Approaches to primary tert-alkyl amines as building blocks

Article abstract of DOI:10.1016/j.tet.2019.06.016

Primary tert-alkyl amines include analogues of amantadine, a fragment commonly linked to pharmacophoric groups to enhance biological activity. The preparation of primary tert-alkyl amines is considered to be a difficult problem. Four synthetic procedures, some of which have been previously reported for the synthesis of amines with primary (RCH₂NH₂) or secondary (RR'CHNH₂) alkyl and/or aryl groups, were tested for the synthesis of primary tert-alkyl amines (RR′R″CNH₂) in aliphatic series including adamantane adducts. These procedures included the formation and reduction of tert-alkyl azides, the Ritter reaction in standard and modified conditions, the addition of organometallic reagents to N-tert-butyl sulfinyl ketimines and one-pot reactions between nitriles and organometallic reagents in the presence of a Lewis acid, Τi(iPrO)₄ or CeCl_3. These synthetic routes are unexplored for primary tert-alkyl amines. Studies on the synthetic routes for primary tert-alkyl amines are currently lacking. The reaction conditions and substrate limitations were studied for each procedure, with the first procedure being the most general and applicable also for compounds bearing bulky adducts.

Full text of DOI:10.1016/j.tet.2019.06.016

Accepted Manuscript
Approaches to primary tert-alkyl amines as building blocks
Christina Tzitzoglaki, Antonios Drakopoulos, Athina Konstantinidi, Ioannis Stylianakis,
Antonios Kolocouris
PII:
S0040-4020(19)30669-6
https://doi.org/10.1016/j.tet.2019.06.016
TET 30408
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 11 May 2019
Revised Date: 7 June 2019
Accepted Date: 11 June 2019
Please cite this article as: Tzitzoglaki C, Drakopoulos A, Konstantinidi A, Stylianakis I, Kolocouris
A, Approaches to primary tert-alkyl amines as building blocks, Tetrahedron (2019), doi: https://
doi.org/10.1016/j.tet.2019.06.016.
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ACCEPTED MANUSCRIPT
Approaches to primary tert-alkyl amines as building blocks
Christina Tzitzoglaki‡, Antonios Drakopoulos‡, Athina Konstantinidi, Ioannis Stylianakis, and Antonios
Kolocouris *
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, National and Kapodistrian University of
Athens, Panepistimioupolis-Zografou, 15771 Athens, Greece
E-mail: ankol@pharm.uoa.gr
In memory of Professor George B. Foscolos
1 Abstract
Primary tert-alkyl amines represent analogues of amantadine, a fragment commonly linked to pharmacophoric
groups to enhance biological activity. The preparation of primary tert-alkyl amines is considered to be a
difficult problem. Four synthetic procedures, which have been previously reported for the synthesis of amines with
primary (RCH2NH2) or secondary (RR'CHNH2) alkyl and/or aryl groups, were tested for the synthesis of primary tert-
alkyl amines (RR'R''CNH2) in aliphatic series including adamantane adducts. These procedures included the
formation and reduction of tert-alkyl azides, the Ritter reaction in standard and modified conditions, the
addition of organometallic reagents to N-tert-butyl sulfinyl ketimines and one-pot reactions between nitriles and
organometallic reagents in the presence of a Lewis acid, Τi(iPrO)4 or CeCl3. These synthetic routes are unexplored
for primary tert-alkyl amines and their unexpected results should be included in organic chemistry literature
.
The reaction conditions and substrate limitations were studied for each procedure, with the first procedure being
the more general and applicable also for compounds bearing bulky adducts.
Keywords: Primary tert-alkyl amine, tert-alkyl azide reduction, Ritter reaction, N-tert-butanesulfinyl imine
reduction, organometallic addition to 1-adamantanecarbonitrile, Τi(iPrO)4
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2 Introduction
Remarkably simple aminoadamantane structures hit targets like viroporins to combat Influenza virus A and the
NMDA receptor for symptomatic relief in Parkinson Disease and Alzheimer Disease.1 Adamantane is a
lipophilic symmetrical hydrocarbon cage which is often used -itself or modified- as a fragment in drug molecule
design and optimization. Amantadine and several simple analogues represent such building blocks which can be
favorably modified and linked with known pharmacophoric groups, resulting in enhanced biological activity.
Examples are molecules: (a) with glucocerebrosidase activity potentially useful for atherosclerosis;2 (b) K+
channel activity and hypoglycemic properties;3 (c) affinity for opioid receptor;4 (d) affinity for σ-receptor5
which is involved in psychotic disorders; (e) affinity for soluble epoxide hydrolase6 which is deemed valuable
for various diseases; (f) dipeptidyl peptidase IV inhibitory potency7 for the treatment of type 2 diabetes mellitus,
(g) influenza A amantadine resistance8 etc (Figure S1).
+
+
+
NH3
NH3
NH3
CH3
H3C
+
+
AdNH3
+
Pr3CNH3
+
CMe3CH2CMe2NH3
AdCMe2NH3
+
+
+
Figure 1. Top: Pr3CNH3 and CMe3CH2CMe2NH3 are open cage analogues of amantadine (AdNH3 ).
+
+
Compounds AdNH3 and AdCMe2NH3 are potent influenza A wild-type M2 protein inhibitors. Bottom: van
der Waals spheres representation of Pr3CNH2 , CMe3CH2CMe2NH2, AdNH2 and AdCMe2NH2.
Although amantadine has been long marketed as an antiviral drug for influenza A, it was only after 2008
that high resolution structures from x-ray and ssNMR experiments showed that the primary binding site of
amantadine is the lumen of the four-helix bundle of tetrameric M2 (M2TM: amino acids 22-46) that forms the
proton transport path.9 We are interested in the preparation of primary tert-alkyl amines in aliphatic series,
including common alkyl chain and adamantane substituents. These compounds may be used as lipophilic amine
building blocks for the development of drug molecules acting against wild type and mutant M2 protein of
amantadine-resistant influenza A virus strains8 or addressing other biological targets. For example, it was
reported that 1,1,3,3-tetramethylbutylamine (CMe3CH2CMe2NH2)10 and 2-(1-adamantyl)-2-propanamine
(AdCMe2NH2)11 block the M2 channel with an efficiency comparable to amantadine (Figure 1).
The preparation of primary tert-alkyl amines or α,α,α-trisubstituted primary amines is considered to be a
difficult problem.12 If one of the substituents of the desired primary tert-alkyl amine is itself a bulky tert-alkyl
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Tzitzoglaki, C.; Drakopoulos, A. et al.
group or adamantyl group, steric crowding is expected to increase the difficulty of the preparation. When the
starting material is a tert-alkyl alcohol, a general and widely used route is the Ritter reaction,13 providing the
primary tert-alkyl amine in two steps. This procedure has some considerable disadvantages, such as the drastic
conditions and moderate overall yields. Therefore, several procedures have been widely applied to convert
primary and secondary alcohols to the corresponding azides -based on the SN2 mechanism- which then can be
reduced to the corresponding amines.14-16 However, only limited examples of robust procedures have been
published on the conversion of tert-alkyl alcohols16-20 to the corresponding amines, and some of them used
elaborate reactants.16,20 Furthermore, while several reagents have been developed for the reduction of primary
and secondary azides to the corresponding amines, when a tert-alkyl azide is the substrate its reduction is
considered to be inconvenient.12. In this work, we present our efforts towards the synthesis of primary tert-alkyl
amines, including adamantyl as one of the alkyl groups, and we compare the various aforementioned
procedures.
3 Results and Discussion
Tert-alkyl azide reduction (Procedure A)
Tert-alkyl azide formation. Procedure A may start with a ketone or other suitable starting material, e.g. an acid
chloride. The tert-alkyl alcohol was obtained by the reaction of the starting material with a suitable
organometallic reagent. Subsequently, it was converted to the tert-alkyl azide which was then subjected to a
reduction, affording the primary tert-alkyl amine. The conversion of tertiary adamantanols to the corresponding
azides was routinely performed in our lab using a mixture of CHCl3/H2SO4 57 % and sodium azide in good
yields.21 These reaction conditions were applied to linear tert-alkyl alcohols, like BuEt(n-Pr)COH (1b),
obtained from 3-heptanone (1a) and PrMgBr. A mixture of the azide BuEtPrCN3 (1c) and the precursor alcohol
13
1a was obtained in 60:40 ratio, based on the integration of C NMR signals (Table S1, entry 1). The reaction
proceeds via the formation of a carbonium ion which is trapped by the azide anion. It seems that the 2-alkyl-2-
adamantyl carbonium intermediates from tertiary 2-alkyl-2-adamantanols are more stable, and thus form more
efficiently compared to those formed by tert-alkyl alcohols.22 A more efficient formation of the aforementioned
linear azide was not achieved after increasing the sulfuric acid concentration to 70 % (Table S1, entry 2);
instead a ketone product was also formed along with the azide. This ketone may be formed through a Schmidt
rearrangement mechanism which produces an imine that can be hydrolyzed to a ketone -as has been previously
reported for the tert-butyl substrate.23 The tert-alkyl alcohol 1b was treated with CHCl3/TFA 0.5M/NaN3
mixture, and the reaction product was a mixture of the azide 1c and the precursor alcohol 1b in a 70:30 ratio -
according to the 13C NMR spectrum. An increase in TFA concentration to 1 M was tested but the same mixture
was afforded (Table S1, entries 3, 4), while further increase of the TFA concentration to 5M caused a
decomposition of the substrate. Changing the solvent from CHCl3 to CH2Cl2 or ClCH2CH2Cl, i.e. from
CHCl3/TFA 1 M/NaN3 to CH2Cl2 or ClCH2CH2Cl/TFA 1 M/NaN3, resulted in the azide as the only product
(Table S1, entry 5; Table 1, entry 1).
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Table 1. Conversion of tert-alkyl alcohols to tert-alkyl azides using a NaN3/TFA in CH2Cl2 or ClCH2CH2Cl
(Procedure A).a
Entry
Ketone + organometallic reagent
Alcohol
R1,R2,R3
Isolat
ed
Azide
R1,R2,R3
Isola
ted
Yield
Yiel
d
1
2
3
4
5
6
7
3-heptanone (1a) + PrMgBr
4-heptanone (2a) + PrMgBr
5-nonanone (3a) + BuMgBr
4-heptanone (2a) + BuMgBr
4-heptanone (2a) + iBuLi
Bu,Et,Pr, 1b
Pr,Pr,Pr, 2b
80%
78%
80%
71%
80%
70%
80%
Bu,Et,Pr, 1cb
Pr,Pr,Pr,, 2cb
Bu,Bu,Bu, 3cb
Bu,Pr,Pr, 4cb
iBu,Pr,Pr, 5cb
Bu,Bu,Pr, 6cb
iBu,iBu,Bu, 7cc
87%
78%
82%
71%
86%
75%
76%
Bu,Bu,Bu, 3b
Bu,Pr,Pr, 4b
iBu,Pr,Pr, 5b
Bu,Bu,Pr, 6b
iBu,iBu,Bu, 7b
5-nonanone (3a) + PrMgBr
2,6-dimethyl-heptan-4-one (4a) +
BuLi
2-adamantanone (5a) + MeMgBr
2-adamantanone (5a) + EtLi
2-adamantanone (5a) +
8
9
10
2Ad, Me, 8b
2Ad, Et, 9b
2Ad, Pr, 10b
88%
80%
89%
2- Ad, Me, 8cb
2- Ad, Et, 9cb
2- Ad, Pr, 10cb
88%
80%
66%
CH2CH=CH2MgBr then PtO2/H2
2-adamantanone (5a) + BuLi
2-adamantanone (5a) + PhLi
2-adamantanone (5a) + BnMgBr
2-adamantanone (5a) + pMeOBn
1AdCOCl (6a) + MeMgBr
1AdCOCl (6a) + EtLi
1AdCOCl (6a) + AllylMgBr
1AdCOCl (6a) + CH2CH=CH2MgBr
then PtO2/H2
11
12
13
14
15
16
17
18
2Ad, Bu, 11b
2Ad, Ph, 12b
2Ad, Bn, 13b
76%
95%
50%
53%
80%
77%
2- Ad, Bu, 11cb
2- Ad, Ph, 12cb
2- Ad, Bn, 13cb
76%
95%
50%
2Ad, MeOBn, 14b
1Ad, Me, Me, 15b
1Ad, Et, Et, 16b
1Ad, Allyl, Allyl, 17b
1Ad, Pr, Pr, 18b
2- Ad, MeOBn, 14c 53%
1Ad,Me,Me, 15cb
1Ad, Et, Et, 16cb
80%
77%
44% 1Ad, Allyl, Allyl, 17cb 44%
59%
1Ad, Pr, Pr, 18cb
37%
19
20
1AdCOCl (6a) + BrMg(CH2)4MgBr
C5H11, 1Ad, 19b
C6H13, 1Ad, 20b
90%
65%
C5H11, 1Ad, 19cb
Cy, 1-Ad, 20cb
90%
65%
2-cyclohexanone (7a) + 1-AdLi
aCompletion of reaction was checked by 13C NMR peaks integration; bCH2Cl2 used; cClCH2CH2Cl used
The aforementioned reaction conditions were then tested against tert-alkyl alcohols 2b-20b for the
preparation of azides 2d-20d (Table 1, entries 2-20). Alcohols 1b-4b, 6b were obtained from the reaction
between the ketones 1a-3a respectively and the suitable Grignard reagent (Table 1, entries 1-4,6). The
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iBuPr2COH (5b) was obtained from the addition of isobutyl lithium to 4-heptanone (2a). Similarly iBuBu2COH
(7b) (Table 1, entry 7) was afforded through addition of isobutyl lithium to 5-nonanone (3a). Starting from
alcohols 1b-7b and using the conditions shown in Table 1, i.e. CH2Cl2 or ClCH2CH2Cl/TFA 1 M/NaN3,
correspondingly, the azides 1c-7c were afforded in yields 71-87% (Table 1). In the adamantane series, tertiary
alcohols 8b, 9b, 11b, 12b were obtained by treating 2-adamantanone 5a with an oganolithium (R=Et,Bu) or an
organomagnesium reagent (R=Me,Ph,PhCH2,pMeOPhCH2), as depicted in Figure S1. For the synthesis of the
propyl derivative 10b, 2-adamantanone reacted with vinyl magnesium bromide and the produced allyl alcohol
was hydrogenated under PtO2. Compound 15b was prepared from the reaction between 1-adamantane carbonyl
chloride (6a) (the corresponding ethyl ester was also successfully trialed) and CH3MgΙ, as expected.11 Alcohol
16b was prepared in high yield from the reaction between 1-adamantane carbonyl chloride (6a) and EtLi. The
reaction of allylmagnesium bromide with 6a afforded diallyl alcohol 17b, which was subsequently
hydrogenated under PtO2 catalyst to afford alcohol 18b (Figure S2). Starting from alcohols 8b-18b and using
the above conditions the azides 8c-18c were afforded in yields 37-88% (Table 1). A trial to prepare the
cyclopentenol precursor of cyclopentanol 19b through cyclization of 17b using first generation Grubbs catalyst
was unsuccessful. Diallyl azide 17c was prepared from 17b with a 44% yield. Compounds 19b, 20b were
synthesized according to the procedure included in reference 30. According to the reaction conditions presented
in Table 1, changing the solvent from CHCl3 to CH2Cl2 or ClCH2CH2Cl increased considerably the tert-alkyl
azide yield. The tert-alkyl azide formation proceeds through an ion pair intermediate, i.e. the tert-alkyl
carbocation/TFA anion, generated by the tert-alkyl alcohol treatment with TFA. This is more favored in
dichloromethane compared to chloroform due to the higher dielectric constant of CH2Cl2 (ε = 8.93) or
ClCH2CH2Cl (ε = 10.4), compared to CHCl3 (ε = 4.81). The former can stabilize the carbonium ion and thus
facilitate its formation, according also to DFT calculations included in the Supplementary material (Table S3,
S4). When ether was used as a solvent (ε = 4.33), the starting alcohol was afforded. Protic solvents have also
high dielectric constants, but tert-alkyl azides are formed in low yields in protic solvents due to the competitive
solvolysis reaction.24
Tert-alkyl azide reduction. It was tested if primary tert-alkyl amines 1d-7d could be formed conventionally
from primary tert-alkyl azides 1c-7c through a LiAlH4 reduction21,25,26 or a catalytic hydrogenation, for example
using Pd/C.27 In general, these methods were considered to be high yielding25,26 without a systematic
investigation regarding the structure of the tert-alkyl substrate; e.g. in one case it was reported that the reduction
took a different route, yielding a triazene.28 On the other hand, the reduction of tert-alkyl azides to tert-alkyl
amines has been reported to be an inconvenient transformation, albeit without further explanations and
citations.12 The reduction of the tert-alkyl azides 1c-20c using LiAlH4 in refluxing ether for 5 h yielded the
primary tert-alkyl amines 1d-20d in good (Table 2, entries 1,2,5,15,17,19,20) to moderate yields (Table 2,
entries 3,4,6,7,16,18). The antiviral bulky aminoadamantanes 8d-13d, 15d-20d11,29,30 were also afforded (Table
2, entries 8-20, Figures S1-S4), with the notable exception of 17d where decomposition took place. The yields
of compounds 15d, 16d, 18d were improved (Figure S2), compared to previous results.11 The reaction was
performed using 4 equivalents of LiAlH4 in a slurry with a concentration of 1 g LiAlH4/80 mL dry ether under
reflux. The resulting amines were isolated through standard hydrolysis conditions and filtration of the reaction
mixture. The ethereal solution was extracted with hydrochloride solution 6%, the acidic solution was made
alkaline with solid sodium carbonate and the mixture was extracted with ether to afford amines 1d-20d. The
purity was higher than 95%, according to the relative integration of amine signals with impurities signals
13
detected in C NMR spectra. The amines were further purified through formation of crystalline ammonium
salts with fumaric acid and recrystallization using ethanol/ether. A probable competitive reaction lowering the
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yield of the amine is the formation of an imine which can be formed through an intramolecular Schmidt
rearrangement via a nitrene intermediate.31 When refluxing THF was used, lower yields were obtained. The
yield was not improved when the refluxing ethereal conditions were changed to ambient temperature. The
LiAlH4 reaction of diallyl azide 17c did not afford the diallylamine but led to decomposition.
