Solvent-free and direct C(sp3)-H amination of adamantanes by grinding

Article abstract of DOI:10.1016/j.tet.2014.01.014

A facile, direct and environmentally benign conversion of C(sp ³)-H bonds to C(sp³)-N bonds using substoichiometric amount of aprotic superelectrophiles polyhalomethane-AlX₃ has been achieved by grinding under solvent-free

Full text of DOI:10.1016/j.tet.2014.01.014

Accepted Manuscript
3
Solvent-free and direct C(sp )-H amination of adamantanes by grinding
Zhen Wei, Jiarong Li, Ning Wang, Qi Zhang, Daxin Shi, Kening Sun
PII:
S0040-4020(14)00030-1
10.1016/j.tet.2014.01.014
TET 25188
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 30 October 2013
Revised Date: 30 December 2013
Accepted Date: 8 January 2014
3
Please cite this article as: Wei Z, Li J, Wang N, Zhang Q, Shi D, Sun K, Solvent-free and direct C(sp )-H
amination of adamantanes by grinding, Tetrahedron (2014), doi: 10.1016/j.tet.2014.01.014.
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Solvent-free and direct C(sp3)-H amination
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of adamantanes by grinding
Zhen Wei, Jiarong Li, Ning Wang, Qi Zhang, Daxin Shi* and Kening Sun*
School of Chemical Engineering and Environment, Beijing Institute of Technology, Beijing, 100081, China.

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Tetrahedron
journal homepage: www.elsevier.com
Solvent-free and direct C(sp3)-H amination of adamantanes by grinding
Zhen Wei, Jiarong Li, Ning Wang, Qi Zhang, Daxin Shi and Kening Sun*
School of Chemical Engineering and Environment, Beijing Institute of Technology, Beijing, 100081, China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A facile, direct and environmentally benign conversion of C(sp3)-H bonds to C(sp3)-N bonds
using substoichiometric amount of aprotic superelectrophiles polyhalomethane-AlX3 has been
achieved by grinding under solvent-free conditions at room temperature in air. It is a general and
simple method for the direct amination of adamantanes, and a series of aminoadamantanes of
azoles, arylamines or heteroarylamines were obtained in good to excellent yields. The
advantages of this amination are atom economy, solvent-free, chemoselectivity, short reaction
time and high yields.
Available online
Keywords:
sp3 C-H amination
2009 Elsevier Ltd. All rights reserved.
Adamantanes
Aprotic superelectrophiles polyhalomethane-AlBr3
Grinding
Solvent-free
1. Introduction
Recently, Solvent-free organic reactions have drawn consi-
derable attention due to their environmentally benign protocols,
Aminoadamantanes represent a valuable class of compounds
with structural and functional motifs that are prevalent in many
biologically active natural products, pharmaceuticals and
materials. For example, 1-aminoadamantane hydrochloride
(amantadine) and 1-(1-adamanty)ethanamine (rimantadine) have
proved to be efficient medicines against influenza.1a,1b Recently,
azolo-adamantanes were found to be new potent antiviral agents
against influenza displaying a broad spectrum of activity and low
toxicity.1c-1e As a result of steric environment of adamantane, the
ligands containing aminoadamantane fragment have become
important ones for the homodimerization reactions of terminal
olefins,2a,2b ethylene polymerization,2c alkene isomerization,2d
enyne cyclization,2e and suzuki cross-coupling reactions.2f Also,
1,2,4-triazole functionalized adamantanes are known to be useful
molecular engineers for the synthesis of metal organic framework
(MOF) materials.3
The traditional routes for the formation of C(sp3)-N bonds of
adamantanes at the tert-carbons position are the nucleophilic
substitution reactions,1c,3,4 but these methods are usually not
atom economic, thus generate substantial waste. Recently, the
nitrene C-H insertion,5 metal-nitrenoid,6 and organo-nitrenoid
direct aminations7 have been reported for the direct C(sp3)-H
amination of adamantanes. These methods often require special
nitrene sources (N-tosylimino-λ3-iodane, sulfamoyl azides, N-
tosyloxycarbamates or aryl azides), directing groups, or strong
oxidants, so they are not very simple and general methods for
C(sp3)-N bond formation.
short reaction time, occasionally-enhanced selectivity and
convenient means of product purification.8 Grinding technique, as
a useful mechanochemistry approach, plays a pivotal role in
various solvent-free reactions.9 As aprotic superelectrophiles
polyhalomethane-AlX3 systems are able to generate carbocations
effectively from saturated hydrocarbons under very mild
condition, they are recognized as a unique possibility to the
halogenation, dichlorophosphorylation, sul-furization, Ritter-type
reaction and carbonylation with CO of cycloalkanes.10 However,
all the procedures employ conditions utilizing organic solvents.
