), 1.85
clobutane-1,3-dione) by thionation using tetraphosphorus deca- (pseudo d, JH,H = 2.5 Hz, 6H, 3CH2(ad)), 2.11, 2.13 (2s, 6H,
sulfide [37]. Adamantan-1-yl trifluoroacetate (CF3CO2Ad) was 2CH3), 2.24 (brs, 3H, 3CH(ad)), 7.37 (s, 1H, HC(2)) ppm;
prepared following a known protocol [38]. 1-Bromo- 13C NMR δ 8.4, 13.3 (2CH3), 30.8 (3CH(ad)), 35.8, 41.0
adamantane, 1-bromopentane (12a) and 1-bromododecane (6CH2(ad)), 84.6 (Cq(ad)-O), 121.4, 129.3, 131.8 (2C=, HC(2))
(12b) were commercial reagents used in the studied reactions ppm; IR υ: 2905 (s), 2851 (m), 1679 (m), 1559 (m), 1440 (m),
with no additional purification.
1353 (m), 1295 (m), 1274 (m), 1095 (m), 1053 (vs), 896 (s),
799 (m), 769 (vs), 633 (m), 594 (m), 504 (s) cm−1; HRMS
General procedure for the preparation of imidazole 3-oxides (ESI+): calcd. for [C15H23N2O]+, 247.1810; found, 247.1811.
7 (procedure A): A solution of 5 mmol of 6 and 4.2 mmol of
the corresponding α-hydroxyiminoketone 2 in 15 mL of glacial Sulfur-transfer reactions; Preparation of 3H-imidazole-2-
acetic acid was stirred magnetically overnight at rt. Then, thiones 10 – general procedure: A solution of the correspond-
4.5 mL of conc. hydrochloric acid were added in small portions. ing imidazole N-oxide 7 (1 mmol) in 3 mL of CH2Cl2 was
Stirring was continued over 15 min, and after this time the treated with 103 mg (0.6 mmol) of dithione 11a and the ob-
acetic acid was evaporated. The semi-solid residue was tritu- tained solution was stirred magnetically at rt for 1 h. The sol-
rated with a portion of diethyl ether and the crystalline material vent was evaporated and the obtained residue was triturated
was separated by filtration. Next, the colorless crystals were with petroleum ether. The solid obtained thereby was filtered
dissolved in a portion of MeOH (10 mL) and while magnetical- off and dried in the air.
ly stirring, sodium hydrocarbonate was added in small portions
until the evolution of carbon dioxide ceased. The mixture was 1-Adamantyloxy-4,5-dimethyl-1H-imidazole-2(3H)-thione
stirred overnight, filtered and the filtrate was evaporated to (10a): Yield: 103 mg (37%). Pale yellow crystals; mp
dryness. The crude product was triturated again with diethyl 137–139 °C; 1H NMR δ 1.64 (pseudo t, JH,H = 3.0 Hz, 6H,
ether and after few minutes filtered off. In some instances, prod- 3CH2(ad)), 2.06, 2.09 (2s, 6H, 2CH3), 2.13 (pseudo d, JH,H =
503

Beilstein J. Org. Chem. 2019, 15, 497–505.