It is noteworthy that a critical reduction in yield was observed when transitioning from Pr3 to Bu3 substrate
(Table 2, see entries 2,3,10,11), due to the formation of unsaturated products and extensive decomposition. To
investigate further the effect of the structure of the tert-alkyl group to the yield of the reduction of the azido
group, the alcohols 5b, 6b and the corresponding azides 5c, 6c including the combination of BuPr2 and Bu2Pr
substitution on the tertiary carbon were synthesized (Table 2, entries 5,6). As depicted in Table 2, the yield for
the BuPr2 substrate in amine 5d (Table 2, entry 5) was 58% and in close proximity to the 60% yield obtained
with Pr3 substrate in amine 2d (Table 2, entry 2). The yield was reduced progressively from 35% in the Bu2Pr
substrate of amine 6d (Table 2, entry 6), to 20% in the Bu3 or iBu2Bu substrates of amines 3d, 7d respectively
(Table 2, entries 3,7). Also, changing the tri-alkyl group from Pr3 to iBuPr2 reduced significantly the yield to
14% in amine 4d (Table 2, entry 4). Although the yields included in Table 2 were not optimized, the procedure
was general for all the substrates applied, except entry 17. While in all cases refluxing ether seems to be an
optimal choice for LiAlH4 reduction of the tert-alkyl azides, these conditions did not work well in one case
(Table 2, entry 14). It was observed that between Bn and pMeOBn substrate (Table 2, entries 13 and 14),
refluxing ether conditions led to complete reduction for Bn substrate (Table2, entry 13), but for pMeOBn the
reduction yield was only 18% and most of the azide 14c was isolated unreacted (Table 2, entry 14). Refluxing
THF was applied for effective reduction of the azide 14c. The p-methoxy group in amine 16d was deprotected
to the p-hydroxy group using BF3 in dry ether at -80 ºC to afford the aminoderivative 21 (Figure S5).
Table 2. Reaction of tert-alkyl azides with LiAlH4 in refluxing dry ether (Procedure A).a
Entry
Azide
R1,R2,R3
Amine product
R1,R2,R3
Isolated Yield
1
2
3
4
5
6
7
8
9
Bu,Et,Pr, 1c
Pr,Pr,Pr, 2c
Bu,Et,Pr, 1d
Pr,Pr,Pr, 2d
67%
60%
20%
14%
58%
35%
20%
77%
71%
74%
23%
55%
Bu,Bu,Bu, 3c
iBu,Pr,Pr, 4c
Bu,Pr,Pr, 5c
Bu,Bu,Pr, 6c
iBu,iBu,Bu, 7c
2Ad, Me, 8cb
2Ad, Et, 9c
2Ad, Pr, 10c
2Ad, Bu, 11c
2Ad, Ph, 12c
Bu,Bu,Bu, 3d
iBu,Pr,Pr, 4d
Bu,Pr,Pr, 5d
Bu,Bu,Pr, 6d
iBu,iBu,Bu, 7d
2Ad, Me, 8d
2Ad, Et, 9d
2Ad, Pr, 10d
2Ad, Bu, 11d
2Ad, Ph, 12d
10
11
12
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13
14
15
16
17
18
19
20
2Ad, Bn, 13c
2Ad, Bn, 13d
2Ad, MeOBn, 14d
1Ad, Me, Me, 15d
1Ad, Et, Et, 16d
1Ad, Allyl, Allyl, 17d
1Ad, Pr, Pr, 18d
45%
18%, 48%a
73%
2Ad, MeOBn, 14c
1Ad, Me, Me, 15c
1Ad, Et, Et, 16c
1Ad, Allyl, Allyl, 17c
1Ad, Pr, Pr, 18c
23%
b
-
14%
56%c
48%c
C5H11, 1Ad, 19c
C6H13, 1Ad, 20c
C5H11, 1Ad, 19d
C6H13, 1Ad, 20d
aCompletion of reaction was observed by NMR; bdecomposition; cprepared as depicted in Figures S3, S4
A few other reagents were tested for reduction of the tert-alkyl azido group; however, no significant
improvement was achieved in yield compared to the LiAlH4 reduction. Some representative trials include the
catalytic hydrogenation with Pd/C (10%)27 for 18 h using different solvents (AcOEt, MeOH, MeOH/NH3(g),
MeOH/CHCl3) or different pressure conditions (50 psi or 1 Atm). For example, for the BuEtPrCN3 (1c) the
highest yield achieved with catalytic hydrogenation was 57% for EtPrBuC-NH2 (1d); while Bu3CN3 (3c)
afforded Bu3C-NH2 (3d) in 11% yield. The catalytic hydrogenation of compound 17c led to a complex mixture
of products. The yields were also low or poor when reduction of EtPrBuCN3 (1c) was attempted with: (a)
FeCl3/NaI32 (10%); (b) Me3SiCl/NaI33 (4%); (c) by applying Staudinger reaction conditions and hydrolysis of
the phosphazene in THF/H2O under reflux19,34 (13%); (d) NaBH4/CuSO4·5H2O35 (23%). When Pr3CN3 (2c) was
used in combination with (EtO)3P/benzene/TosOH/EtOH19,34,36 or with SnCl2/PhSH/Et3N37 the yields of the
obtained amine 2d were 35% and 33% respectively. When Bu3CN3 (3c) was used as the substrate, the same
reagents afforded Bu3C-NH2 (3d) in yields 18% and 8%. The conclusion drawn from the trials described is that
the weak spot of procedure A, which is responsible for the serious decrease of the overall yield, is the reduction
step of the tert-alkyl azide to the corresponding primary tert-alkyl amine, particularly when the alkyl chain
length is increasing. Other possibly more efficient procedures were then investigated, especially for the
synthesis of crowded amines like Bu3CN3 (3d) which was produced in low yield with procedure A.
Ritter reaction (Procedure B)
Common Ritter reaction. The Ritter reaction12 was tested using common12,38 (KCN, c.H2SO4, heat; see Table
S2, entries 1,2) or slightly modified conditions (urea, c.H2SO4, heat; see Table S2, entry 3). The results showed
that these common Ritter reaction conditions proved, at best equally effective, compared to procedure A, for the
preparation of the BuEtPrCNH2 (1d) in 47% yield (see Table S2, entry 1), and significantly worse for the
preparation of Bu3CNH2 (3d) in 4-5% (yield see Table S2, entry 3).
Modified Ritter reaction. A modified Ritter reaction scheme was tested, which was suggested as a general
scheme for the synthesis of primary tert-alkyl amines.39 This methodology is reported to employ the formation
of N-tert-alkyl chloroacetamides after reaction of tert-alkyl alcohols with chloroacetonitrile. The chloroacetyl
group can be subsequently cleaved smoothly with thiourea, leading to the formation of the respective amine
(Table 3).
Table 3. Modified Ritter reaction through chloroacetamides which are hydrolyzed with thiourea for the
preparation of primary tert-alkyl amines (Procedure B).
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S
O
R1
R3
R1
R1
NCCH2Cl
H2N
NH2
Cl
R2
OH
R2
N
R2
NH2
c. H2SO4
AcOH
H
R3
R3
EtOH, AcOH (5:1)
then OH- (aq)
Entry
Alcohol
R1,R2,R3
Chloroacetamide
R1,R2,R3
Isolated
Yield
48%
Amine
R1,R2,R3
Isolated
Yield
80%
1
2
Pr,Pr,Pr, 2b
Bu,Bu,Bu, 3b
Pr,Pr,Pr, 22
Bu,Bu,Bu, 23
Pr,Pr,Pr, 2d
Bu,Bu,Bu, 3d
51%
61%
Using this procedure, Pr3C-NH2 (2d) and Bu3C-NH2 (3d) were successfully obtained from the
corresponding tert-alkyl alcohols 2b and 3b through intermediate chloroacetamides 22 and 23. In the latter case,
the yield of the chloroacetyl group cleavage step was lower. However, as the alkyl group size was increasing,
the efficiency of Ritter-like procedures for the synthesis of primary tert-alkyl amines was reduced; possibly due
to a retro-Ritter reaction.40 Especially, when the common Ritter reaction conditions were applied, the yield was
reduced dramatically (Table S2, entries 2,3). After work-up of the reaction mixture in the second step and the
isolation of amines 2d or 3d through extraction with an aqueous hydrochloric acid solution, the organic layer
contained an unsaturated product, possibly formed through a retro-Ritter reaction. The modified Ritter reaction
scheme included as a second step a more efficient chloroacetyl group cleavage, affording the primary tert-alkyl
amine in yields 80% and 60% for substrates Pr3C and Bu3C respectively. The azide reduction had moderate to
low yields, 60% and 20% respectively, for the same substrates. However, in the first step the tert-alkyl azides
2c, 3c are formed in higher yields compared to the tert-alkyl chloroacetamides 22 and 23. Procedure B, while
providing amine 11d through chloroacetamide 24 successfully, was not productive when applied for the
synthesis of amines 15d or 18d. The relevant trials afforded chloroacetamides 25, 26 in low to moderate yield,
due to the formation of an alkene by-product, and the cleavage of the chloroacetyl group with thiourea gave
correspondingly the tert-alkyl amines 15d, 18d only in traces (Figure S5).
Addition of organometallic reagents to N-tert-butylsulfinyl imines (Procedure C)
The procedure consisting of the addition of organomagnesium or organolithium reagents to the N-tert-
butylsulfinyl imines41,42 28 and 29 and deprotection of N-tert-butylsulfinamides 30 and 31,41,42 proved
successful for the synthesis of the tert-alkyl amines 2d and 3d (Table 4). However, more elaborate conditions
and more expensive reagents (e.g. tert-butanesulfinamide) were needed, compared to the previous procedures.
For the preparation of Bu3C-NH2 (3d), the addition of BuLi/AlMe3 to imine 28 was applied, which proved to be
more efficient compared to BuMgBr or BuLi.41,42
Table 4. Synthesis of primary tert-alkyl amines by the addition of organometallic reagents to N-tert-
butylsulfinyl imines (Procedure C).
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Entry
Ketone
R1,R2
N-tBu-sulfinylimine Isolated
tBu-sulfinamidea
R1,R2,R3
Amine
R1,R2,R3
Isolatedb
Yield
40%
R1,R2
Yield
70%
77%
1
2
Pr,Pr, 2a
Bu,Bu, 3a
Pr,Pr, 28
Bu,Bu, 29
Pr,Pr,Pr, 30
Bu,Bu,Bu, 31
Pr,Pr,Pr, 2d
Bu,Bu,Bu, 3d
25%
ayield not determined; bfrom the N-tert-butylsulfinyl imine
Starting from the same commercially available ketone, procedure A applied the sequence ketone → tert-
alkyl alcohol → tert-alkyl azide → tert-alkyl amine; procedure B using the modified Ritter reaction applied the
sequence ketone → tert-alkyl alcohol → tert-alkyl chloroacetamide → tert-alkyl amine; procedure C applied
the sequence ketone → tert-butylsulfinyl imines → tert-butanesulfinamide → tert-alkyl amine. From 5-
nonanone (3a) the synthesis of Bu3CNH2 (3d) was accomplished using the procedure A, B (modified Ritter)
and C in 13%, 25%, and 19% yield respectively. Starting from 4-heptanone (2a), the synthesis of Pr3CNH2 (2d)
was accomplished in 37%, 30%, 28% yield respectively. Procedure C, similarly to procedure B (modified
Ritter), was also not productive in the adamantane series. The reaction of 1-adamantyl ethyl ketone 32 with tert-
butanesulfinamide did not yield the corresponding N-tert-butylsulfinyl imine 33. The formation of intermediates
27 and 33 suffers from steric hindrance, as suggested by Molecular Mechanics calculations (see Figure S5).
Addition of organometallic reagents to nitriles (Procedure D)
The one-pot synthesis of primary tert-alkyl amines through addition of organometallic reagents to nitriles in the
presence of Lewis acid catalysts was investigated.43-47 The synthesis of few tert-alkyl amines was first tested
through a procedure following the Kulinkovich-de Meijere reaction conditions: addition of an excess of
organometallic reagent (3-4 equivalents) to nitriles (1eq) mediated by Ti(iPrO)4 (1 eq) in one-pot (Table 5).12
Table 5. One-pot synthesis of primary tert-alkyl amines by the addition of organometallic reagents to nitriles
mediated by Ti(iPrO)4 (Procedure D).
Entry
1
nitrile
reagents, protocol
(1), (2)
Product: yield
(1)
(2)
a
a
BuMgBr ether,Ti(iPrO)4
Not tested
C N
BuMgBr ether,Ti(iPrO)4
2
Not tested
35
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Tzitzoglaki, C.; Drakopoulos, A. et al.
a
PrMgBr ether, Ti(iPrO)4
3
4
Not tested
a
MeMgBr ether,Ti(iPrO)4
Not tested
Not tested
a
EtMgBr ether, Ti(iPrO)4
5
6
BrMg(CH2)4MgBr
NH2
b
ether,Ti(iPrO)4
Not tested
19d: 10%
1. MeMgBr ether, Ti(iPrO)4
2. MeLi, ether c
7
8
1. EtMgBr ether, Ti(iPrO)4 2.
EtLi, ether c
1. MeMgBr, Ti(iPrO)4, ether
2. MeMgBr, ether d
9
MeLi,CeCl3, THF, -65 oC e
10
(1) Kulinkovich-DeMeijere; (2) Kulinkovich-Szymoniak; aRMgBr(3eq)/Ti(iPrO)4(1eq)/ether/24h/reflux;
c
bBrMg(CH2)4MgBr(2eq)/Ti(iPrO)4 (1eq)/ether/24h/reflux; 1.RMgBr(1eq)/Ti(iPrO)4 (1eq)/ether/1h/rt 2.MeLi
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d
e
(2eq) ether/24h/reflux. MeMgBr (1eq)/Ti(iPrO)4 (1eq)/ether/1h/rt 2. MeMgBr (2 eq)/ether/1h, rt. MeLi (3
eq)/CeCl3 (3 eq)/THF/4h/-65 oC.
One equivalent of the Grignard reagent reacted first with the nitrile, forming an imino derivative. Then
Ti(iPrO)4 was added to activate the imino functionality for the addition of a second equivalent of an
organometallic reagent, which can be a different Grignard or an organolithium reagent (see Figure S6 for the
detailed desciption of the original protocol).12 Starting from the commercially available butanenitrile (34) and
pentanenitrile (35), the preparation of PrBu2CNH2 (6d) and Bu3CNH2 (3d) was accomplished in 25% and 20%
yield respectively (Table 5, entries 1, 2). In the original papers, the reaction was tested for nitriles up to
secondary or benzonitrile.10,45 We applied the Kulinkovich-de Meijere reaction to pivalonitrile (36). Treatment
of nitrile 33 with propylmagnesium bromide (3 eq)/Ti(iPrO)4 afforded the t-BuPr2CNH2 (38) in 20% yield
(Table 5, entry 3). Following a work-up of the reaction mixture, the yield was determined for the reactions
depicted in Table 5 after fumarate salt formation and recrystallization of the amine product, as previously. The
Kulinkovich-de Meijere protocol was applied for the reaction of 1-adamantanecarbonitrile (37) and the simple
Grignard reagents RMgBr (R=Me, Et) in the presence of Ti(iPrO)4 for the synthesis of primary tert-alkyl
adamantanamines 15d and 16d (Table 5, entries 4-9). The addition of ethylmagnesium bromide to 1-
adamantanecarbonitrile (37) using the above conditions afforded a mixture of AdEtCHNH2 (40) in 3% yield
and AdEt2CNH2 16d in 4% yield; the ratio of 40 to 16d was 60:40 according to the 13C NMR spectrum (Table
5, entry 5). It was thought that a β-hydride addition from the second equivalent of the organometallic reagent to
an imino group might explain the formation of the sec-alkyl amine 40 along with the tert-alkyl amine 16d.
However, it was striking that the application of MeMgBr afforded the secondary amine, that is, rimantadine
AdMeCHNH2 (39) in 15% yield (Table 5, entry 4); while unreacted AdMeC=NH imine was identified in the
filtrate after filtration of the solid fumarare salt of the amine 39. The application of an organolithium compound
as the organometallic reagent in the second step was also tested using the Kulinkovich-de Meijere protocol
(Figure S6). The desired tert-alkyl amines 15d, 16d were obtained in 10% yield (Table 5, entries 7, 8). In the
fumarate salt, a small amount of the secondary amine 37 was again detected as a 10% contamination.