To the best of our knowledge, the solvent-free reaction for
aprotic superelectrophiles polyhalo-methane-AlX3 systems has
not been disclosed.
In the continuation of our interest in the utilization of aprotic
superelectrophiles systems in mechanochemical reactions, herein
we report a general, environmentally friendly, effective and
chemoselective method for the direct C(sp3)-H amination of
adamantanes by employing a mixture of polyhalomethane-AlX3
and amine by grinding under solvent-free conditions. It is worth
mentioning that, very common nitrogen sources, such as azole,
heteroarylamine and arylamine derivatives, are readily employed
in this procedure.
2. Results and discussion
In our initial studies, adamantane (1a) and 1H-benzotriazole
(2b) were chosen as model substrates to find a green, chemo-
selective and effective condition for the grinding reaction. As
———
Corresponding author. Tel.: +86-010-6891-8012; fax: +86-010-6891-8012; e-mail: shidaxin@bit.edu.cn (D. Shi), sunkn@bit.edu.cn (K. Sun).

2
Tetrahedron
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shown in Table 1, the activity of different Lewis acids, such as
Table 2 The amination of adamantanes and norbornane
FeCl3, CoCl2, BiCl3, ZnBr2, InBr3, AlCl3 and AlBr3, was scanned
(entries 1–9). Gratifyingly, we found that the AlX3-CBr4 (X = Cl,
Br) was an efficient catalyst to activate the C-H bond of
adamantane in grinding condition, and the reaction using AlBr3-
CBr4 as the catalyst resulted in higher yields than those using
AlCl3-CBr4. Without CBr4 in the system, the amination of
adamantane could not occur (entry 10). It proved that the
formation of polyhalomethane cation promoted by the strong
Lewis acid played the key role in the grinding reaction. The 0.5
eq AlBr3-CBr4 was the best (entry 8). With the increasing of the
amount of catalyst, the bromination of 1-adamantyl-1H-benzo-
triazole would occur (entry 9). It is worth mentioning that the
mechanochemistry grinding is a considerable effective and
environmentally friendly method compared with the solvent
condition (entries 11, 12).
Entry
1
Amine/azole
Product
Time (min)
5
Yield (%)
90a,d
2
5
91a,d
Table 1 Opitimization Conditions
N
3
4
5
5
93a,d
79a,d
N
N
3c
Amount of
Lewis acid
(equiv)
Amount of
CBr4
(equiv)
H
N
Lewis
acid
Time
(minute)
Yield
(%)
Entry
N
N
5
6
5
71a,d
75a,c
N
3e
2e
1
2
FeCl3
CoCl2
BiCl3
ZnBr2
InBr3
AlCl3
AlBr3
AlBr3
AlBr3
AlBr3
AlBr3
AlBr3
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
1
0.5
0.5
0.5
0.5
0.5
0.5
0.25
0.5
1
5
5
0a
0 a
0 a
10
3
5
7
8
5
5
81a,c
90a,c
4
5
0 a
0 a
5
5
6
5
15 a, c
67 a, c
91 a, d
71 a, c
0 a
7
5
8
5
9
5
5
84a,c
83a,c
9
5
10
11
12
1
0
5
10
0.5
2
0.5
1
60
60
trace b
76 b, c
11
12
5
5
91a,c
64b,c
a Reaction conditions: adamantane (1 mmol) and 1H-benzotriazole (1 mmol).
b Reaction conditions: adamantane (1 mmol), 1H-benzotriazole (1 mmol) and
CH2Br2 (5 ml).
c Isolated yield after purification by column chromatography.
d Isolated yield by filtration and recrystallisation.
Ad
Ad
N
N
N
H
H
3l
The possible amination mechanism of adamantanes by poly-
halomethane-AlX3 is shown in the Scheme 1. Firstly, the
superelectrophiles [Al2X7]-CX3+ I are produced by the CX4 and 2
eq AlX3, then trihalomethyl cations are capable of hydride
abstraction from AdH to generate Ad+. The latter, in turn, can be
converted into amination product. The newly generated CX3H
13
14
2b
2i
5
5
89a,d
87a,c
15
16
17
2k
2b
2h
5
5
5
92a,c
88a,d
79a,c
a Reaction conditions: cycloalkane (1 mmol), azole/ heteroarylamine/aromatic
amine (1 mmol), AlBr3 (0.5 mmol) and CBr4 (0.5 mmol). b Reaction
conditions: adamantane (2 mmol), 2,6-diaminopyridine (1 mmol) AlBr3 (1
mmol) and CBr4 (1 mmol). c Isolated yield after purification by column
chromatography. d Isolated yield by filtration and recrystallisation.