3.1 Hz, 6H, 3CH2(ad)), 2.23 (brs, 3H, 3CH(ad)), 12.0 (brs, 1H, 1,3-Di(adamantyloxy)imidazolium bromide (15): Yield:
NH) ppm; 13C NMR δ 9.3, 9.4 (2CH3), 31.5 (3CH(ad)), 35.9, 190 mg (41%). Colorless crystals; mp ca. 160 °C (dec.);
42.0 (6CH2(ad)), 88.8 (Cq(ad)-O), 117.4, 121.7 (2C=), 157.4 1H NMR δ 1.59, 1.63 (AB-system, JH,H = 12.5 Hz, 12H,
(C=S) ppm; IR υ: 3065 (m), 2907 (vs), 2853 (m), 1493 (vs), 6CH2(ad)), 1.95 (pseudo d, JH,H = 2.4 Hz 12H, 6CH2(ad)), 2.29
1428 (m), 1399 (m), 1367 (m), 1248 (s), 1046 (vs), 889 (s), (brs, 6H, 6CH(ad)), 7.71 (pseudo d, JH,H = 1.7 Hz, 2H, 2CH=),
900 (s), 773 (s), 743 (vs), 698 (vs), 577 (m) cm−1; HRMS 11.03 (pseudo t, JH,H = 1.9 Hz 1H, HC(2)) ppm; 13C NMR δ
(ESI+): calcd. for [C15H23N2OS]+, 279.1531; found, 279.1532. 31.0, 35.3, 40.2 (12CH2(ad)), 6CH(ad)), 90.8 (2C(ad)-O), 120.2
(2CH=), 133.7 (HC(2)) ppm; IR υ: 2903 (s), 2847 (m),
Preparation of non-symmetric 1,3-dialkoxyimidazolium 1546 (m), 1449 (m), 1358 (m), 1293 (m), 1045 (s), 1001 (s),
bromides 13a–g – general procedure: The corresponding 961 (s), 881 (s), 726 (s), 542 (vs), 449 (vs) cm−1; anal. calcd for
imidazole N-oxide 7 (1 mmol) dissolved in 2–3 mL of chloro- C23H33BrN2O2∙H2O (467.44): C, 59.10; H, 7.55; N, 5.99;
form was treated with alkylating reagent 12a (227 mg, found: C, 59.08; H, 7.62; N, 5.79.
1.50 mmol) or 12b (262 mg, 1.05 mmol), which were added
drop-wise at rt. The obtained reaction mixtures were stirred
Supporting Information
magnetically at rt and the progress of the reaction was moni-
tored by TLC (SiO2, CH2Cl2). When the starting 7 was com-
Supporting Information File 1
pletely consumed, the solvent was evaporated and the residue
was triturated with diethyl ether. In most cases, solid, colorless
or beige colored products were formed. In the case of 13e, a
semi-solid product was formed; no crystallization was observed
even after several days at rt. Similar properties were displayed
by product 13d, which did not crystallize at all and was
analyzed as an oily material.
Experimental and analytical data and copies of NMR
spectra.
[https://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-15-43-S1.pdf]
Acknowledgements
The authors acknowledge generous financial support within the
grant Beethoven-2: a) National Science Centre, Cracow (G.
Mlostoń, grant # 2016/23/G/ST5/04115/l) and b) German
Research Foundation, Bonn (P. R. Schreiner, grant # Schr 597/
34-1).
1-Adamantyloxy-4,5-dimethyl-3-pentyloxy-1H-imidazolium
bromide (13a): Yield: 325 mg (79%). Beige crystals; mp 73 °C
(dec.); 1H NMR δ 0.94 (t, JH,H= 7.1 Hz, 3H, CH3(p)),
1.38–1.40 (m, 2H, CH2(p)), 1.46–1.50 (m, 2H, CH2(p)), 1.69
(brs, 6H, 3CH2(ad)), 1.85–1.87 (m, 2H, CH2(p)), 2.02 (pseudo
d, 6H, 3CH2(ad)), 2.27 (s, 3H, CH3-C=), 2.30 (s, 3H, CH3-C=),
2.35 (brs, 3H, 3CH(ad)), 4.79 (t, JH,H = 6.5 Hz,2H, CH2-O),
11.46 (s, HC(2)) ppm; 13C NMR δ 7.3, 8.8, 13.9 (3CH3), 22.4,
27.5, 27.8 (3CH2(p)), 31.2 (3CH(ad)), 35.4, 40.7 (6CH2(ad)),
83.9 (CH2-O), 91.5 (Cq(ad)-O), 120.0, 123.8 (2C=), 131.3
(HC(2)) ppm; IR υ: 2952 (s), 2911 (s), 1628 (m), 1373 (m),
1356 (m), 1039 (s), 958 (s), 877 (s), 593 (s) cm−1; HRMS
(ESI+): calcd. for [C20H33N2O2]+, 333.2542; found, 333.2552.
ORCID® iDs
Grzegorz Mlostoń - https://orcid.org/0000-0003-3631-3239
Marcin Jasiński - https://orcid.org/0000-0002-8789-9690
Peter R. Schreiner - https://orcid.org/0000-0002-3608-5515
Heinz Heimgartner - https://orcid.org/0000-0002-5145-4251
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