The organocerium reagent prepared from anhydrous cerium (III) chloride and methyl lithium was tested as
candidate to a higher yield formation of tert-alkyl amine 16d. This one-pot sequence was assumed to proceed
through an activated imino functionality to give primary tert-alkylamines (Figure S7). The reaction of 3 equiv
of MeCeCl2 with 1-adamantanecarbonitrile (32) at -78 ºC and stirring the mixture at -65 ºC for 4 h was reported
to afford 15d in 75%.46 We tested this procedure twice and the maximum yield obtained was 12% for 15d
(Table 5, entry 10).
The Kulinkovich-Szymoniak43 reaction conditions were also tested for the preparation of 15d and 16d. In
this protocol, the nitrile, Ti(iPrO)4 and organometallic reagent were initially placed together in the reaction flask
(see Figure S8 for the detailed desciption of the original protocol). Subsequently, an additional amount of
organometallic reagent (the same as previously or different) is added. In our trials, we employed one equivalent
of EtMgBr and then one equivalent of EtLi, or two equivalents of EtMgBr (Figure S8). This reaction sequence
is based on the formation of a titatanocene compound including an electrophilic imine bond, which reacts with
the second organometallic reagent (see Figure S8 for the detailed desciption of the original protocol). Using
these conditions the pure amine 15d or 16d was isolated as crystalline fumarate in 10% yield (Table 5, entries
7,8). When the Kulinkovich-de Meijere protocol or the Kulinkovich-Szymoniak protocol was applied for the
treatment of 1-adamantanecarbonitrile (32) with Ti(iPrO)4/RMgBr and RLi, the tert-alkyl amine 15d or 16d
was afforded in 10 to 11% yield (Table 5, entries 7,8). A recent report applied Ti(iPrO)4 in combination with
ethylmagnesium bromide under Kulinkovich-Szymoniak conditions was reported to afford 16d in 52% yield.47
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This result was not reproduced after several trials; the application of the Kulinkovich-Szymoniak protocol for
the treatment of 1-adamantanecarbonitrile (32) with Ti(iPrO)4, MeMgBr (1eq) and MeMgBr (2 eq) afforded the
tert-alkyl amine 15d in 8% yield (Table 5, entry 9). The Kulinkovich-de Meijere protocol with Ti(iPrO)4 and
MeMgBr (1eq) and MeMgBr (2 eq) afforded amine 15d in 10% yield (Table 5, entry 9). The way that the
organomagnesium reagent was added influenced the yield, in comparison to entry 4; applying the addition of
the 3 equivalents in one step before addition of Ti(iPrO)4 did not afford the desired amine 15d. Trials using
allylmagnesium bromide afforded a complex mixture of products either using Kulinkovich-de Meijere or
Kulinkovich-Szymoniak. The reaction of adamantanacarbonitrile (37) with 1,4-bis(bromomagnesiobutane)
afforded cyclopentanamine21 19d in 10% yield (Table 5, entry 6). The overall yield using procedure A for the
transformation of alcohol to amine 19d starting from the commercially available 1-adamantanacarboxylic acid
using treatment of 1-adamantanecarboxylate with 1,4-bis(bromomagnesiobutane) was ~ 32%.
4 Conclusions
Although elegant procedures have been developed for the preparation of primary sec-alkyl amines through the
formation of carbon-carbon bonds in position alpha to the respective nitrogen (see for example reference 48), the
synthesis of primary tert-alkyl amines, which are of great interest to the field of medicinal chemistry, is still not
trivial. A systematic study of four standard procedures on the preparation of primary tert-alkyl amines was
presented. Under procedure A, the tert-alkyl azides can be prepared from tert-alkyl alcohols using NaN3 and
dichloromethane or 1,2-dicholoroethane as optimal solvents, and the target amines are prepared by azides
reduction with LiAlH4, generally in refluxing ether. It was found that subtle changes of the size of the linear
alkyl chain can influence the yield in the reduction step of this procedure. For example, a gradual reduction in
yield from Pr3C to Bu3C substrate was observed. A modified Ritter reaction employing a tert-alkyl
chloroacetamide intermediate (procedure B), the addition of organometallic reagents to N-tert-butyl sulfinyl
ketimines (procedure C) or the one-pot reaction of nitriles with organometallic reagents in the presence of
Ti(iPrO)4 or CeCl3 (procedure D) can be useful routes, but were not efficient when the substrate includes unique
bulky adducts. The first protocol via azide reduction is rather general even for unique adamantane adducts.
5 Experimental Section
1
General. IR spectra were recorded on a Perkin-Elmer 833 spectrometer. H and 13C NMR spectra were
recorded on a Bruker DRX 400 and AC 200 spectrometer at 400 and 50 MHz, respectively, using CDCl3 as the
solvent and TMS as the internal standard. Carbon multiplicities were established by the DEPT experiments. The
2D NMR techniques, HMQC and COSY, were used for the elucidation of the structures of intermediates and
final products. Microanalyses were carried out by the Microanalyses lab of the National Center for Scientific
Research, Demokritos, Athens, and the results obtained had a maximum deviation of ± 0.4% from the
theoretical value. Compounds 9d-13d were synthesized in reference 29 (see Figure S1); compounds 15d, 16d
were synthesized in reference 11 but in this work were synthesized with improved yield (see Figure S2);
compounds 19d, 20d were synthesized using the procedure described in reference 49 and in reference 30 as
modification of the procedure applied in reference 48 (see Figures S3, S4). Caution should be kept when using
NaN3 or KCN in strong acid which can generate the toxic HCN or HN3 respectively. When the adamantane ring
is 2,2-disubstituted with A, B substituents one of the cyclohexane rings has the 2-substituent A in an axial
position and another cyclohexane ring has the 2-substituent B in an axial position. Therefore 4,9-carbons of the
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adamantane in one cyclohexane ring has protons 4ax,9ax and 4eq,9eq due to the 2-axial substituent A and 8,10-
carbons of the adamantane in the other relevant cyclohexane ring has has protons 8ax,10ax and 8eq,10eq due to
the 2-axial substituent B (Figure S9).
Procedure A
4-Ethyloctan-4-amine (BuEtPrCNH2) 1d. 4-Ethyloctan-4-ol 1b was obtained after treating a solution of 3-
heptanone 1a (1g, 8.77 mmol) in dry ether (30% solution w/v) with 1.2-molar excess of CH3CH2CH2MgBr
(obtained from an 20% solution w/v solution of 1-bromopropane (2.1 g, 17.54 mmol) in dry ether and 1.3
equivalents of Mg (548 mg, 22.8 mmol)) under argon atmosphere and stirring the mixture overnight. After
treating the mixture with saturated ammonium chloride following usual workup the corresponding tertiary
1
alcohol 1b was obtained. Yield 1.1 g, (80%); IR (Nujol) ν(OH) 3392 cm-1; H NMR (CDCl3, 400 MHz): δ
(ppm) 0.85 (t, J=7.1 Hz, 3H, (CH2)3CH3), 0.91 (t, J=7.1 Hz, 6H, (CH2)2CH3, CH2CH3), 1.22-1.48 (m, 13H,
(CH2)3CH3, (CH2)2CH3, CH2CH3, OH); 13C NMR (CDCl3, 50 MHz) δ (ppm) 7.9 ((CH2)3CH3), 14.3
((CH2)2CH3), 14.9 (CH2CH3), 16.9 ((CH2)2CH2CH3), 23.5 (CH2CH2CH3), 25.8 (CH2CH2CH2CH3), 31.7
(CH2CH3), 38.6 (CH2(CH2)2CH3), 41.4 (CH2CH2CH3), 74.3 (COH).
To a stirred mixture of sodium azide (488 mg, 7.50 mmol) and dry dichloromethane (15 mL),
trifluoroacetic acid (2 mL, 25 mmol) was added at 0 °C. The resulting mixture was stirred for 10 min at 0 °C
and a solution of the 4-ethyl-4-octanol 1b (400 mg, 2.50 mmol) in 10 mL of dichloromethane was added
dropwise. The mixture was stirred at 0-5 °C for 4 h and 24 h at ambient temperature. The mixture was made
alkaline by adding NH3 12 % (40 mL) and the organic phase was separated. The aqueous phase was extracted
with dichloromethane and the combined organic phases were washed with water, brine and dried (Na2SO4).
Solvent was evaporated in vacuo to afford 4-azido-4-ethyloctane, 1c. Yield 398 mg, (87%); IR (Nujol) ν(Ν3)
2093 cm-1; 13C NMR (CDCl3, 50 MHz) δ (ppm) 8.1 ((CH2)3CH3), 14.2 ((CH2)2CH3), 14.6 (CH2CH3),
17.0((CH2)2CH2CH3), 23.2 (CH2CH2CH3), 25.8 (CH2CH2CH2CH3), 29.3 (CH2CH3), 35.8 (CH2(CH2)2CH3),
38.5 (CH2CH2CH3), 67.3 (CN3).
To a stirred suspension of LiAlH4 (223 mg, 5.87 mmol) in dry ether (20 mL) was added dropwise at 0 °C a
solution of the alkyl azide 1c (269 mg, 1.47 mmol) in dry ether (15 mL). The mixture was refluxed for 5 h and
then was treated with water, NaOH 10 % and water. The insoluble inorganic material was filtered-off, washed
with ether and the filtrate was extracted with HCl 6%. The aqueous phase was made alkaline with solid sodium
carbonate and was extracted with diclhoromethane or ether. The organic phase was washed with brine, dried
(Na2SO4) and evaporated in vacuo to afford the amine 1d. Yield 150 mg, (65%); 1H NMR (CDCl3, 200 MHz) δ
(ppm) 0.82 (t, J=7.1 Hz, 3H, (CH2)3CH3), 0.90 (t, J=7.1 Hz, 6H, (CH2)2CH3, CH2CH3), 1.26-1.37 (m, 14H,
(CH2)3CH3, (CH2)2CH3, CH2CH3, NH2); 13C NMR (CDCl3, 50 MHz) δ (ppm) 7.9
((CH2)3CH3),
14.3((CH2)2CH3), 15.0(CH2CH3), 16.8((CH2)2CH2CH3), 23.6 (CH2CH2CH3), 25.9 (CH2CH2CH2CH3), 32.6
(CH2CH3), 39.6 (CH2(CH2)2CH3), 42.4 (CH2CH2CH3), 53.6 (CNH2). MS (ES+) : C10H24N+ (M+H+) 158.2
Found: 158.2. Anal. (C14H27NO4). Calcd. : C, 61.51; H, 9.96; N, 5.12. Found: C, 61.54; H, 10.16; N, 5.01.
4-Propylheptan-4-amine (Pr3CNH2) 2d. Tertiary alcohol 2b was obtained after treating a solution of 4-
heptanone 2a (1g, 8.77 mmol) in dry diethyl ether (30% solution w/v) with 1.2-molar excess CH3CH2CH2MgBr
(obtained from an 20% solution w/v solution of 1-bromopropane (2.1 g, 17.54 mmol) in dry ether and 1.3
equivalents of Mg (548 mg, 22.8 mmol)) under argon atmosphere and stirring the mixture overnight. After
treating the mixture with saturated ammonium chloride following usual workup 4-propylheptan-4-ol 2b was
obtained. Yield 1.1 g, (78%); IR (Nujol) ν(OH) 3392 cm-1; 1H NMR (CDCl3, 200 MHz) δ (ppm) 0.91 (t, J=7.1
13
Hz, 9H, 3x CH2CH2CH3), 1.15-1.41 (m, 12H, 3xCH2CH2CH3 , 3xCH2CH2CH3), 2.10 (br s, OH); C NMR
(CDCl3, 50 MHz) δ 14.9 (CH3), 17.0 (CH2CH2CH3), 42.0 (CH2CH2CH3), 74.7 (COH).
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The 4-azido-4-propylheptane 2c was prepared by treatment of the tertiary alcohol 2b (400 mg, 2.50 mmol)
with CH2Cl2 (15 mL)/NaN3 (488 mg, 7.50 mmol)/TFA (2 mL, 25 mmol) according to the same procedure
followed for 4-azido-4-ethyloctane 1c. Yield 356 mg, (78%); IR (Nujol) ν(Ν3) 2101 cm-1; 13C NMR (CDCl3, 50
MHz) δ (ppm) 14.4 (3xCH2CH2CH3), 16.9 (3xCH2CH2CH3), 38.9 (3xCH2CH2CH3), 66.8 (CN3).
The oily amine 2d was prepared through LiAlH4 (288 mg, 7.60 mmol) reduction of azide 2c (350 mg, 1.90
mmol) in refluxing ether (20 mL) for 5h according to the same procedure followed for 4-ethyloctan-4-amine 1d.
1
13
950 mg, Yield 50%; H NMR (CDCl3, 400 MHz): δ (ppm) 0.88 (t, J=7.1 Hz, 9H), 1.27-1.45 (m, 12H); C
NMR (CDCl3, 50 MHz) δ (ppm) 14.9 (CH3), 16.8(CH2CH2CH3), 42.9(CH2CH2CH3), 53.4 (CNH2). MS (ES+)
C10H24N+ (M+H+) 158.2 Found 158.2. Anal. (C14H27NO4). Calcd. C, 61.51; H, 9.96; N, 5.12. Found: C, 61.66;
H, 10.06; N, 5.13.
5-Butyl-nonan-5-amine (Bu3CNH2) 3d. 5-Butyl-nonan-5-ol, 3b was obtained after treating a solution of 5-
nonanone 3a (1 g, 7.04 mmol) in dry diethyl ether (30% solution w/v) with 1.2-molar excess
CH3CH2CH2CH2MgBr (obtained from an 20% solution w/v solution of 1-bromobutane (1.9 g, 14.08 mmol) in
dry ether and 1.3 equivalents of Mg (440 mg, 18.3 mmol) under argon atmosphere and stirring the mixture
overnight. After treating the mixture with saturated ammonium chloride following usual workup the
corresponding tertiary alcohol 3b was obtained. Yield 1.1g, (80%); IR (Nujol) ν(OH) 3392 cm-1; 1H NMR
(CDCl3, 200 MHz) δ (ppm) 0.88 (t, J=7.1 Hz, 9H, 3xCH3CH2CH2CH2), 1.18-1.31 (m, 13H,
3xCH3CH2CH2CH2, 3x CH3CH2CH2CH2, OH), 1.34-1.42 (m, 6H, 3x CH3CH2CH2CH2); 13C NMR (CDCl3, 50
MHz) δ (ppm) 14.2 (3xCH3), 23.4 (3xCH3CH2CH2CH2), 25.8 (3xCH3CH2CH2CH2), 39.1 (3xCH3CH2CH2CH2),
74.4 (COH).
The 5-azido-5-butylnonane 3c was prepared by treatment of the tertiary alcohol 3b (500 mg, 2.50 mmol)
with CH2Cl2 (20 mL)/NaN3 (489 mg, 7.50 mmol)/TFA (2 mL, 25 mmol) according to the same procedure
followed for 4-azido-4-ethyloctane 1c. Yield 460 mg, (82%); IR (Nujol) ν(Ν3) 2095 cm-1; 13C NMR (CDCl3, 50
MHz) δ (ppm) 14.2 (3xCH3), 23.2 (3xCH3CH2CH2CH2), 25.9 (3xCH3CH2CH2CH2), 36.4 (3xCH3CH2CH2CH2),
66.9 (CN3).
The oily amine 3d was prepared through LiAlH4 (270 mg, 7.11 mmol) reduction of azide 3c (400 mg, 1.78
mmol) in refluxing ether (20 mL) for 5h according to the same procedure followed for 4-ethyloctan-4-amine 1d.
1
Yield 20%; H NMR (CDCl3, 400 MHz) δ (ppm) 0.89 (t, J=7.0 Hz, 9H, 3xCH2CH2CH2CH3), 1.15-1.30 (m,
18H, 3xCH2CH2CH2CH3); 13C NMR (CDCl3, 50 MHz) δ (ppm) 14.3 (3xCH3), 23.6 (3xCH3CH2CH2CH2), 25.9
(3xCH3CH2CH2CH2), 40.1 (3xCH3CH2CH2CH2), 53.2 (CNH2). MS(ES+) (M+H+) C13H30N+ 200.24 Found:
200.04. Anal. (C17H33NO4) Calcd. C, 64.73; H, 10.54; N, 4.44. Found C, 64.54; H, 10.42; N, 4.63.
2-Methyl-4-propyl-heptan-4-amine (i-BuPr2CNH2) 4d. 2-methyl-4-propyl-heptan-4-ol 4b was obtained after
adding to i-butyllithium (14 mL, 21.9 mmol) reagent (1.6 M in hexanes) a solution of 4-heptanone 2a (1g, 8.77
mmol) in dry ether (30% solution w/v) at 0 °C under argon atmosphere and stirring the mixture overnight, with
lithium reagent being in a 2.5-molar excess. After treating the mixture with saturated ammonium chloride
following usual workup the corresponding tertiary alcohol 4b was obtained. Yield 1.2 g, (80%); IR (Nujol)
1
ν(OH) 3422 cm-1; H NMR (CDCl3, 400 MHz) δ (ppm) 0.86-0.89 (m, 6H, 2x(CH2)2CH3) 0.92 (d, J=7.1 Hz,
6H, CH2CH(CH3)2), 1.23-1.25 (m, 4H, 2xCH2CH2CH3), 1.31 (d, J=6.9 Hz, 2H, CH2CH(CH3)2), 1.37-1.41 (m,
13
4H, 2xCH2CH2CH3), 1.73 (sep, J=6.9 Hz, 1H, CH2CH(CH3)2); C NMR (CDCl3, 50 MHz) δ (ppm) 14.78
(2xCH2CH2CH3), 17.01 (2xCH2CH2CH3), 23.8 (CH2CH(CH3)2), 24.9 (CH2CH(CH3)2), 42.23 (2xCH2CH2CH3),
48.13 (CH2CH(CH3)2), 75.22 (COH).