Scheme 1. The possible amination mechanism of adaman-
tanes by polyhalomethane-AlX3

3
can still react with AlX3 to product superelectrophiles [Al2X7]-
4-C substituted compound 5 (Scheme 3). The molecular
1
ACCEPTED MANUSCRIPT
CX2H+ II which also can generate Ad+ from AdH.10c
structure of 5 had been confirmed by MS, H and 13C NMR
spectra. The 13C NMR spectra data (31.27 ppm or 31.17 ppm) of
the connected carbon of 5 indicated the formation of C-C bond,
while the chemical shift of the same carbon would be about
50~60 ppm if the C-N one was connected. The 1H NMR chemical
shifts of hydrogen on both 3- and 5-positions were equal, it
confirmed that the structure of 5a was symmetric and the
connection between adamantane and pyrazole should be 1-
position of adamantane and 4-position of pyrazole.
With these results in hand, we surveyed the scope of this
reaction by subjecting a series of azole, arylamine and heteroaryl-
amine compounds 2a-l to react with adamantanes 1, and the
results were presented in Table 2. As summarized in Table 2,
various azoles such as tetrazole, triazole and imidazole, were
found to undergo the reaction well and selectively (entries 1-5).
Compared to N-alkylation of tetrazole and benzotriazole in 1- or
2-position,1e the direct sp3 C-H amination catalyzed by the
superelectrophiles polyhalomethane-AlX3 was highly selective
N-alkylation in 1-position, and 1-adamantanylazoles 3a and 3b
were synthesized. Adamantylation of 3-amino-1,2,4-triazole in
the 1-position promoted by the superelectophiles polyhalo-
methane-AlX3 was similar to the nucleophilic substitution
reaction.4d
Encouraged by these exciting results, subsequently we
investigated the reaction of adamantane 1a with a range of
arylamine (entries 6-9). Generally, electron-deficient arylamine
showed better results than electron-rich ones. The result was
different from the conventional nucleophilic substitution
reaction.11 Heteroarylamines also provided good to excellent
yields (entries 10-12). Bialkylation product of N2,N6-
di(adamantanyl)-pyridine-2,6-diamine 3l was obtained in the
presence of 2 eq adamtance and 1eq AlBr3-CBr4. Additionally,
dimethyladaman-tane 1b, norbornane 1c also could react with
azoles, arylamines and heteroarylamines to give the
corresponding amines ( entries 13-17).
Scheme 3. Forming C-C bond catalyzed by AlBr3-CBr4 under
grinding
3. Conclusions
In summary, we have developed an efficient, chemoselectivity
and environmentally benign method for the amination of
adamantanes in
a
substoichiometric amount of AlX3-
polyhalomethane by grinding under solvent-free condition. The
purification of amination products is very simple. In the
meanwhile, this method make it possible for the bifunctional
reaction by direct C(sp3)-H amination in one step, and offers
significant advantage of time efficiency, ease of manipulation
and atom economy.
When the reaction of adamantance 1a and 1,2,4-triazole 2c in
2 eq. AlBr3-CBr4, the expected 1-(1-adamantanyl)-1,2,4-triazole
3c was obtained as minor product (11%), while an bifunctional
product 1,3-di(1H-1,2,4-triazolyl)-adamantane 4 was the major
one (81%) (Scheme 2). Perhaps the main reason is that, when 2
eq. AlBr3-CBr4 was used, the mono-substituted intermediate 3c
4. Experimental section
4.1 General information
+
could react with excess of CX3 to give the di-substituted product
4. The structure of 4 has been undoubtedly confirmed by X-ray
All the reactions were carried out at room temperature that is
15-20 . Unless otherwise noted, all reagents were purchased
from commercial suppliers and used without purification. All
reactions were conducted by grinding in a mortar and pestle.
Melting points were determined using XT4 microscope melting
point apparatus (uncorrected). Infrared (IR) spectra were
recorded on a Perkin Elmer FT-IR spectrophotometer with KBr
crystallographic analysis (Fig. 1).12
1
pellets. H and 13C NMR spectra were recorded at a Bruker 400
Scheme 2. The formation of the bifunctional product 4
catalyzed by AlBr3-CBr4 under grinding in one step
(400 MHz) spectrometer with TMS as the internal standard. Mass
spectra were recorded on a ZAB-HS mass spectrometer using
ESI ionization. Elemental analyses were performed on an
Elementar Vario EL.
4.2 General Procedure for synthesis of compounds 3 and 5
A mixture of the appropriate adamantane/norbornane (1
mmol), amine (1 mmol), AlBr3 (0.5 mmol) and CBr4 (0.5 mmol)
was ground in a mortar and pestle at room temperature till the
completion of reaction as indicated by TLC (5-10 min). The
product of azole derivatives were purified by recrystallisation
from ethyl alcohol, and the other amine derivatives were purified
by column chromatography using ethyl acetate and petroleum
ether mixtures as the mobile phase.
Fig. 1. ORTEP diagram of 4
Pilar and his companions reported that, reaction of NH-
pyrazoles with 1-bromoadamantane in a high pressure gave
regioselectively 1-(1-adamantyl)- or 4-(1-adamantyl)-pyrazoles
depending on the reaction temperature.4c We found that the direct
C(sp3)-H amination catalyzed by the superelectrophiles
polyhalomethane-AlX3 was the highly selective synthesis of the
4.2.1. 1-((3s,5s,7s)-adamantan-1-yl)-1H-tetrazole (3a). White
crystal; m.p. 135-136 ℃; IR (KBr, v, cm-1): 3348, 3148, 3121,
2913, 2855, 1626, 1556, 1453; H NMR (400MHz, CDCl3) (δ,
ppm): 1.83 (6H, s, Ad-H), 2.27 (6H, s, Ad-H), 2.31 (3H, s, Ad-
H), 8.63 (1H, s, tetrazole-H); 13C NMR (100 MHz, CDCl3) (δ,
ppm): 29.2 (3C), 35.6 (3C), 42.5 (3C), 59.7, 139.3; ESI-MS (m/z)
1

4
Tetrahedron
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= 205.2 ([M+H]+).
(3H, s, Ad-H), 4.38 (1H, s, N-H), 6.61-6.65 (1H, m, phenyl-H),
7.01 (1H, d, J = 9.6 Hz, phenyl-H), 7.28-7.32 (1H, m, phenyl-H),
7.36 (1H, d, J = 8.0 Hz, phenyl-H); 13C NMR (100 MHz, CDCl3)
(δ, ppm): 29.6 (3C), 36.3 (3C), 42.6 (3C), 52.7, 97.7, 114.7,
116.4, 118.3, 133.2, 133.4, 149.1; ESI-MS (m/z) = 253.2
([M+H]+).
4.2.2. 1-((3s,5s,7s)-adamantan-1-yl)-1H-benzo[d][1,2,3]triazole
(3b). White crystal; m.p. 164-165 ℃; IR (KBr, v, cm-1): 3051,
1
2918, 2849, 1671, 1620, 1454, 740; H NMR (400MHz, CDCl3)
(δ, ppm): 1.91 (6H, s, Ad-H), 2.38 (3H, s, Ad-H), 2.56 (6H, s,
Ad-H), 7.36 (1 H, td, J = 7.6, 1.6 Hz, benzotriazole-H), 7.45 (1 H,
td, J = 7.2, 0.8 Hz, benzotriazole-H), 7.85 (1 H, d, J = 8.0 Hz,
benzotriazole-H), 8.11 (1 H, d, J = 9.2 Hz, benzotriazole-H); 13C
NMR (100 MHz, CDCl3) (δ, ppm): 29.3 (3C), 35.7 (3C), 42.8
(3C), 61.6, 112.5, 120.4, 123.4, 126.3, 131.7, 147.0; ESI-MS
(m/z) = 254.2 ([M+H]+).
4.2.10.
N-((3s,5s,7s)-adamantan-1-yl)pyridin-2-amine
(3j).
White crystal; m.p. 171-172 ℃; IR (KBr, v, cm-1): 3372, 3011,
1
2904, 2847, 1602, 1507, 1485; H NMR (400MHz, CDCl3) (δ,
ppm): 1.70 (6H, s, Ad-H), 2.04 (6H, s, Ad-H), 2.12 (3H, s, Ad-
H), 4.48 (1H, s, N-H), 6.48-6.53 (2H, m, pyridine-H), 7.32-7.37
(1H, m, pyridine-H), 8.03 (1H, d, J=3.6 Hz, pyridine-H); 13C
NMR (100 MHz, CDCl3) (δ, ppm): 29.1 (3C), 35.6 (3C), 41.7
(3C), 56.4, 112.3, 114.5, 138.4, 147.8, 156.9; ESI-MS (m/z) =
229.2 ([M+H]+).