The 4-azido-2-methyl-4-propylheptane 4c was prepared by treatment of the tertiary alcohol 4b (500 mg,
2.90 mmol) with CH2Cl2 (25 mL)/NaN3 (570 mg, 8.72 mmol) TFA (2.3 mL, 29 mmol) according to the same
procedure followed for 4-azido-4-ethyloctane 1c. Yield 490 mg, (86%); IR (Nujol) ν(Ν3) 2101 cm-1; 13C NMR
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(CDCl3, 50 MHz) δ (ppm) 14.6 (2xCH2CH2CH3), 17.1 (2xCH2CH2CH3), 23.9 (CH2CH(CH3)2), 24.4
(CH2CH(CH3)2), 39.1(2xCH2CH2CH3), 45.1 (CH2CH(CH3)2), 67.0 (CN3).
The oily amine 4d was prepared through LiAlH4 (309 mg, 8.12 mmol) reduction of azide 4c (400 mg, 2.03
mmol) in refluxing ether (20 mL) for 5h according to the same procedure followed for 4-ethyloctan-4-amine 1d.
1
Yield 49 mg, (14%); H NMR (CDCl3, 400 MHz): δ (ppm) 0.84-0.88 (m, 6H, 2x(CH2)2CH3) 0.89 (d, J=7.1
Hz, 6H, CH2CH(CH3)2), 1.20-1.25 (m, 10H, 2xCH2CH2CH3, CH2CH(CH3)2); 1.62-1.71 (m, 1H, CH2CH(CH3)2
) ; 13C NMR (CDCl3, 50 MHz) δ (ppm) 14.86 (2xCH2CH2CH3), 16.93 (2xCH2CH2CH3), 23.8 (CH2CH(CH3)2),
25.4 (CH2CH(CH3)2), 43.36 (2xCH2CH2CH3), 49.15 (CH2CH(CH3)2), 54.17 (CNH2). MS (ES+) C11H26N+
(M+H+) 172.2 Found 172.1. Anal. (C15H29NO4) Calcd. C, 62.69; H, 10.17; N, 4.87. Found C, 62.34; H, 10.16;
N, 4.61.
4-Propyl-octan-4-amine (BuPr2C-NH2) 5d. 4-Propyl-octan-4-ol 5b was obtained after treating a solution of 4-
heptanone 2a (1g, 8.77 mmol) in dry diethyl ether (30% solution w/v) with 1.2-molar excess
CH3CH2CH2CH2MgBr (obtained from an 20% solution w/v solution of 1-bromobutane (2,4 g, 17.54 mmol) in
dry ether and 1.3 equivalents of Mg (548 mg, 22.8 mmol)) under argon atmosphere and stirring the mixture
overnight. After treating the mixture with saturated ammonium chloride following usual workup the
1
corresponding tertiary alcohol 5b was obtained. Yield 990 mg, (71 %); IR (Nujol) ν(Ν3) 3392 cm-1; H NMR
(CDCl3, 200 MHz) δ (ppm) 0.85-0.91 (m, 9H, CH3), 1.21-1.31 (m, 9H, 2xCH3CH2CH2, CH3CH2CH2CH2, OH),
1.34-1.42 (m, 6H, 2x CH3CH2CH2, CH3CH2CH2CH2); 13C NMR (CDCl3, 50 MHz) δ (ppm) 14.2 ((CH2)3CH3),
14.8 (2x(CH2)2CH3), 16.8 ((CH2)2CH2CH3), 23.5 (2xCH2CH2CH3), 25.8 (CH2CH2CH2CH3),
(2xCH2CH2CH3), 41.8 (CH3CH2CH2COH), 74.5 (COH).
39.1
The 4-azido-4-propyloctane 5c was prepared was prepared by treatment of the tertiary alcohol 5b (900
mg, 5.23 mmol) with CH2Cl2 (20 mL)/NaN3 (1 g, 15.7 mmol)/TFA (4.1 mL, 52 mmol) according to the same
procedure followed for 4-azido-4-ethyloctane 1c. Yield 730 mg, (71%); IR (Nujol) ν(Ν3) 2095 cm-1; 13C NMR
(CDCl3, 50 MHz) δ (ppm) 14.2 ((CH2)3CH3), 14.6 (2x(CH2)2CH3), 17.0 ((CH2)2CH2CH3), 23.2
(2xCH2CH2CH3), 25.9 (CH2CH2CH2CH3), 36.4 (2xCH2CH2CH3), 39.0 (CH3CH2CH2CN3), 66.9 (CN3).
The oily amine 5d was prepared through LiAlH4 (540 mg,14.2 mmol) reduction of azide 5c (700 mg, 3.55
mmol) in refluxing ether (25 mL) for 5h according to the same procedure followed for 4-ethyloctan-4-amine 1d.
1
Yield 365 mg, (60%); H NMR (CDCl3, 400 MHz): δ (ppm) 0.85-0.89 (m, 9H, CH3), 1.16-1.27 (m, 14H,
2xCH3CH2CH2, CH3CH2CH2CH2); 13C NMR (CDCl3, 50 MHz) δ (ppm) 14.0 ((CH2)3CH3), 14.8
(2x(CH2)2CH3), 16.7 ((CH2)2CH2CH3), 23.4 (2xCH2CH2CH3), 25.7 (CH2CH2CH2CH3), 39.9 (2xCH2CH2CH3),
42.8 (CH3CH2CH2CNH2), 53.2 (CNH2). Anal. (C15H29NO4) Calcd. C, 62.69; H, 10.17; N, 4.87. Found C,
62.66; H, 10.53; N, 4.89.
5-Propyl-nonan-5-amine (Bu2PrCNH2) 6d. 5-Propyl-nonan-5-ol 6b was obtained after treating a solution of
5-nonanone 3a (1 g, 7.04 mmol) in dry diethyl ether (30% solution w/v) with 1.2-molar excess
CH3CH2CH2MgBr (obtained from 20% solution w/v solution of 1-bromopropane (1.9 g, 14.08 mmol) in dry
ether and 1.3 equivalents of Mg (440 mg, 18.3 mmol) under argon atmosphere and stirring the mixture
overnight. After treating the mixture with saturated ammonium chloride following usual workup the
corresponding tertiary alcohol 6b was obtained. Yield 915 mg, (70%); IR (Nujol) ν(OH) 3392 cm-1; 13C NMR
(CDCl3, 50 MHz) δ (ppm) 14.2 (2x CH3(CH2)3), 14.8 (CH3(CH2)2), 16.8 (2xCH3CH2(CH2)2), 23.5
(2xCH3CH2CH2CH2), 25.8 (CH2CH2CH3), 39.2 (2xCH3(CH2)2CH2), 41.8 (CH2CH2CH3), 74.5 (COH).
The 5-azido-5-propylnonane 6c was prepared by treatment of the tertiary alcohol 6b (500 mg, 2.69 mmol)
with CH2Cl2 (20 mL)/NaN3 (524 mg, 8.06 mmol)/TFA (2.2 mL, 27 mmol) according to the same procedure
followed for 4-azido-4-ethyloctane 1c. Yield 425 mg, (75%); IR (Nujol) ν(Ν3) 2094 cm-1; 13C NMR (CDCl3, 50
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MHz) δ (ppm) 14.1 (2x CH3(CH2)3), 14.6 (CH3(CH2)2), 17.0 (2xCH3CH2(CH2)2), 23.2 (2xCH3CH2CH2CH2),
25.8 (CH2CH2CH3), 36.4 (2xCH3(CH2)2CH2), 39.1 (CH2CH2CH3), 66.9 (CN3).
The oily amine 6d was prepared through LiAlH4 (289 mg, 7.60 mmol) reduction of azide 6c (400 mg, 1.90
mmol) in refluxing ether (20 mL) for 5h according to the same procedure followed for 4-ethyloctan-4-amine
1c. Yield 35%; 1H NMR (CDCl3, 400 MHz): δ 0.89 (t, J=7.0 Hz, 9H, CH3), 1.24-1.31 (m, 9H, CH2), 1.34-1.40
(m, 6H, CH2); 13C NMR (CDCl3, 50 MHz) δ (ppm) 14.4 2x CH3(CH2)3), 15.1 (CH3(CH2)2), 16.9
(2xCH3CH2(CH2)2), 23.7 (2xCH3CH2CH2CH2), 25.9 (CH2CH2CH3), 40.4 (2xCH3(CH2)2CH2), 42.9
(CH2CH2CH3), 53.4 (CNH2). Anal. (C16H31NO4) Calcd. C, 63.75; H, 10.37; N, 4.65. Found C, 63.84; H, 10.16;
N, 5.01.
2-Methyl-4-isobutyl-octan-4-amine (i-Bu2BuCNH2) 7d. 2-Methyl-4-isobutyl-octan-4-ol 7b was obtained after
adding a solution of 2,6-dimethyl-heptan-4-one 4a (1 g, 7.04 mmol) in dry diethyl ether (30% solution w/v) to
n-butyllithium (1.6 M in hexanes), (13.5 mL, 21.1 mmol) at 0 °C under argon atmosphere and stirring the
mixture overnight, with lithium reagent being in a 3.0 molar excess; After treating the mixture with saturated
ammonium chloride following usual workup the corresponding tertiary alcohol 7b was obtained. Yield 1.1 g,
1
(80%); IR (Nujol) ν(OH) 3460 cm-1; H NMR (CDCl3, 400 MHz): δ (ppm) 0.88 (t, J=7.0 Hz, 3H, (CH2)2CH3)
0.92-0.95 (m, 12H, 2xCH2CH(CH3)2), 1.19-1.35 (m, 10H, CH2CH2CH2CH3, 2xCH2CH(CH3)2), 1.74 (sep, 2H,
13
J=6.9 Hz, 2xCH2CH(CH3)2); C NMR (CDCl3, 50 MHz) δ (ppm) 14.2 (CH3(CH2)3), 23.5 (CH3CH2(CH2)2),
23.9 (2xCH2CH(CH3)2), 25.0 (2xCH2CH(CH3)2), 26.4 (CH2CH2CH2CH3), 39.9 (CH2(CH2)2CH3), 48.7
(2xCH2CH(CH3)2), 75.9 (COH).
The 4-azido-2-methyl-4-isobutyloctane 7c was prepared by treatment of the tertiary alcohol 7b (500 mg,
2.69 mmol) with CH2Cl2 (25 mL)/NaN3 (525 mg, 8.07mmol)/TFA (2.2 mL, 26.9 mmol) according to the same
procedure followed for 4-azido-4-ethyloctane 1c. Yield 430 mg, (76%); IR (Nujol) ν(Ν3) 2099 cm-1; 13C NMR
(CDCl3, 50 MHz) δ (ppm) 14.2 (CH3(CH2)3), 24.0 (CH3CH2(CH2)23), 24.2 (2xCH2CH(CH3)2), 24.6
(2xCH2CH(CH3)2), 26.3 (CH2CH2CH2CH3), 36.4 (CH2(CH2)2CH3), 45.5 (2xCH2CH(CH3)2), 67.1 (CN3).
The oily amine 7d was prepared through LiAlH4 (288 mg, 7.58 mmol) reduction of azide 7c (400 mg, 1.90
mmol) in refluxing ether (20 mL) for 5h according to the same procedure followed for 4-ethyloctan-4-amine 1d.
1
Yield 70 mg, (20%); H NMR (CDCl3, 400 MHz) δ (ppm) 0.89 (t, J=7.0 Hz, 3H, CH3(CH2)3) 0.89-0.94 (m,
12H, 2x CH2CH(CH3)2), 1.25-1.32 (m, 10H, CH2CH2CH2CH3, 2xCH2CH(CH3)2), 1.66-1.74 (m, 2H,
2xCH2CH(CH3)2); 13C NMR (CDCl3, 50 MHz) δ (ppm) 14.3 (CH3(CH2)3), 23.5 (CH3CH2(CH2)2), 23.8
(2xCH2CH(CH3)2), 25.5 (2xCH2CH(CH3)2), 26.3 (CH2CH2CH2CH3), 40.9 (CH2(CH2)2CH3), 49.7
(2xCH2CH(CH3)2), 55.1 (CNH2). Anal. (C17H33NO4). Calcd. C, 64.73; H, 10.54; N, 4.44. Found C, 64.34; H,
10.08; N, 4.81.
2-Methyl-tricyclo[3.3.1.13,7]decan-2-amine 8d. Tertiary alcohol 8b was obtained after treating a solution of
adamantanone (5a) (500 mg, 3.33 mmol) in dry THF (30% solution w/v) with 2-molar excess CH3MgI
(obtained from 20% solution w/v solution of CH3I (940 mg, 6.67 mmol) in dry ether and 1.3 equivalents of Mg
(210 mg, 8.67 mmol)) under argon atmosphere and stirring the mixture overnight. After treating the mixture
with saturated ammonium chloride the organic phase was separated and the aqueous phase was extracted twice
with an equal volume of diethyl ether. The combined organic phase was washed with water and brine, dried
(Na2SO4) and evaporated to afford the corresponding tertiary alcohol 8b; yield 525 mg (95 %); IR (Nujol)
13
ν(OH) 3423 cm-1; C NMR (CDCl3, 50 MHz) δ (ppm) 27.2,27.5 (5,7 adamantane-C), 27.4 (CH3), 33.1 (8,10
adamantane-C), 35.2 (4,9 adamantane-C), 38.4 (1,3 adamantane -C), 39.3 (6 adamantane-C), 74.0 (2
adamantane-C).
To a stirred mixture of sodium azide (187 mg, 2.88 mmol) and dry dichloromethane (5 mL), trifluoroacetic
acid (0.8 mL, 9.6 mmol) was added at 0 °C. The resulting mixture was stirred for 10 min at 0 °C and a solution
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of the tertiary alcohol 8b (160 mg, 0.96 mmol) in 5 mL of dichloromethane was added dropwise. The mixture
was stirred at 0-5 °C for 4 h and 24 h at ambient temperature. The mixture was made alkaline by adding NH3 12
% (30 mL) and the organic phase was separated. The aqueous phase was extracted with dichloromethane and
the combined organic phases were washed with water, brine and dried (Na2SO4). Solvent was evaporated in
vacuo to afford azide 8c yield 0.161g (88 %); IR (Nujol) ν(Ν3) 2213cm-1.
To a stirred suspension of LiAlH4 (127 mg, 3.35 mmol) in dry ether (10 mL) was added dropwise at 0 °C a
solution of the azide 8c (160 mg, 0.84 mmol) in dry ether (5 mL). The mixture was refluxed for 5 h and then
was treated with water, NaOH 10 % and water. The insoluble inorganic material was filtered-off, washed with
ether and the filtrate was extracted with HCl 6%. The aqueous phase was made alkaline with solid sodium
carbonate and was extracted with diclhoromethane or ether. The organic phase was washed with brine, dried
(Na2SO4) and evaporated in vacuo to afford the amine 8d; yield 117 mg, (83 %); 1H NMR (CDCl3, 400 MHz):
δ (ppm) 1.17 (br s, 3H, CH3), 1.46-1.48 (d, J=12.1 Hz, 2H, 4eq,9eq adamantane-H), 1.54 (d, J=12.1 Hz, 2H,
8eq,10eq adamantane-H), 1.56-1.63 (br m, 4H, 1,3,6 adamantane-H), 1.76 (br s, 2H, 5,7 adamantane-H), 1.93
(d, J=12.1 Hz, 2H, 8ax,10ax adamantane-H), 2.01 (d, J=12.1 Hz, 2H, 4ax,9ax adamantane-H); 13C NMR
(CDCl3, 50 MHz) δ (ppm) 27.3 (7 adamantane-C), 27.7 (5 adamantane-C), 27.9 (CH3), 33.2 (4,9 adamantane-
C), 34.7 (8,10 adamantane-C), 38.9 (6 adamantane-C), 39.6 (1,3 adamantane-C), 52.9 (2 adamantane-C).
Hydrochloride: mp > 250 ºC (EtOH-Et2O); Anal. (C11H20ClN) C, H, N. Calcd. C, 65.49; H, 9.99; N, 6.94.
Found C, 65.34; H, 10.08; N, 6.64.