4.2.3. 1-((3s,5s,7s)-adamantan-1-yl)-1H-1,2,4-triazole (3c).
White crystal; m.p. 87-88 ℃; IR (KBr, v, cm-1): 3119, 2909,
2861, 1742, 1498, 1276; H NMR (400MHz, CDCl3) (δ, ppm):
1.78 (6H, s, Ad-H), 2.17 (6H, s, Ad-H), 2.24 (3H, s, Ad-H), 7.93
(1H, s, triazole-H), 8.12 (1H, s, triazole-H); 13C NMR (100 MHz,
CDCl3) (δ, ppm): 29.3 (3C), 36.0 (3C), 42.6 (3C), 58.6, 139.4,
151.3; ESI-MS (m/z) = 204.2 ([M+H]+).
1
4.2.11. 2-((3s,5s,7s)-adamantan-1-ylamino)nicotinonitrile (3k).
White crystal; m.p. 169-170 ℃; IR (KBr, v, cm-1): 3359, 3003,
2902, 2849, 2219, 1591, 1576, 1506, 1461, 1415; 1H NMR
(400MHz, CDCl3) (δ, ppm): 1.73 (6H, s, Ad-H), 2.13 (3H, s, Ad-
H), 2.16 (6H, s, Ad-H), 4.93 (1H, s, N-H), 6.51-6.54 (1H, m,
pyridine-H), 7.58-7.60 (1H, m, pyridine-H), 8.22-8.24 (1H, m ,
pyridine-H); 13C NMR (100 MHz, CDCl3) (δ, ppm): 29.7 (3C),
36.5 (3C), 41.8 (3C), 53.2, 91.9, 111.2, 117.8, 141.3, 152.1,
158.5; ESI-MS (m/z) = 254.2 ([M+H]+).
4.2.4.
1-((3s,5s,7s)-adamantan-1-yl)-1H-1,2,4-triazol-3-amine
(3d).White crystal; m.p. 223-225 ℃; IR (KBr, v, cm-1): 3349,
3183, 2909, 2855, 1646, 1557; 1H NMR (400MHz, DMSO-d6) (δ,
ppm): 1.68 (6H, s, Ad-H), 2.01 (6H, s, Ad-H), 2.13 (3H, s, Ad-
H), 5.15 (2H, s, N-H), 7.94 (1H, s, azole-H); 13C NMR (100
MHz, DMSO-d6) (δ, ppm): 28.7 (3C), 35.5 (3C), 41.8 (3C), 56.4,
138.7, 162.2; ESI-MS (m/z) = 219.2 ([M+H]+).
4.2.12. N2,N6-di((3s,5s,7s)-adamantan-1-yl)pyridine-2,6-diamine
(3l). Green crystal; m.p. 144-145 ℃; IR (KBr, v, cm-1): 3393,
3323, 2905, 2849, 1591, 1498, 1452; 1H NMR (400MHz, CDCl3)
(δ, ppm): 1.67 (12H, s, Ad-H), 2.05 (12H, s, Ad-H), 2.09 (6H, s,
Ad-H), 4.13 (2H, s, N-H), 5.73 (2H, d, J = 7.6 Hz, pyridine-H),
7.07 (1H, t, J = 7.6 Hz, pyridine-H); 13C NMR (100 MHz,
CDCl3) (δ, ppm): 29.7 (6C), 36.5 (6C), 42.6 (6C), 49.3, 51.3,
97.2 (2C), 137.9, 157.0 (2C); ESI-MS (m/z) = 378.5 ([M+H]+);
Anal. Calcd for C25H35N3: C, 79.53; H, 9.34; N, 11.13; Found: C,
79.31; H, 9.27; N, 11.08.
4.2.5. 1-((3s,5s,7s)-adamantan-1-yl)-1H-imidazole (3e). White
crystal; m.p. 110-112 ℃; IR (KBr, v, cm-1): 3052, 2914, 2832,
1432, 933; H NMR (400MHz, CDCl3) (δ, ppm): 1.77 (6H, s,
Ad-H), 2.08 (6H, s, Ad-H), 2.24 (3H, s, Ad-H), 7.06 (1H, s,
imidazole-H), 7.08 (1H, s, imidazole-H), 7.64 (1H, s, imidazole-
H); 13C NMR (100 MHz, CDCl3) (δ, ppm): 29.5 (3C), 36.0 (3C),
43.8 (3C), 55.0, 115.3, 128.8, 133.6; ESI-MS (m/z) = 203.2
([M+H]+).