2-Ethyl-tricyclo[3.3.1.13,7]decan-2-amine 9d. Tertiary alcohol 9b was obtained after treating a solution of
adamantanone (5a) (500 mg, 3.33 mmol) in dry THF (30% solution w/v) with n-ethyllithium (0.5 M in
1
benzene), (20 mL, 10,0 mmol) at 0 °C and stirring the mixture overnight; yield 560 mg (94%); H NMR
(CDCl3, 400 MHz): δ (ppm) 0.86 (t, J=7.0 Hz, CH2CH3), 1.40-1.70 (m, 10 H, 1,3, 4eq,9eq,6,8eq,10eq
adamantane-H, CH2CH3), 1.75-1.83 (m, 2H, 5,7 adamantane-H),1.94 (d, J=12.1 Hz, 2H, 8ax,10ax adamantane-
H), 2.07 (d, J=12.1 Hz, 2H, 4ax,9ax adamantane-H); 13C NMR (CDCl3, 50 MHz) δ (ppm) 6.4 (CH2CH3), 27.4,
27.5 (5,7 adamantane-C), 30.6 (CH2CH3), 33.0 (8,10 adamantane -C), 34.6 (4,9 adamantane-C), 36.6 (1,3
adamantane-C), 38.5 (6 adamantane-C), 74.9 (2 adamantane-C).
The tertiary azide 9c was prepared by treatment of the tertiary alcohol 9b (0.180g, 1.0mmol with CH2Cl2 (5
mL) / NaN3 (195 mg, 3.00 mmol) / TFA (0.8 mL, 10.0 mmol) according to the same procedure followed for the
azide 8c.; yield 0.160 g (80%); IR (Nujol) ν(Ν3) 2100 cm-1.
The oily amine 9d was prepared through LiAlH4 (0.120 g, 0.78 mmol) reduction of azide 9c (160 mg, 3.12
mmol) in refluxing ether (10 mL) for 5h according to the same procedure followed for amine 8d; yield 100 mg
(71%); 1H NMR (CDCl3, 400 MHz) δ (ppm) 0.85 (t, J=7.1 Hz, 3H, CH2CH3), 1.55 (br s, 2H, 1,3 adamantane-
H), 1.58-1.68 (m, 7H, 4eq,9eq-H, 8eq, 6 adamantane-H, CH2CH3), 1.78 (br s, 1H, 5 adamantane-H), 1.81 (br s,
1H, 7 adamantane-H), 1.93 (d, J=12.1Hz, 2H, 8ax,10ax adamantane-H), 2.06 (d, J=12.1 Hz, 2H, 4ax,9ax
adamantane-H); 13C NMR (CDCl3, 50 MHz) δ (ppm) 6.5 (CH2CH3), 27.2, 27.6 (5,7 adamantane-C), 30.7
(CH2CH3), 33.0 (4,9 adamantane-C), 33.8 (8,10 adamantane-C), 36.6 (1,3 adamantane-C), 38.5 (6 adamantane-
C), 74.9 (2 adamantane-C). Hydrochloride: mp > 250 ºC (EtOH-Et2O); Anal. (C12H22ClN). Calcd. C, 66.80; H,
10.28. Found C, 67.01; H, 10.08.
2-n-Propyl-tricyclo[3.3.1.13,7]decan-2-amine 10d. The CH2CH=CH2MgBr reagent was obtained by adding a
20% solution w/v solution of CH2CH=CH2Br (1.6 g, 13.34 mmol) in dry ether to 1.05 equivalents of Mg (340
mg, 14.01 mmol) under argon atmosphere. Tertiary alcohol was obtained after adding a solution of
adamantanone 11 (1000 mg, 6.67 mmol) in dry diethyl ether (30% solution w/v) to the above prepared
CH2CH=CH2MgBr under argon atmosphere and stirring the mixture overnight. After treating the mixture with
saturated ammonium chloride following usual workup the corresponding tertiary unsaturated alcohol; yield 1.1
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g, (89%);
δ (ppm)
1.52 (d, J=12.1 Hz, 2H, 4eq,9eq adamantane-H), 1.53-1.90 (m, 10H,
1,3,5,6,7,8eq,10eq,8ax,10ax adamantane-H), 2.15 (d, J=12.1 Hz, 1H, 4ax,9ax-H), 2.40 (d, J=5.8 Hz, 2H,
CH2CH=CH2), 5.05-5.15 (m, 2H, CH2CH=CH2), 5.75-6.0 (m, 1H, CH2CH=CH2).
The unsaturated alcohol was hydrogenated under PtO2 (catalyst was used in 1/20 percentage to the weight of the
1
unsaturated compound) to afford the n-propyl alcohol 10b; yield quant.: H NMR (CDCl3, 400 MHz) δ (ppm)
0.92 (t, J=7.0 Hz, 3H, CH2CH2CH3), 1.30-1.40 (m, 2H, CH2CH2CH3), 1.52 (d, J=12.1 Hz, 2H, 4eq,9eq
adamantane-H), 1.58-1.61 (m, 2H, CH2CH2CH3), 1.68 (d, J=12.1 Hz, 2H, 8eq,10eq adamantane-H), 1.67 (br s,
2H, 6 adamantane-H), 1.68 (br s, 2H, 1,3 adamantane -H), 1.79 (m, 2H, 5,7 adamantane-H), 1.83 (d, J=12.1 Hz,
13
2H, 8ax,10ax adamantane-H), 2.16 (d, J=12.1 Hz, 2H, 4ax,9ax adamantane-H); C NMR (CDCl3, 50 MHz) δ
(ppm) 14.9 (CH2CH2CH3), 15.4 (CH2CH2CH3), 27.4, 27.6 (5, 7 adamantane-C), 33.1 (CH2CH2CH3), 34.7 (4, 9
adamantane-C), 37.1 (8, 10 adamantane-C), 38.5 (1, 3 adamantane-C), 40.9 (6 adamantane-C), 75.2 (2
adamantane-C).
The tertiary azide 10c was prepared by treatment of the tertiary alcohol 10b (640 mg, 3.27 mmol with
CH2Cl2 (20 mL)/NaN3 (640 mg, 9.83 mmol)/TFA (2.6 mL, 32.7 mmol) according to the same procedure
1
followed for the azide 8c; yield 470 mg (66%); IR (Nujol) ν(Ν3) 2100 cm-1; H NMR (CDCl3, 400 MHz): δ
(ppm) 0.96 (t, J=7.1 Hz, 3H, CH2CH2CH3), 1.42 (m, 2H, CH2CH2CH3), 1.59 (d, J=12.1 Hz, 2H, 8eq,10eq
adamantane-H), 1.68 - 2.03 (m, 12H, CH2CH2CH3, 1,3,4eq,5,7,8ax,9eq,10ax adamantane-H), 2.10 (d, J=12.1
Hz, 2H, 4ax,9ax adamantane-H); 13C NMR (CDCl3, 50 MHz) δ (ppm) 14.7 (CH2CH2CH3), 16.4 (CH2CH2CH3),
27.2, 27.4 (5, 7 adamantane-C), 33.8 (CH2CH2CH3) 34.4 (4, 9 adamantane-C), 37.9 (8, 10 adamantane-C), 38.5
(1, 3 adamantane-C), 40.0 (6 adamantane -C), 69.7 (2 adamantane -C).
The oily amine 10d was prepared through LiAlH4 (390 mg, 10.3 mmol) reduction of azide 10c (490 mg,
2.57 mmol) in refluxing ether (10 mL) for 5h according to the same procedure followed for amine 10d; yield
1
350 mg (74%); H NMR (CDCl3, 400 MHz) δ (ppm) 0.92 (t, J=7 Hz, 3H, CH2CH2CH3), 1.29-1.40 (m, 2H,
CH2CH2CH3), 1.52 (d, J=12.1 Hz, 2H, 4eq,9eq adamantane-H), 1.58-1.61 (m, 2H, CH2CH2CH3), 1.67 (d,
J=12.1 Hz, 2H, 8eq,10eq adamantane-H), 1.66 (br s, 2H, 6 adamantane-H), 1.68 (br s, 2H, 1,3 adamantane-H),
1.78 (br s, 2H, 5,7 adamantane-H), 1.83 (d, J=12.1 Hz, 2H, 8ax,10ax adamantane-H), 2.16 (d, J=12.1 Hz, 1H,
4ax,9ax adamantane-H); Hydrochloride: mp> 250 ºC (EtOH-Et2O); Anal. (C13H24ClN). Calcd. C, 67.95; H,
10.53; N, 6.10. Found C, 68.15; H, 10.28; N, 6.50.
2-n-Butyl-(tricyclo[3.3.1.13,7]decan)-2-amine 11d. The 2-n-Butyl-tricyclo[3.3.1.13,7]decan-2-azide 11c was
prepared by treatment of the tertiary alcohol 11b (300 mg, 1.44 mmol) with CH2Cl2 (20 mL) / NaN3 (281 mg,
4.32 mmol)/TFA (1.2 mL, 14.4 mmol) according to the same procedure followed for azide 8c. Yield 255 mg,
1
(76%); IR (Nujol) ν(Ν3) 2088 cm-1; H NMR (CDCl3, 400 MHz): δ (ppm) 0.96 (t, J = 7 Hz, 3H,
CH3CH2CH2CH), 1.32-1.42 (m, 4H, CH3CH2CH2CH2), 1.62 (d, J=12.1 Hz, 2H, 4eq,9eq adamantane-H), 1.70-
13
1.93 (m, 12H, adamantane-H, CH3CH2CH2CH2), 2.14 (d, J=12.1 Hz, 2H, 4ax,9ax adamantane-H); C NMR
(CDCl3, 50 MHz) δ (ppm) 14.2 (CH3CH2CH2CH2), 23.3 (CH2CH2CH2CH3), 24.9 (CH3CH2CH2CH3), 27.2, 27.4
(5,7-adamantane C), 33.8 (4,9-adamantane C), 33.7 (8,10-adamantane C), 34.4 (1,3-adamantane C), 35.2
(CH3CH2CH2CH2), 38.5 (6-adamantane C), 69.7 (2-adamantane C). The oily amine 11d was prepared through
LiAlH4 (130 mg, 3.43 mmol) reduction of azide 11c (200 mg, 0.860 mmol) in refluxing ether (15 mL) for 5h
1
according to the same procedure followed for amine 8d. Yield 41 mg, (23%); H NMR (CDCl3, 400 MHz) δ
(ppm) 0.88 (t, J=7.1 Hz, 3H, CH3CH2CH2CH), 1.18-1.32 (m, 4H, CH3CH2CH2CH2), 1.45-165 (m, 10H,
adamantane-H, CH3CH2CH2CH2), 1.77 (br s, 2H, 5,7 adamantane-H), 1.93 (d, J=12.1 Hz, 2H, 8ax,10ax
13
adamantane-H), 2.03 (d, J=12.1 Hz, 2H, 4ax,9ax adamantane-H), 2,13 (br s, 2H, NH2); C NMR (CDCl3, 50
MHz) δ (ppm) 14.3 (CH3CH2CH2CH2), 23.7 (CH2CH2CH2CH3), 24.6 (CH3CH2CH2CH3), 27.5, 27.8 (5,7
adamantane-C), 34.1 (4,9 adamantane-C), 33.2 (8,10 adamantane-C), 37.5 (1,3 adamantane-C), 38.6 (6
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o
adamantane-C), 39.1 (CH3CH2CH2CH2), 54.5 (2 adamantane-C). Fumarate: mp 220 C (EtOH-Et2O); Anal.
(C18H29NO4). Calcd. C, 66.84; H, 9.04; N, 4.33; Found C, 66.34; H, 9.22; N, 4.84.
2-Phenyl-(tricyclo[3.3.1.13,7]decan)-2-amine 12d. The 2-Phenyl-tricyclo[3.3.1.13,7]decan-2-azide 12c was
prepared by treatment of the tertiary alcohol 12b (300 mg, 1.32 mmol) with CH2Cl2 (20 mL) / NaN3 (265 mg,
3.95 mmol)/TFA (1.1 mL, 13.2 mmol) according to the same procedure followed for azide 8c. Yield 290 mg,
13
(95%); IR (Nujol) ν(Ν3) 2098 cm-1; C NMR (CDCl3, 50 MHz) δ (ppm) 26.8, 27.4 (5,7-adamantane-C), 33.1
(4,9-adamantane-C), 33.4 (8,10-adamantane-C), 34.1 (1,3-adamantane-C), 37.7 (6-adamantane-C), 70.3 (2-
adamantane-C), 125.6, 127.3, 127.8, 128.9, 140.3 (phenyl).
The oily amine 12d was prepared through LiAlH4 (897 mg, 3.95 mmol) reduction of azide 12c in refluxing
1
ether (15 mL) for 5h according to the same procedure followed for amine 8d. Yield 123 mg, (55%); H NMR
(CDCl3, 400 MHz) δ (ppm) 1.53 (br s, 2H, 6 adamantane-H), 1.61-1.80 (m, 6H, adamantane-H), 1.90 (br s, 2H,
5,7 adamantane-H), 2.33 (d, J=12.1 Hz, 1H, 4ax,9ax adamantane-H), 2.45 (br s, 2H, 1,3 adamantane-H), 7.18-
7.25 (m, 5H, phenyl-H); 13C NMR (CDCl3, 50 MHz) δ (ppm) 27.2, 27.6 (5,7 adamantane-C), 32.9 (4,9
adamantane-C), 34.6 (8,10 adamantane-C), 35.8 (1,3 adamantane-C), 38.2 (6 adamantane-C), 57.8 (2
o
adamantane-C), 125.2, 126.2, 128.8, 148.7 (Ph). Hydrochloride: mp> 265 C (EtOH-Et2O); Anal. (C16H22ClN)
Calcd. C, 72.84; H, 8.41; N, 5.31. Found C, 72.12; H, 8.32; N, 5.02.
2-Benzyl-(tricyclo[3.3.1.13,7]decan)-2-amine 13d. The 2-Benzyl-tricyclo[3.3.1.13,7]decan-2-azide 13c was
prepared by treatment of the tertiary alcohol 13b (500 mg, 2.07 mmol) with CH2Cl2 (25 mL)/NaN3 (540 mg,
8.28 mmol)/TFA (1.7 mL, 20.7 mmol) according to the same procedure followed for azide 8c. Yield 280 mg,
13
(50%); IR (Nujol) ν(Ν3) 2096 cm-1; C NMR (CDCl3, 50 MHz) δ (ppm) 27.1, 27.4 (5,7-adamantane C), 33.7
(4,9-adamantane C), 33.8 (8,10-adamantane C), 34.1 (1,3-adamantane C), 38.4 (6-adamantane C), 41.4
(CH2Ph), 69.8 (2-adamantane C), 126.7, 128.2, 130.3, 136.6 (Ph).
The oily amine 13d was prepared through LiAlH4 reduction of azide 13c in refluxing ether for 5h according
to the same procedure followed for amine 8d. Yield 45%; 1H NMR (CDCl3, 400 MHz) δ (ppm) 1.61 (d, J=12.1
Hz, 2H, 4eq, 9eq adamantane-H), 1.61 (br s, 1H, 6 adamantane-H), 1.73 (br s, 1H, 5,7 adamantane-H), 1.78 (d,
J=12.1 Hz, 2H, 8eq,10eq adamantane-H), 1.87 (br s, 1H, 3 adamantane-H), 1.97 (br s, 1H, 1 adamantane-H),
2.09 (d, J=12.1 Hz, 1H, 8ax,10ax adamantane-H), 2.29 (d, J=12.1 Hz, 1H, 4ax,9ax adamantane-H), 2.97 (s, 2H,
13
CH2Ph), 7.10-7.32 (m, 5H, phenyl-H); C NMR (CDCl3, 50 MHz) δ (ppm) 27.6, 27.8 (5,7-adamantane C),
33.2 (4,9- adamantane C), 34.3 (8,10-adamantane C), 37.3 (1,3-adamantane C), 39.2 (6-adamantane C), 44.2
(CH2Ph), 55.1 (2-adamantane C), 126.3, 128.1, 130.7, 138.4 (Ph). Fumarate: mp 205 ºC (EtOH-Et2O); Anal.
(C21H27NO4). Calcd. C, 70.56; H, 8.41; N, 5.31. Found C, 70.99; H, 8.53; N, 5.02.
2-(p-Methoxy)benzyl-(tricyclo[3.3.1.13,7]decan)-2-amine 14d. 2-(p-Methoxy)benzyl-2-adamantanol 14b was
obtained after adding dropwise a solution of 2-adamantanone (500 mg, 3.33 mmol) in dry THF (6 mL) to a
solution of pMeOBnMgCl (0.25 M in THF, 27 mL, 6.66 mmol) at room temperature and under argon
atmosphere. The resulting mixture was stirred overnight and then heated at 45 ºC for 2 hours. After treating the
mixture with saturated ammonium chloride following usual workup the corresponding tertiary alcohol 14b was
1
obtained. Yield 725 mg, (80%); H NMR (CDCl3, 400 MHz) δ (ppm) 1.48 (d, J=12.1 Hz, 2H, 4eq,9eq
adamantane-H), 1.53 (br s, 1H, OH), 1.66 (br s, 1H, 6 adamantane-H), 1.71 (br s, 1H, 5,7 adamantane-H), 1.77
(br s, 1H, 3 adamantane-H), 1.80 (d, J=12.1 Hz, 2H, 8eq,10eq adamantane-H), 1.91 (br s, 1H, 1 adamantane-H),
2.08 (d, J=12.1 Hz, 1H, 8ax,10ax adamantane-H), 2.22 (d, J=12.1 Hz, 1H, 4ax,9ax adamantane-H), 2.93 (s, 2H,
13
CH2Ar), 3.79 (s, 3H, OCH3), 6.85 (d, J = 6 Hz, 2H, phenyl-H), 7.15 (d, J = 6 Hz, 2H, phenyl-H); C NMR
(CDCl3, 50 MHz) δ (ppm) 27.4, 27.5 (5,7 adamantane-C), 33.1 (4,9 adamantane-C), 34.7 (8,10 adamantane-C),
36.9 (1,3 adamantane-C), 38.5 (6 adamantane-C), 43.9 (CH2Ar), 74.7 (2 adamantane-C), 126.5, 128.3, 130.7,
137.4 (Ar).