1
4.2.6. (3s,5s,7s)-N-(p-tolyl)adamantan-1-amine (3f). White
crystal; m.p. 95-96 ℃; IR (KBr, v, cm-1): 3408, 2909, 2848, 1609,
1517, 1449, 803; 1H NMR (400MHz, CDCl3) (δ, ppm): 1.66 (6H,
s, Ad-H), 1.82 (6H, s, Ad-H), 2.09 (3H, s, Ad-H), 2.26 (1H, s,
Me-H), 6.74-6.77 (2H, m, phenyl-H), 6.97-7.00 (2H, m, phenyl-
H); 13C NMR (100 MHz, CDCl3) (δ, ppm): 20.6, 29.7 (3C), 36.5
(3C), 43.6 (3C), 52.4, 120.9 (2C), 129.2 (3C), 143.2; ESI-MS
(m/z) = 242.3 ([M+H]+).
4.2.13. 1-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)-1H-benzo
[d][1,2,3]triazole (3m). White crystal; m.p. 104-105 ℃; IR (KBr,
v, cm-1): 3103, 2915, 2848, 1611, 1454, 750; 1H NMR (400MHz,
CDCl3) (δ, ppm): 0.98 (6H, s, Me-H), 1.35 (2H, s, Ad-H), 1.46-
1.58 (4H, m, Ad-H), 2.10-2.20 (4H, m, Ad-H), 2.35 (2H, s, Ad-
H), 2.37-2.39 (1H, m, Ad-H), 7.32 (1 H, td, J = 7.2, 0 Hz,
benzotriazole-H), 7.41 (1 H, td, J = 7.4, 1.2 Hz, benzotriazole-H),
7.78 (1 H, d, J = 8.0 Hz, benzotriazole-H), 8.07 (1 H, d, J = 8.4
Hz, benzotriazole-H); 13C NMR (100 MHz, CDCl3) (δ, ppm):
30.1 (2C), 32.9, 40.6 (2C), 42.4 (3C), 48.0 (2C), 50.4, 63.1, 112.3,
120.3, 123.3, 126. 2, 131.6, 146.8; ESI-MS (m/z) = 282.1
([M+H]+); Anal. Calcd for C18H23N3: C, 76.83; H, 8.24; N, 14.93;
Found: C, 76.65; H, 8.12; N, 14.81.
4.2.7. (3s,5s,7s)-N-(4-nitrophenyl)adamantan-1-amine (3g).
Yellow crystal; m.p. 169-170 ℃; IR (KBr, v, cm-1): 3371, 2919,
2850, 1595, 1535, 1450, 1275; 1H NMR (400MHz, DMSO-d6) (δ,
ppm): 1.64-1.69 (6H, m, Ad-H), 1.96 (6H, s, Ad-H), 2.09 (3H, s,
Ad-H), 6.84 (2H, d, J = 9.2 Hz, phenyl-H), 7.92 (2H, d, J = 9.2
Hz, phenyl-H); 13C NMR (100 MHz, DMSO-d6) (δ, ppm): 29.6
(3C), 36.5 (3C), 41.7 (3C), 53.3, 112.5 (2C), 126.1 (2C), 137.3,
150.0; ESI-MS (m/z) = 273.0 ([M+H]+).
4.2.14.
2-(((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)amino)-
benzonitrile (3n). White crystal; m.p. 75-76 ℃; IR (KBr, v, cm-
1
1): 3403, 2945, 2893, 2205, 1605, 1576, 1514, 1463; H NMR
(400MHz, CDCl3) (δ, ppm): 0.90 (6H, s, Me-H), 1.20 (2H, s, Ad-
H), 1.33-1.42 (4H, m, Ad-H), 1.57-1.68 (4H, m, Ad-H), 1.85 (2H,
s, Ad-H), 2.21-2.23 (1H, m, Ad-H), 4.45 (1H, s, N-H), 6.64-6.68
(1H, m, phenyl-H), 7.00 (1H, d, J = 8.8 Hz, phenyl-H), 7.30-7.34
(1H, m, phenyl-H), 7.38 (1H, d, J = 8.0 Hz, phenyl-H); 13C NMR
(100 MHz, CDCl3) (δ, ppm): 30.3 (2C), 32.7, 41.0 (2C), 42.6
(3C), 48.7 (2C), 50.6, 54.5, 95.3, 114.9, 116.6, 120.9, 133.2,
133.4, 152.0; ESI-MS (m/z) = 281.1 ([M+H]+); Anal. Calcd for
C19H24N2: C, 81.38; H, 8.63; N, 9.99; Found: C, 81.25; H, 8.52;
N, 9.91.
4.2.8. (3s,5s,7s)-N-(3-nitrophenyl)adamantan-1-amine (3h).
Yellow crystal; m.p. 125-126 ℃; IR (KBr, v, cm-1): 3413, 2906,
2849, 1621, 1577, 1529, 1338; H NMR (400MHz, CDCl3) (δ,
ppm): 1.63 (6H, s, Ad-H), 1.86 (6H, s, Ad-H), 2.08 (3H, s, Ad-
H), 6.89-6.92 (1H, m, phenyl-H), 7.13-7.19 (1H, m, phenyl-H),
7.43-7.45 (1H, m, phenyl-H), 7.48-7.49 (1H, m, phenyl-H); 13C
NMR (100 MHz, CDCl3) (δ, ppm): 29.6 (3C), 36.3 (3C), 42.9
(3C), 53.0, 110.4, 112.2, 122.5, 129.4, 149.2, 150.5; ESI-MS
(m/z) = 273.3 ([M+H]+).
1
4.2.9.
2-((3s,5s,7s)-adamantan-1-ylamino)benzonitrile
(3i).
White crystal; m.p. 153-154 ℃; IR (KBr, v, cm-1): 3395, 2917,
4.2.15.
2-(((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)amino)-
nicotinonitrile (3o). White crystal; m.p. 70-71 ℃; IR (KBr, v, cm-
1
2846, 2209, 1603, 1579, 1519, 1465, 741; H NMR (400MHz,
1): 3398, 2941, 2843, 2215, 1591, 1575, 1416; 1H NMR
CDCl3) (δ, ppm): 1.70 (6H, s, Ad-H), 1.99 (6H, s, Ad-H), 2.15

5
(400MHz, CDCl3) (δ, ppm): 0.88 (6H, s, Me-H), 1.18-1.20 (2H,
m, Ad-H), 1.30-1.44 (4H, m, Ad-H), 1.73-1.84 (4H, m, Ad-H),
2.00 (2H, s, Ad-H), 2.17-2.19 (1H, m, Ad-H), 4.93 (1H, s, N-H),
6.51-6.54 (1H, m, pyridine-H), 7.57-7.59 (1H, m, pyridine-H),
8.22-8.24 (1H, m , pyridine-H); 13C NMR (100 MHz, CDCl3) (δ,
ppm): 30.2 (2C), 32.5, 40.1 (2C), 42.7 (3C), 47.7 (2C), 50.6, 54.7,
100.7, 111.2, 117.2, 141.1, 152.2, 160.5; ESI-MS (m/z) = 282.3
([M+H]+); Anal. Calcd for C18H23N3: C, 76.83; H, 8.24; N, 14.93;
Found: C, 76.65; H, 8.32; N, 14.91.
(2C), 139.4, 151.6; ESI-MS (m/z) = 271.2 ([M+H]+); Anal.
ACCEPTED MANUSCRIPT
Calcd for C14H18N6: C, 62.20; H, 6.71; N, 31.09; Found: C, 62.18;
H, 6.64; N, 31.15.
Acknowledgments
This work was supported by the grant of Beijing Institute of
Technology. We are grateful for analytical help of Institute of
Chemistry, Chinese Academy of Sciences. Financials supports
from special programs graduate innovative activities in BIT and
International Cooperation in Science and Technology
(2012DFR40240) are gratefully acknowledged.