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The corresponding azide 14c was prepared from alcohol 14b (720 mg, 2.64 mmol) according to the same
procedure followed for azide 8c using CH2Cl2 (30 mL)/NaN3 (515.5 mg, 7.93 mmol)/TFA (3.01 mg, 26.4
mmol). Yield 730mg, (93 %).
The oily amine 14d was prepared through LiAlH4 (358 mg, 9.43 mmol) reduction of azide 14c (700 mg,
1
2.36mmol) in refluxing THF (20 mL) for 5h. Yield 307 mg, (48%); H NMR (CDCl3, 400 MHz) δ (ppm) 1.62
(d, J=12 Hz, 2H, 4eq,9eq adamantane-H), 1.73 (d, J=12.1 Hz, 2H, 8eq,10eq adamantane-H), 1.77 (br s, 1H, 5,7
adamantane-H), 1.84 (br s, 1H, 6 adamantane-H), 1.93 (br s, 1H, 3 adamantane-H), 1.97 (br s, 1H, 1
adamantane-H), 2.09 (d, J=12.1 Hz, 1H, 8ax,10ax adamantane-H), 2.24 (d, J=12.1 Hz, 1H, 4ax,9ax
adamantane-H), 2.93 (s, 2H, CH2Ar), 3.80 (s, 3H, OCH3), 6.84 (d, J=6.2 Hz, 2H, phenyl-H), 7.15 (d, J=6.2 Hz,
2H, phenyl-H). Fumarate: mp 205 °C (EtOH–Et2O). Anal. (C21H36NO5) Calcd. C, 65.94; H, 9.49; N, 3.66.
Found C, 65.05; H, 9.58; N, 3.72.
1-Adamantyl-2-propanol (AdMe2COH) 15b. Methylmagnesium iodide was prepared from magnesium
turnings (1.99 g, 83.1mmol) and methyl iodide (10.7 g, 75.6mmol) in 40 mL of dry diethyl ether. A solution of
1-adamantanecarbonyl chloride (6a) (2.5 g, 12.6 mmol) in 60 mL of dry diethyl ether was added dropwise
under Ar atmosphere and stirring. The reaction mixture was heated at gentle reflux for 4h under stirring and Ar
atmosphere. The mixture was treated with an equal volume of saturated solution of ammonium chloride under
ice-cooling. The organic layer was separated and the aqueous phase was extracted with diethyl ether 2 times.
The combined organic phases were washed with water and brine, dried (Na2SO4) and evaporated under vacuum
to yield a white solid residue of 2-(1-adamantyl)-propan-2-ol 15b. Yield 2.09 g (85.5%); IR (Νujol) ν(ΟΗ) 3400
1
(br s, OH) cm-1; H-NMR (400MHz, CDCl3) δ (ppm) 1.12 (s, 6H, 2xCH3), 1.62-1.69 (m, 12H, 2,4,6,8,9,10
adamantane-H), 1.99 (br s, 3H, 3,5,7 adamantane-H); 13C-NMR (50 MHz, CDCl3) δ (ppm) 24.34 (CH3), 28.74
(3,5,7-C, adamantane C), 36.35 (2,8,9-C, adamantane C), 37.22 (4,6,10-C, adamantane C), 38.84 (1-C,
adamantane C), 74.88 (C-OH).
2-(1-adamantyl)-2-azidopropane (AdMe2CN3) 15c. The oily 2-(1-adamantyl)-2-azidopropane 3c was
prepared by treatment of the tertiary alcohol 15b with CH2Cl2/NaN3/TFA. To a stirring mixture of sodium azide
(503 mg, 7.74 mmol) and dry dichloromethane (15 mL), trifluoroacetic acid (2.94 g, 25.8mmol) was added at 0
°C. The resulting mixture was stirred for 10 min at 0 °C and a solution of 2-(1-adamantyl)-propan-2-ol 15b (500
mg, 2.58 mmol) in 15mL of dry dichloromethane was added dropwise under ice-cooling. The mixture was
stirred vigorously at 0-5 °C for 4 h and additional 24 h at ambient temperature. The mixture was made alkaline
by adding NH3 12 % (40 mL) and the organic phase was separated and washed with 30 mL of water two times.
The aqueous phase was extracted two times with dichloromethane (30 mL) and the combined organic phases
were washed with water, brine and dried (Na2SO4). Solvent was evaporated in vacuo to afford 2-(1-adamantyl)-
1
propan-2-azide 15c. Yield: 80%; IR (Νujol) ν(Ν3) 2098 cm-1 (s); H-NMR (400MHz, CDCl3) δ (ppm) 1.23 (s,
6H, 2xCH3), 1.60-1.71 (m, 12H, 2,4,6,8,9,10 adamantane-H), 2.0 (br s, 3H, 3,5,7 adamantane-H); 13C-NMR (50
MHz, CDCl3) δ (ppm) 20.79 (CH3), 28.66 (3,5,7-C, adamantane C), 36.56 (2,8,9-C, adamantane C), 37.07
(4,6,10-C, adamantane C), 39.10 (1-C, adamantane C), 67.57 (C-N).
2-(1-adamantyl)-propan-2-amine (AdMe2CNH2) 15d. A solution of 2-azido-2-(1-adamantyl)propane 15c
(250 mg, 1.14 mmol) in 10 mL of dry diethyl ether was added dropwise to a solution of lithium aluminum
hydride (173 mg, 4.56mmol) in 10 mL of dry diethyl ether under ice-cooling. The mixture was heated at reflux
for 5 h under stirring. Then the mixture was hydrolyzed with a dropwise addition of 2 mL water, 2 mL of
sodium hydroxide 10% w/v solution and 6 mL water under stirring and ice-cooling. The mixture was filtered
under vacuum and the residue was washed 2 times with diethyl ether. Another 30 mL of diethyl ether was added
to the ethereal filtrate and the solution was extracted with 60 mL (2×30 mL) of hydrochloric acid 6% w/v. The
aqueous phase was separated and made alkaline through addition of an excess solid sodium carbonate under ice-
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cooling. The aqueous phase was extracted two times with 30 mL of dichloromethane. The combined organic
extracts were dried (Na2SO4) and evaporated under vacuum, to yield a light yellow colored solid residue of 2-
(1-adamantyl)-propan-2-amine 15d. Yield: 73%; IR (Film) ν(ΝΗ2) 3373 cm-1 (s); 1H-NMR (400 MHz, CDCl3)
δ (ppm) 0.99 (s, 6H, 2xCH3), 1.60-1.68 (m, 12H, 2,4,6,8,9,10 adamantane-H), 1.99 (br s, 3H, 3,5,7 adamantane-
H); 13C-NMR (50 MHz, CDCl3) δ (ppm) 25.30 (CH3), 28.87 (3,5,7-C, adamantane C), 36.23 (2,8,9-C,
adamantane C), 37.26 (4,6,10-C, adamantane C), 38.12 (1-C, adamantane C), 53.68 (C-N). Hydrochloride
(EtOH-Ether); Anal. (C13H24ClN). Calcd. C, 61.51; H, 9.96; N, 5.12. Found C, 61.66; H, 10.06; N, 5.13.
3-(1-adamantyl)-pentan-3-ol (AdEt2COH) 16b. A solution of 1-adamantanecarbonyl chloride (6a) (700 mg,
3.53 mmol) in 25 mL of dry diethyl ether was added dropwise under Ar atmosphere and stirring, to a solution of
5 mL ethyl lithium (0.5 M in benzene/cyclohexane, 12.5 mmol). The mixture was stirred for 26 h under Ar
atmosphere at room temperature. The reaction mixture was hydrolyzed with an equal volume of saturated
ammonium chloride solution under ice-cooling. The organic layer was separated and the aqueous phase was
extracted with diethyl ether two times. The combined organic phase was washed two times with a solution of
sodium hydroxide 3% w/v, water and brine, and dried over anhydrous sodium sulfate. After evaporation of the
solvent under vacuum, a light yellow coloured solid residue of the alcohol 16b was obtained. Yield 357 mg
1
(45.5%); IR (Nujol) v(OH) 3502 cm-1 (br s); H-NMR (400MHz, CDCl3) δ (ppm) 0.93 (t, J=7.0 Hz, 6H,
2xCH3), 1.56 (q, J=7.0 Hz, 4H, 2xCH3CH2), 1.61-1.70 (m, 12H, 2,4,6,8,9,10 adamantane-H), 2.05 (br s, 3H,
3,5,7 adamantane-H); 13C-NMR (50 MHz, CDCl3) δ (ppm) 9.47 (CH3), 25.93 (CH3CH2), 28.90 (3,5,7
adamantane C), 36.71 (2,8,9 adamantane C), 37.40 (4,6,10 adamantane C), 38.51 (1 adamantane C), 40.48 (C-
OH).
3-(1-adamantyl)-pentan-3-amine (AdEt2CNH2) 16d. The oily 3-(1-adamantyl)-3-azidopentane 16c was
prepared by treatment of the tertiary alcohol 16b with CH2Cl2/NaN3/TFA according to the same procedure
followed for 2-(1-adamantyl)-2-azido-propane 15d. The reaction afforded an oily mixture of azide 16c along
with 3-(1-adamantyl)-pent-2-ene as an elimination by-product. The yield of the azide preparation was 65 %
based on the integration of 13C NMR peaks. The crude oily mixture was used without further purification for the
LiAlH4 reduction step.
3-(1-Adamantyl)-3-pentanamine 16d was prepared through LiAlH4 reduction of azide 16c in refluxing
ether for 5h according to the same procedure followed for 2-(1-adamantyl)-propan-2-amine 15d. Amine 16d
was afforded as light yellow colored oil. Yield: 10.9%; MS 222.4; 1H-NMR (400 MHz, CDCl3) δ (ppm) 0.88 (t,
J=7.1 Hz, 6H, 2xCH3), 1.08 (br s, 2H, NH2), 1.33-1.52 (m, 2H, 2xCH3CH2), 1.60-1.69 (m, 12H, 2,4,6,8,9,10
adamantane-H), 1.97 (br s, 3H, 3,5,7 adamantane-H); 13C-NMR (50 MHz, CDCl3) δ (ppm) 9.90 (CH3), 26.73
(CH3CH2), 29.04 (3,5,7 adamantane C), 36.75 (2,8,9 adamantane C), 37.45 (4,6,10 adamantane C), 38.60 (1
adamantane C), 39.86 (CNH2). Fumarate (EtOH-Ether). Anal. (C19H31NO4). Calcd. C, 67.63; H, 9.26; N, 4.15.
Found C, 67.33; H, 9.06; N, 4.35.
1-1-adamantyl)-1-allylbut-3-enyl azide (AdAllyl2COH) 17b. Allylmagnesium bromide was prepared from
magnesium turnings (1.33 g, 55.4 mmol) and allyl bromide (6.1 g, 50.4 mmol) in 60 mL of dry diethyl ether. A
solution of 1-adamantanecarbonyl chloride (6a) (2 g, 10.1 mmol) in 60 mL of dry diethyl ether was added
dropwise to the first solution, under Ar atmosphere and stirring. The reaction mixture was heated at gentle
reflux for 4h under stirring and Ar atmosphere and an additional 24 h at room temperature under stirring and Ar
atmosphere. The mixture was hydrolyzed with an equal volume of saturated solution of ammonium chloride
under ice-cooling. The organic layer was separated and the aqueous phase was extracted with diethyl ether two
times. The combined organic phase was washed with water and brine, dried (Na2SO4) and evaporated under
vacuum to yield a yellow colored oil residue of 1-(1-adamantyl)-1-allylbut-3-enol 17b. Yield: 1.74 g (70%); IR
(Film) ν(ΟΗ) 3568 cm-1 (s), ν(=C-H) 3074 cm-1 (s), 3008 cm-1 (m), ν(C=C) 1636 cm-1 (s); 1H-NMR (400MHz,
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CDCl3) δ (ppm) 1.70 (m, 12H, 2,4,6,8,9,10 adamantane-H), 1.99 (br s, 3H, 3,5,7 adamantane-H), 2.28-2.40 (m,
13
J=7.1 Hz, 4H, 3,5-CH2), 5.09 (t, J=7.1 Hz, 4H, 2xCH2=), 5.88-5.98 (m, J=7 Hz, 2H, 2xCH=); C-NMR (50
MHz, CDCl3) δ (ppm) 28.81 (3,5,7-C, adamantane C), 36.57 (2,8,9-C, adamantane C), 37.29 (4,6,10-C,
adamantane C), 39.29 (CH2), 40.34 (1-C, adamantane C), 76.08 (C-OH), 118.11 (=CH2), 135.82 (CH=).
4-(1-adamantyl)-hept-1,6-dien-4-azide (AdAllyl2C-N3) 17c. The 4-(1-Adamantyl)-hept-1,6-dien-4-azide 17c
was prepared by treatment of the tertiary alcohol 17b (500 mg, 2.03 mmol) with CH2Cl2 (20 mL) / NaN3 (396
mg, 6.09 mmol) / TFA (1.6 mL, 20.3 mmol) according to the same procedure followed for azide 15c. Yield 265
1
mg, (44%); H-NMR (400MHz, CDCl3) δ (ppm) 1.64-1.75 (m, 12H, 2,4,6,8,9,10 adamantane-H), 1.82 (br s,
3H, 3,5,7 adamantane-H), 1.99-2.20 (m, 4H, 3,5-CH2), 5.09 (t, J=7.1 Hz, 4H, 2xCH2=), 5.90-5.98 (m, 2H,
2xCH=); 13C-NMR (50 MHz, CDCl3) δ (ppm) 28.78 (3,5,7-C, adamantane-C), 36.57 (2,8,9-C, adamantane-C),
37.01 (4,6,10-C, adamantane-C), 39.28 (CH2), 41.09 (1-C, adamantane-C), 55.14 (C-N3), 118.06 (=CH2),
135.61 (CH=).
1-(1-Adamantyl)cyclopentanamine 19d. The corresponding cyclopentanol 19b used as a starting material was
prepared from ethyl 1-adamantanecarboxylate 17 and 1,4-bis(bromomagnesiobutane) in dry ether with a 70%
yield according to a published procedure;21 1H NMR (CDCl3, 400 MHz): δ 1.30-1.40 (m, 2H, cyclopentane-H),
1.50-1.80 (m, 18H, adamantane-H, cyclopentane-H), 1.98 (br s, 3H, 3,5,7 adamantane-H), 2.16 (s, 1H, OH); 13C
NMR (CDCl3, 50 MHz) δ 24.2 (3,4 cyclopentane-C), 28.6 (3,5,7 adamantane-C), 33.8 (2,5-cyclopentane-C),
37.1 (4,6,10 adamantane-C), 37.3 (2,8,9 adamantane-C), 39.5 (1 adamantane -C), 87.6 (1 cyclopentane-C).
To a stirred mixture of NaN3 (0.270 g, 4.08mmol) and dry dichloromethane (40 mL) at 0 °C, TFA
(13.6mmol) was added. To the stirred mixture a solution of tertiary alcohol 19b (0.300 g, 1.36 mmol) in dry
dichloromethane (20 mL) was added and stirring was maintained at 0 °C for 4 h. The mixture was stirred at
ambient temperature for 24 h and then was treated with NH3 12% (30 mL) at 0 °C. The organic phase was
separated and the aqueous phase was extracted twice with an equal volume of dichloromethane. The combined
organic phase was washed with water and brine, dried (Na2SO4) and evaporated to afford oily azide 19c; yield
1
0.290 g (88%); IR (Nujol) ν(Ν3) 2097 cm-1; H NMR (CDCl3, 400 MHz) δ 1.50-1.80 (m, 20H, adamantane-H,
cyclopentane-H), 1.99 (br s, 3H, 3,5,7 adamantane-H); 13C NMR (CDCl3, 50 MHz) δ 24.2 (3,4-cyclohexane-C),
28.6 (3,5,7 adamantane-C), 30.7 (2,5 cyclohexane-C), 37.1 (4,6,10 adamantane -C), 36.7 (2,8,9 adamantane-C),
41.8 (1 adamantane-C), 81.2 (1 cyclopentane-C).
To a stirred suspension of LiAlH4 (161 mg, 4.24 mmol) in dry ether (20 mL) was added, drop-wise at 0 °C,
a solution of the azide 19c (260 mg, 1.06 mmol) in dry ether (10 mL). The reaction mixture was refluxed for 5 h
(TLC monitoring) and then hydrolyzed with water and NaOH (15%) under ice cooling. The inorganic
precipitate was filtered off and washed with ether, and the filtrate was extracted with HCl (6%). The aqueous
layer was made alkaline with solid Na2CO3 and the mixture was extracted with ether. The combined ether
extracts were washed with water and brine and dried (Na2SO4). After evaporation of the solvent the oily amine
1
19d was obtained; yield: 151 mg (65%); H NMR (CDCl3, 400 MHz) δ (ppm) 1.08-1.18 (m, 4H, 3,4
cyclopentane-H), 1.50-1.80 (m, 18H, adamantane-H, cyclopentane-H, NH2), 1.98 (br s, 3H, 3,5,7 adamantane-
H); 13C NMR (CDCl3, 50 MHz) δ (ppm) 24.9 (3,4-cyclopentane-C), 28.8 (3,5,7 adamantane-C), 34.4 (2,5
cyclopentane-C), 37.0 (4΄,6΄,10΄-C), 37.4 (2,8,9 adamantane-C), 39.0 (1 adamantane-C), 66.8 (1 cyclopentane-
C). Fumarate: mp 255 ºC (EtOH-Et2O).
1-(1-Adamantyl)cyclohexanamine (20d). Tertiary alcohol 21 was obtained from 1-adamantyl lithium (formed
by 1-bromoadamantane and lithium wire under sonication) and cyclohexanone in dry THF according to a
published procedure with 70% yield.49,50 To a stirred mixture of NaN3 (0.170 g, 2.61mmol) and dry
dichloromethane (20 mL) at 0 °C, TFA (8.70mmol) was added. To the stirred mixture a solution of tertiary
alcohol 20b (0.204 g, 0.87 mmol) in dry dichloromethane (10 mL) was added and stirring was maintained at 0
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°C for 4 h. The mixture was stirred at ambient temperature for 24 h and then was treated with NH3 12% (30
mL) at 0 °C. The organic phase was separated and the aqueous phase was extracted twice with an equal volume
of dichloromethane. The combined organic phase was washed with water and brine, dried (Na2SO4) and
13
evaporated to afford oily azide 20c; yield 0.140 g (60%); IR (Nujol) ν(Ν3) 2101 cm-1; C NMR (CDCl3, 50
MHz) δ (ppm) 21.9 (4 cyclohexane-C), 25.6 (3,5 cyclohexane-C), 28.8 (3,5,7 adamantane-C), 30.8 (2,6
cyclohexane-C), 35.7 (4,6,10 adamantane-C), 37.2 (2,8,9 adamantane-C), 42.0 (1 adamantane-C), 70.1 (1-
cyclohexane-C).
To a stirred suspension of LiAlH4 (65 mg, 1.70mmol) in dry ether (7 mL) was added, drop-wise at 0 °C, a
solution of the azide 20c (110 mg, 0.425mmol) in dry ether (5 mL). The reaction mixture was refluxed for 5 h
(TLC monitoring) and then hydrolyzed with water and NaOH (15%) under ice cooling. The inorganic
precipitate was filtered off and washed with ether, and the filtrate was extracted with HCl (6%). The aqueous
layer was made alkaline with solid Na2CO3 and the mixture was extracted with ether. The combined ether
extracts were washed with water and brine and dried (Na2SO4). After evaporation of the solvent the oily amine
1
20d was obtained; yield: 50 mg (30%); H NMR (CDCl3, 400 MHz) δ (ppm) 1.35-1.42 (m, 6H, 3,4,5
cyclohexane-H), 1.48-1.55 (m, 3H, 2,8,9 adamantane-H), 1.56-1.70 (m, 12H, 2,6 cyclohexane-H, 4,6,10
adamantane-H, NH2), 1.98 (br s, 3H, 3,5,7 adamantane-H); 13C NMR (CDCl3, 50 MHz) δ (ppm) 22.1 (4-
cyclohexane-C), 26.4 (3,5-cyclohexane-C), 29.0 (3΄,5΄,7΄-C), 30.5 (2,6-cyclohexane-C), 35.7 (4,6,10
adamantane-C), 37.5 (2,8,9 adamantane-C), 38.7 (1 adamantane-C), 54.5 (1 cyclohexane-C). Fumarate: mp 264
ºC (EtOH-Et2O); Anal. (C20H31NO4) Calcd. C, 68.74; H, 8.94; N, 4.01. Found C, 68.43; H, 9.06; N, 4.35.
2-(p-Hydroxy)benzyl-(tricyclo[3.3.1.13,7]decan)-2-amine (21). 2-(p-hydroxy)benzyl-2-adamantanamine 21
1
was obtained after deprotection of amine 14d (120 mg, 0.44 mg) using BBr3 at -80oC. Yield 90 mg (80%); H
NMR (CDCl3, 400 MHz) δ (ppm) 1.48 (m, 2H, 4eq,9eq adamantane-H), 1.71-1.80 (m, 7H, 3,5,6,7,8eq,10eq
adamantane-H), 1.93-2.0 (m, 3H, 1,8ax,10ax adamantane-H), 2.24 (d, J=12.1 Hz, 1H, 4ax,9ax adamantane-H),
2.92 (s, 2H, CH2Ar), 3.58 (s, 1H, OH), 6.73 (d, J=6.2 Hz, 2H, phenyl-H), 7.06 (d, J=6.2 Hz, 2H, phenyl-H).
Fumarate (EtOH–Et2O). Anal. (C20H34NO5) Calcd: C, 65.19; H, 9.30; N, 3.80. Found: C, 65.05; H, 9.58; N,
3.72.
Procedure B (standard Ritter reaction)
4-Ethyloctan-4-amine (BuEtPrCNH2) 1d. A solution of conc. H2SO4 (6 mL) and AcOH (6 mL) was added
dropwise to a mixture of alcohol 1b (500 mg, 3.16 mmol), AcOH (6 mL) and KCN (258 mg, 3.96 mmol) at 70
ºC and heating was maintained for 2 h. The resulting mixture was treated with water (10 mL) and NaOH 10%
(10 mL) and stirred for 15 min. The mixture was extracted with ether (2x15 mL), the combined organic phases
were washed with water and the solvent was evaporated in vacuo to afford the amine 1d acetamide. A mixture
of the amine 1d acetamide (430 mg, 2.32 mmol) and KOH (1.04 g, 18.6 mmol) in di(ethylene glycol) (2 mL)
was heated for 24h in a sealed tube at 180 o C. After cooling, the tube was opened and the mixture poured into
water (50 mL). The mixture was extracted with diclhoromethane (3x20 mL) and washed with HCl 6%. The
aqueous phase was made alkaline with solid sodium carbonate and was extracted with diclhoromethane. The
organic phase was washed with brine, dried (Na2SO4) and evaporated in vacuo to afford the 4-ethyloctan-4-
amine 1d; Yield 47%. Amine 3d was prepared according to the same procedure; Characterization of compound
1d is included in compounds synthesized by Procedure A.
5-Butylnonan-5-amine (Bu3CNH2) 3d. The amine 3d acetamide was prepared as above for the preparation of
tert-alkyl amine 1d through treatment of alcohol 3b (500 mg, 2.50 mmol), with conc.H2SO4 (6 mL) / AcOH (6
mL) / KCN (203 mg, 3.13 mmol). The amine 3d was prepared through treatment of 3d acetamide (400 mg, 1.76
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Tzitzoglaki, C.; Drakopoulos, A. et al.
mmol) with KOH (780 mg, 18.6 mmol) in di(ethylene glycol) (2 mL) and following the same workup. Yield 20
mg (4%). Characterization of compound 3d is included in compounds synthesized by Procedure A.
Procedure B (modified Ritter reaction)
4-propylheptan-4-amine (Pr3CNH2) 2d. To a mixture of the alcohol 2b (300 mg, 1.90 mmol) and ClCH2CN
(287 mg, 3.80 mmol), AcOH (0.3 mL, 5.25 mmol) was added and the mixture was cooled to 0-3 °C. H2SO4 (0.3
mL, 5.70 mmol) was added dropwise keeping the temperature below 10 °C. The reaction mixture was allowed
to reach rt, stirred for 24 h and poured into ice water (10 mL). Chloroacetamide 22 was extracted with ether (3 ×
10 mL). The combined extracts were washed with NaHCO3 10% and brine, and dried (NaSO4). Solvent was
evaporated in vacuo to afford compound 22 which was used without further purification for the next step. Yield
1
200 mg (45%); IR (Nujol) ν(C=O) 1668 cm-1; H NMR (CDCl3, 400 MHz) δ (ppm) 0.96 (t, J=7.1 Hz, 9H,
3xCH2CH2CH3), 1.33-1.47 (m, 12H, 3xCH2CH2CH3 , 3xCH2CH2CH3), 4.27 (s, COCH2Cl).
A solution of the amide 22 (180 mg, 0.772 mmol) and thiourea (70.6 mg, 0.927 mmol) in EtOH (6
mL)/AcOH (1.2 mL) was refluxed for 10 h. Then water (15 mL) was added to the reaction mixture and the
resulting precipitate was filtered off. The filtrate was made alkaline with NaOH 20%, washed with ether (3 × 30
mL) and extracted with HCl 6%. The aqueous phase was made alkaline with solid sodium carbonate and was
extracted with dichloromethane or ether. The organic phase was washed with brine, dried (Na2SO4) and
evaporated in vacuo to afford the amine 2d. Yield 100 mg (80 %); Characterization of compound 2d is included
in compounds synthesized by Procedure A.
5-Butylnonan-5-amine (Bu3CNH2) 3d. Chloroacetamide 23 was prepared through treatment of
tributylsubstituted methanol 3b (300 mg, 1.50 mmol) with NCCH2Cl (282 mg, 3.00 mmol), H2SO4 (0.3 mL,
5.70 mmol) / AcOH (0.3 mL, 5.25 mmol) according to the same procedure followed for the chloroacetamide 22.
1
Yield 252 mg, (61%); IR (Nujol) ν(C=O) 1689 cm-1; H NMR (CDCl3, 400 MHz) δ (ppm) 0.97 (t, J=7.1 Hz,
9H, 3xCH3CH2CH2CH2), 1.29-1.35 (m, 12H, 3xCH3CH2CH2CH2, 3x CH3CH2CH2CH2), 1.38-1.47 (m, 6H, 3x
CH3CH2CH2CH2), 4.27 (s, COCH2Cl). The amine 3d was prepared as above for the preparation of tert-alkyl
amine 2d through treatment of 23 (200 mg, 0.725 mmol) with thiourea (66 mg, 0.871 mmol) in EtOH (6
mL)/AcOH (1.2 mL) and following the same workup. Yield 19 mg (13%). Characterization of compound 3d is
included in compounds synthesized by Procedure A.
2-n-Butyl-(tricyclo[3.3.1.13,7]decan)-2-amine 11d. Chloroacetamide 24 was prepared through treatment of
tert-alkyl alcohol 11b (300 mg, 1.44 mmol) with NCCH2Cl (271 mg, 2.88 mmol), H2SO4 (0.3 mL, 5.70 mmol) /
AcOH (0.3 mL, 5.25 mmol) according to the same procedure followed for the chloroacetamide 22. Yield 209
1
mg, (51%); IR (Nujol) ν(C=O) 1690 cm-1; H NMR (CDCl3, 400 MHz) δ (ppm) 0.96 (t, J=7.1 Hz, 3H,
CH3CH2CH2CH), 1.35-1.45 (m, 4H, CH3CH2CH2CH2), 1.63 (d, J=12.1 Hz, 2H, 4eq,9eq-adamantane-H), 1.76-
2.02 (m, 12H, adamantane-H, CH3CH2CH2CH2), 2.05 (d, J=12.1 Hz, 2H, 4ax,9ax adamantane-H), 4.32 (s,
COCH2Cl). The amine 11d was prepared as above for the preparation of tert-alkyl amine 2d through treatment
of 24 (200 mg, 0.704 mmol) with thiourea (67 mg, 0.880 mmol) in EtOH (6 mL)/AcOH (1.2 mL) and following
the same workup. Yield 57 mg (39%). Characterization of compound 11d is included in compounds synthesized
by Procedure A.
2-(Tricyclo[3.3.1.13.7]dec-1-yl)-propan-2-amine 15d. Chloroacetamide 25 was prepared through treatment of
tert-alkyl alcohol 15b (300 mg, 1.55 mmol) with NCCH2Cl (290 mg, 3.09 mmol), H2SO4 (0.3 mL, 5.70 mmol) /
AcOH (0.3 mL, 5.25 mmol) according to the same procedure followed for the chloroacetamide 22. Yield 42
mg, (10%); IR (Nujol) ν(C=O) 1673 cm-1; 1H NMR (CDCl3, 400 MHz) δ (ppm) 0.80 (s, 6H, 2xCH3), 1.58-1.70
(m, 12H, 2,4,6,8,9,10 adamantane H), 2.01 (br s, 3H, 3,5,7 adamantane H), 4.30 (s, COCH2Cl). The amine 15d
was prepared in traces as above for the preparation of tert-alkyl amine 2d through treatment of 23 (40 mg, 0.150
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Tzitzoglaki, C.; Drakopoulos, A. et al.
mmol) with thiourea (9 mg, 0.118 mmol) in EtOH (3 mL)/AcOH (0.6 mL) and following the same workup.
Yield traces.
4-(Tricyclo[3.3.1.13.7]dec-1-yl)-heptan-4-amine 18d. Chloroacetamide 26 was prepared through treatment of
tert-alkyl alcohol 18d (300 mg, 1.20 mmol) with NCCH2Cl (226 mg, 2.40 mmol), H2SO4 (0.3 mL, 5.70 mmol) /
AcOH (0.3 mL, 5.25 mmol) according to the same procedure followed for the chloroacetamide 22. Yield 144
mg, (37%); IR (Nujol) ν(C=O) 1690 cm-1; 1H NMR (CDCl3, 400 MHz) δ (ppm) 0.92 (t, J=7.1 Hz, 6H, 2xCH3),
1.35-1.43 (m, 8H, 2x CH2CH2CH3), 1.63-1.70 (m, 12H, 2,4,6,8,9,10 adamantane H), 2.01 (br s, 3H, 3,5,7
adamantane H), 4.28 (s, COCH2Cl). The amine 18d was prepared in traces as above for the preparation of tert-
alkyl amine 2d through treatment of 26 (140 mg, 0.430 mmol) with thiourea (26 mg, 0.344 mmol) in EtOH (3
mL)/AcOH (0.6 mL) and following the same workup.
Procedure C
4-Propylheptan-4-amine (Pr3CNH2) 2d. To a stirred mixture of 4-heptanone 2a (224 mg, 1.97 mmol) and
Ti(EtO)4 (900 mg, 3.93 mmol) in dry THF (4 mL), tert-butanesulfinamide (250 mg, 2.06 mmol) was added and
the resulting reaction mixture was refluxed overnight. The mixture was cooled at 0 ºC and the solvent was
evaporated in vacuo. The residue was purified by flash chromatography on silica gel (40-63 ꢀm) using 40:60
1
Et2O/hexane as an eluent to afford the sulfinyl ketimine 28. Yield 48%; H NMR (CDCl3, 400 MHz) δ (ppm)
0.88-0.98 (m, 6H, (CH2)2CH3), 1.20 (s, 9H, C(CH3)3), 1.56-1.60 (sex, J=7.1, 4H CH2CH2CH3), 2.32-2.38 (m,
2H, CH2CH2CH3), 2.54-2.71 (m, 2H, CH2CH2CH3).
Propylmagnesium bromide (2.07 mmol) (obtained from 20% solution w/v 1-bromopropane in dry ether and
1.3 equivalents of Mg) was cooled at -78 °C and treated dropwise with a solution of the tert-butyl sulfinyl
ketimine 28 (205 mg, 0.942 mmol) in dry ether (2 mL). The resulting mixture was stirred for 1 h at -78°C and
then allowed to reach slowly ambient temperature and stirred for additional 15 h. The mixture was then cooled
at 0 °C, treated with sat. aq. Na2SO4 (5 mL) and stirred for 10 min. After suction filtration, the mixture was
extracted with ethyl acetate (2 x 15 mL) and the organic phase was washed with brine, dried (Na2SO4) and
evaporated in vacuo to afford crude tert-butyl sulfinamide 30 which was used without further purification for
the next step.
A solution of sulfinamide 30 (121 mg, 0.463 mmol) in dioxane (1 mL) was cooled at 0 ºC and treated
dropwise with HCl 2.5 M in ethanol (4.0 mL, 2.31 mmol). The resulting solution was allowed to reach ambient
temperature and stirred for 40 min. The solution was concentrated under vacuum to a volume of 1 mL and 2 mL
of ether was added to afford amine 2d hydrochloride as a precipitate. Yield 13 mg (18%); Characterization of
compound 2d is included in compounds synthesized by Procedure A.
5-Butylnonan-5-amine (Bu3CNH2) 3d. Tert-butyl sulfinyl ketimine 29 was prepared according to the same
1
procedure followed for tert-butyl sulfinyl ketimine 10. Yield 77% ; H NMR (CDCl3, 400 MHz) δ (ppm) 0.89
(t, J = 7, 6H, (CH2)3CH3), 1.19 (s, 9H, C(CH3)3), 1.33 (sextet, J=7, 4H, (CH2)2CH2CH3), 1.54 (q, J=7.1, 4H,
13
CH2CH2CH2CH3), 2.38 (t, J=7.1, 2H, CH2(CH2)2CH3), 2.58-2.73 (m, 2H, CH2(CH2)2CH3); C NMR (CDCl3,
50 MHz) δ (ppm) 13.9 (2x(CH2)3CH3), 22.3 (C(CH3)3), 23.0 (2x(CH2)2CH2CH3), 27.8 (CH2CH2CH2CH3), 29.6
(CH2CH2CH2CH3), 36.4 (2xCH2CH2CH2CH3), 56.2 (C(CH3)3), 189.1 (C=N).
A 0.7 M solution of sulfinyl ketimine 29 (387 mg, 1.58 mmol,) in dry toluene (2 mL) was cooled at -78 ºC
and treated dropwise with a 2M solution of AlMe3 in toluene (0.8 mL, 1.1 molar excess). The mixture was
stirred for 5 min and a solution of 1.6M n-butyl lithium in hexanes (2 mL, 0.4 M in toluene, 2.2 molar excess)
o
was added dropwise at -78 ºC. The resulting mixture was stirred for additional 4 h at -78 C and then allow to
reach 0 ºC. The mixture was treated with sat. aq. Na2SO4 (5 mL) and stirred for 10 min. After suction filtration,
the mixture was extracted with ethyl acetate (2 x 15 mL) and the organic phase was washed with brine, dried
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Tzitzoglaki, C.; Drakopoulos, A. et al.
(Na2SO4) and evaporated in vacuo to afford crude tert-butyl sulfinamide 31 which was used without further
purification for the next step.
A solution of sulfinamide 31 (227 mg, 0.750 mmol) in dioxane (1 mL) was cooled at 0 ºC and treated
dropwise with HCl 2.5 M in ethanol (6.5 mL, 3.75 mmol). The resulting solution was allowed to reach ambient
temperature and stirred for 40 min. The solution was concentrated under vacuum to a volume of 1 mL and 2 mL
of ether was added to afford amine 3d hydrochloride as a precipitate. Yield 45 mg (25 %); Characterization of
compound 3d is included in compounds synthesized by Procedure A.
Procedure D
5-Propyl-nonan-5-amine (Bu2PrCNH2) 6d. Kulinkovich-de Meijere reaction protocol: A solution of
butanenitrile (34) (1.0 g, 14.5 mmol) in 40 mL anhydrous ether was added dropwise to a 3.2 molar excess of
BuMgBr (3M in dry ether, obtained from 1-bromobutane (5.9 g, 46.4 mmol) with 1.2 equivalents of Mg (1.4 g,
55.7 mmol)). After stirring the mixture for 30 min, 1 equiv of Ti(iPrO)4 (4.1 g, 14.5 mmol) was added
successively at rt and the reaction mixture was gently refluxed for 24 h. After treating the mixture with NaOH
10%, following usual workup the corresponding amine 6d was obtained. Yield 670 mg (25%), (Table 5, entry
1); Characterization of compound 6d is included in compounds synthesized by Procedure A.
5-Butyl-nonan-5-amine (Bu3CNH2) 3d. Kulinkovich-de Meijere reaction protocol: A solution of
pentanenitrile 35 (1.0 g, 12.0 mmol) in 40 mL anhydrous ether was added dropwise to a 3.2 molar excess of
BuMgBr (3M in dry ether, obtained from 1-bromobutane (4.9 g, 36.0 mmol) and 1.2 equivalents of Mg (1.0 g,
43.2 mmol)). After stirring the mixture for 30 min, 1 equiv of Ti(iPrO)4 (3.4 g, 12.0 mmol) was added
successively at rt and the reaction mixture was gently refluxed for 24 h. After treating the mixture with NaOH
10% following usual workup the corresponding amine 3c was obtained. Yield 510 mg (20%), (Table 5, entry 2);
characterization of compound 3d is included in compounds synthesized by Procedure A.
4-(Tert-butyl)-heptane-4-amine (tBuMe2CNH2) (38). Kulinkovich-de Meijere reaction protocol: Tert-alkyl
amine 38 was prepared through the reaction of pivalonitrile (36) (500 mg, 6.02 mmol) in 30 mL of anhydrous
diethyl ether with a 3M PrMgBr in dry ether (obtained from PrBr (2.20 g, 18.07 mmol) and 1.2 equivalents of
Mg (520 mg, 21.7 mmol)) and Ti(iPrO)4 (2.0 g, 7.22 mmol) according to the same procedure described above
for the amines 3d and 6d. Fumaric salt formation and recrystallization afforded 340 mg of fumaric salt of amine
38. Yield 20%, (Table 5, entry 3); 1H NMR (CDCl3, 400 MHz) δ (ppm) 0.84-0.90 (m, 15H, (CH2)2CH3,
(CH2)2CH3, C(CH3)3), 1.28-1.40 (m, 8H, (CH2)2CH3); 13C NMR (CDCl3, 50 MHz) δ (ppm) 15.37
(2x(CH2)2CH3), 18.62 (2xCH2CH2CH3), 26.3 (C(CH3)3), 38.9 (2xCH2CH2CH3), 42.2 (C(CH3)3), 57.5(CNH2).
3-(1-Adamantyl)-propan-2-amine (AdMe2CNH2) 15d. Kulinkovich-de Meijere reaction protocol: A solution
of 3M MeMgBr (1 mL, 3.11 mmol) in diethyl ether was added dropwise to 1-adamantanecarbonitrile (37) (500
mg, 3.11 mmol) in ether (30 mL). After stirring the mixture for 30 min, 1.2 equiv of Ti(iPrO)4 (975 mg, 3.43
mmol) was added successively at rt. The mixture was allowed to stir at room temperature under argon
atmosphere for 1 h. Then, 4 mL of methylithium solution (1.6 M in diethyl ether, 6.22 mmol) was added
dropwise and the reaction mixture was gently refluxed for 24 h. After treating the mixture with NaOH 10%
following usual workup the corresponding amine 15d was obtained. Yield 60 mg (10%), (Table 5, entry 7);
Characterization of compound 15d is included in compounds synthesized by Procedure A.
3-(1-Adamantyl)-propan-2-amine (AdMe2CNH2) 15d. Kulinkovich-de Meijere reaction protocol: A solution
of 3M MeMgBr (1 mL, 3.11 mmol) in diethyl ether was added dropwise to 1-adamantanecarbonitrile (37) (500
mg, 3.11 mmol) in ether (30 mL). After stirring the mixture for 30 min, 1.2 equiv of Ti(iPrO)4 (975 mg, 3.43
mmol) was added successively at rt. The mixture was allowed to stir at room temperature under argon
atmosphere for 1 h. Then, 2.1 mL of MeMgBr solution (3 M in diethyl ether, 6.22 mmol) was added dropwise
and the reaction mixture was gently refluxed for 24 h. After treating the mixture with NaOH 10% following
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Tzitzoglaki, C.; Drakopoulos, A. et al.
usual workup the corresponding amine 15d was obtained. Yield 60 mg (10%), (Table 5, entry 9);
Characterization of compound 15d is included in compounds synthesized by Procedure A.
3-(1-Adamantyl)-propan-2-amine (AdMe2CNH2) 15d. Kulinkovich-Szymoniak reaction protocol:
Tetraisopropoxy titanium (975 mg, 3.43 mmol) was added in a solution of 1-adamantanecarbonitrile (37) (500
mg, 3.11 mmol) in 30 mL of anhydrous diethyl ether, under stirring and argon atmosphere. After 20 min, 1 mL
of MeMgBr solution in diethyl ether (3 M, 6.22 mmol) was added dropwise and the mixture was allowed to stir
at room temperature under argon atmosphere for 1 h. Then, 4 mL of methylithium solution (1.6 M in diethyl
ether, 6.22 mmol) was added dropwise and the reaction mixture was gently refluxed for 24 h. After treating the
mixture with NaOH 10% following usual workup the corresponding amine 15d was obtained. Yield 66 mg
(11%), (Table 5, entry 7); Characterization of compound 15d is included in compounds synthesized by
Procedure A.
3-(1-Adamantyl)-propan-2-amine (AdMe2CNH2) 15d. Kulinkovich-Szymoniak reaction protocol: A solution
of 3M MeMgBr (2.1 mL, 6.22 mmol) in diethyl ether was added dropwise to 1-adamantanecarbonitrile (37)
(500 mg, 3.11 mmol) in ether (30 mL). After stirring the mixture for 30 min, 1.2 equiv of Ti(iPrO)4 (975 mg,
3.43 mmol) was added successively at rt. The mixture was allowed to stir at room temperature under argon
atmosphere for 1 h. Then, 1 mL of MeMgBr solution (3 M in diethyl ether, 3.11 mmol) was added dropwise and
the reaction mixture was gently refluxed for 24 h. After treating the mixture with NaOH 10% following usual
workup the corresponding amine 15d was obtained. Yield 60 mg (10%), (Table 5, entry 9); Characterization of
compound 15d is included in compounds synthesized by Procedure A.
3-(1-Adamantyl)-propan-2-amine (AdMe2CNH2) 15d. CeCl3 applied protocol: Commercial dry CeCl3 (2.37
g, 9.61 mmol) was further subjected to stirring at 140-150 ºC (0.1 mm) for 3 h. Argon was added slowly, and
the flask was cooled in an ice bath. Anhydrous THF (20 mL) was added, and the suspension was stirred at 25 ºC
for 2 h. Then MeLi (6 mL of a 1.6 M solution in ether, 9.61 mmol) was added keeping the temperature at -78
ºC with a dry ice/acetone bath. The mixture was stirred in the dry ice/acetone bath for 30 min, and 1-
adamantanecarbonitrile (37) (0.500 g, 3.10 mmol) in 2 mL of THF was added. Stirring at -65 ºC was continued
o
for 5 h. Concentrated NH3 (10 mL) was added at less than -40 C, and the mixture was brought to 25 ºC and
filtered with the aid of Celite. The solids were washed several times with dichloromethane, and the aqueous
layer of the filtrates was extracted twice with dichloromethane. The combined organic phases were dried and
concentrated. The residue was taken up in 10 mL of toluene and stirred with 10 mL of 3% H3P04 for 20 min.
The toluene layer was extracted with two l0 mL portions of water, and the combined aqueous phases were
washed once with toluene and made basic with conc. NH3. The mixture was extracted several times with
dichloromethane, and the residue was obtained on removal of the solvent from the dried (Na2SO4) extracts;
Yield 70 mg (12%) of 15d. (Table 5, entry 10)
3-(1-Adamantyl)-pentan-3-amine (AdEt2CNH2) 16d. Kulinkovich-de Meijere reaction protocol using 3 eq.
EtMgBr. Amine 16d was prepared through the reaction of 1-adamantanecarbonitrile (37) (500 mg, 3.11 mmol)
in 30 mL of anhydrous diethyl ether with EtMgBr 3M in dry ether (obtained from EtBr (1.02 g, 9.33 mmol)
and 1.2 equivalents of Mg (672 mg, 28.0 mmol) and Ti(iPrO)4 (970 mg, 3.42 mmol) according to the same
procedure described above for the amines 3d and 6d to afford 120 mg of mixture. For purification of the crude
product 2 mL of an ethanolic solution of fumaric acid (66 mg, 0.569 mmol) was added to a solution of the crude
amine in 2 mL ethanol. The mixture was evaporated under vacuum, to yield a white colored crystal residue
which was treated with diethyl ether and filtered under vacuum to afford a non-separable mixture of AdEtCH-
NH2 (40) in 3% yield and AdEt2C-NH2 16d in a 4% yield (ratio 60:40 according to 13C NMR spectrum), (Table
5, entry 5). Characterization of compound 16d is included in compounds synthesized by Procedure A.
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3-(1-Adamantyl)-pentan-3-amine (AdEt2CNH2) 16d. Kulinkovich-de Meijere reaction protocol using
EtMgBr and EtLi. Amine 16d was prepared through the reaction of 1-adamantanecarbonitrile (37) (500 mg,
3.11 mmol) in 30 mL of anhydrous diethyl ether with EtMgBr 3M in dry ether (obtained from EtBr (340 mg,
3.11 mmol) and 1.2 equivalents of Mg (90 mg, 3.73 mmol) and Ti(iPrO)4 (970 mg, 3.42 mmol) according to the
same procedure described above for the amines 3d and 6d. The mixture was allowed to stir at room
temperature under argon atmosphere for 1 h. Then, 12 mL of ethyllithium solution (0.5 M in
cyclohexane/benzene, 6.22 mmol) or 6.22 mmol of ethyl magnesium bromide solution was added dropwise and
the reaction mixture was gently refluxed for 24 h. After treating the mixture with NaOH 10% following usual
workup the corresponding amine 16d was obtained. Yield 70 mg (10%), (Table 5, entry 8); Characterization of
compound 16d is included in compounds synthesized by Procedure A.
3-(1-Adamantyl)-pentan-3-amine (AdEt2CNH2) 16d. Kulinkovich-Szymoniak reaction
protocol:
Tetraisopropoxy titanium (975 mg, 3.43 mmol) was added in a solution of 1-adamantanecarbonitrile (37) (500
mg, 3.11 mmol) in 30 mL of anhydrous diethyl ether, under stirring and argon atmosphere. After 20 min, 3.1
mL of ethyl magnesium bromide solution in diethyl ether (1 M, 3.11 mmol) was added dropwise and the
mixture was allowed to stir at room temperature under argon atmosphere for 1 h. Then, 12 mL of ethyllithium
solution (0.5 M in cyclohexane/benzene, 6.22 mmol) was added dropwise and the reaction mixture was gently
refluxed for 24 h. After treating the mixture with NaOH 10% following usual workup to yield 300 mg of a
yellow oily product, which was purified by recrystallization; 2 mL of an ethanolic solution of fumaric acid (166
mg, 1.43 mmol) was added to a solution of the crude amine in 2 mL ethanol. The mixture was evaporated under
vacuum, to yield a white colored crystal residue which was treated with diethyl ether and filtered under vacuum
to afford 60 mg (yield 10%) of the fumarate salt of amine 16d; Yield 65 mg (10%), (Table 5, entry 8);
Characterization of compound 16d is included in compounds synthesized by Procedure A.
1-(1-adamantyl)cyclopentanamine 19d. Kulinkovich-de Meijere reaction protocol: A solution of 1-
adamantanecarbonitrile (37) (300 mg, 1.86 mmol) in ether (5 mL) was added dropwise to a 2 molar excess of
BrMg(CH2)2MgBr (3M in dry ether, obtained from dibromobutane with 2.2 equivalents of Mg). After stirring
the mixture for 30 min, 1 equiv of Ti(iPrO)4 (529 mg, 1.86 mmol) was added successively at rt and the reaction
mixture was allowed to stir at room temperature under argon atmosphere for 24 h. After a dropwise addition of
an equal volume of a sodium hydroxide 10% w/v solution under ice cooling, the mixture was stirred for 30 min
and filtered under vacuum. The filtrate was extracted with diethyl ether (2x10mL). The combined ethereal
phases were extracted with 30 mL (2x15 mL) of hydrochloric acid 6% w/v. The aqueous phase was separated
and made alkaline through addition of an excess solid sodium carbonate under ice-cooling. The aqueous phase
was extracted two times with 15 mL of dichloromethane. The combined organic extracts were washed 2 times
with an equal volume of water and brine, dried (Na2SO4) and evaporated under vacuum to yield 173 mg of a
yellow oily product, which was purified by recrystallization; 2 mL of an ethanolic solution of fumaric acid (94
mg, 0.829 mmol) was added to a solution of the crude amine in 2 mL ethanol. The mixture was evaporated
under vacuum, to yield a white colored crystal residue which was treated with diethyl ether and filtered under
vacuum to afford 60 mg (yield 10%) of the fumarate salt of 3-(1-adamantyl)-pentan-3-amine 19d. (Table 5,
entry 6). Characterization of compound 19d is included in compounds synthesized by Procedure A.
Author Information
‡: These authors contributed equally to the work.
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Tzitzoglaki, C.; Drakopoulos, A. et al.
This research is part of C.T. Ph.D thesis and part of A.D. Master's thesis. A.D. current address: Chair of
Pharmaceutical and Medicinal Chemistry, Institute of Pharmacy and Food Chemistry, Julius-Maximilians-
Universität Würzburg, Am Hubland, 97074 Würzburg, Germany. A.K. designed this research project. C.T. and
A.D. performed the synthesis work. Ath. K. performed some reactions. I.S. did the calculations. A.K. and A.D.
wrote the manuscript.
7 Achnowlegments
We are grateful to Chiesi Hellas for supporting this research and the thesis work of C.T., A.D. Ath.K.
8 Suppementary Information
Figures S1-S9, Tables S1-S4
9 References
(1) Wanka, L.; Iqbal, K.; Schreiner, P. R. Chem. Rev. 2013, 113, 3516.
(2) Yu, Z.; Sawkar, A. R.; Whalen, L. J.; Wong, C. H.; Kelly, J. W. J. Med. Chem. 2007, 50, 94.
(3) Meisheri, K. D.; Humphrey, S. J.; Khan, S. A.; Cipkus-Dubray, L. A.; Smith, M. P.; Jones, A. W. J.
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