4.2.16. 1-((1R,4S)-bicyclo[2.2.1]heptan-2-yl)-1H-benzo[d][1,2,3]
triazole (3p). White crystal; m.p. 75-76 ℃; IR (KBr, v, cm-1):
1
3062, 2960, 2867, 1613, 1453, 741; H NMR (400MHz, CDCl3)
(δ, ppm): 1.31-1.47 (4H, m, norbornane-H), 1.61-1.77 (2H, m,
norbornane-H), 1.96-2.03 (2H, m, norbornane-H), 2.55-2.70 (2H,
m, norbornane-H), 4.56-4.59 (1H, m, norbornane-H), 7.35 (1 H,
td, J = 7.6, 0.0 Hz, benzotriazole-H), 7.45 (1 H, td, J = 7.2, 0.8
Hz, benzotriazole-H), 7.53 (1 H, d, J = 9.2 Hz, benzotriazole-H),
8.04 (1 H, d, J = 8.0 Hz, benzotriazole-H); 13C NMR (100 MHz,
CDCl3) (δ, ppm): 27.1, 28.7, 35.9, 36.0, 37.3, 42.9, 61.9, 109.7,
119.9, 123.8, 126.8, 133.0, 146.2; ESI-MS (m/z) = 214.1
([M+H]+).
References and notes
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3516-3604. (b) Schnell, J. R.; Chou, J. J. Nature 2008, 451, 591-
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Claramunt, R. M.; Sanz, D.; Elguero, J. Eu. J. Med. Chem. 1985,
20, 359-362.
4.2.17. (1R,4S)-N-(3-nitrophenyl)bicyclo[2.2.1]heptan-2-amine
(3q). Yellow crystal; m.p. 65-66 ℃; IR (KBr, v, cm-1): 3413,
2960, 2867, 1621, 1571, 1534, 1332; 1H NMR (400MHz, CDCl3)
(δ, ppm): 1.18-1.23 (4H, m, norbornane-H), 1.43-1.56 (3H, m,
norbornane-H), 1.77-1.82 (1H, m, norbornane-H), 2.19-2.25 (2H,
m, norbornane-H), 3.19 (1H, m, norbornane-H), 3.87 (1H, s, NH),
6.72-6.75 (1H, m, phenyl-H), 7.15-7.19 (1H, m, phenyl-H), 7.39-
7.41 (1H, m, phenyl-H), 7.46-7.47 (1H, m, phenyl-H); 13C NMR
(100 MHz, CDCl3) (δ, ppm): 26.4, 28.4, 35.5, 35.7, 41.0, 41.2,
56.5, 106.7, 111.5, 119.0, 129.7, 148.3, 149.6; ESI-MS (m/z) =
233.2 ([M+H]+).
2. (a) Lauren, E. R.; Myles, B. H.; Vanessa, M. M.; Benjamin, K. K.;
Robert, H. G. J. Am. Chem. Soc. 2013, 135, 1276-1279. (b)
Benjamin, K. K.; Koji, E.; Paresma, R. P.; Myles, B. H.; Robert, H.
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Daniel, K.; Scott, L. R.; Allen, M. Organometallics 2012, 31,
7359-7367. (e) Hwimin, S.; Benjamin, P. R.; Khalil, A. A.;
Kenneth, M. M.; Sukwon, H. Org. Lett. 2010, 12, 4860-4863. (f)
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(a) Ganna, A. S.; Andrey, B. L.; Ishtvan, B.; Eduard, B. R.;
Alexander, N. C.; Harald, K.; Konstantin, V. D. Dalton Trans.
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R.; Alexander, N. C.; Harald, K.; Konstantin, V. D. Inorganica
Chimica Acta 2009, 362, 4439–4448.
4.2.18. 4-((3s,5s,7s)-adamantan-1-yl)-1H-pyrazole (5a). White
crystal; m.p. 208-210 ℃; IR (KBr, v, cm-1): 3155, 2902, 2846,
1
1449, 958; H NMR (400MHz, CDCl3) (δ, ppm): 1.76 (6H, s,
4. (a) Kazimierczuk, Z.; Gorska, A.; Switaj, T.; Lasek, W. Bioorg.
Med. Chem. Lett. 2001, 11, 1197-1200. (b) Saraev, V. V.; Golod,
E. L. Russ. J. Org. Chem. 1997, 33, 571-574. (c) Cabildo, P.;
Claramunt, R. M.; Forfar, I.; Foces, C.; Llamas, A. L.; Elguero, J.
Heterocycles 1994, 37, 1623-1636. (d) Saraev, V. V.; Kanakina,
T. P.; Pevzner, M. S.; Golod, E. L.; Ugrak, B. I.; Kachala, V. V.
Chem. Heterocycl. Compd. 1996, 32, 928-936.
Ad-H), 1.86 (6H, s, Ad-H), 2.04 (3H, s, Ad-H), 4.73 (1H, s, N-H),
7.44 (2H, s, pyrazole-H); 13C NMR (100 MHz, CDCl3) (δ, ppm):
28.7 (3C), 31.2, 36.8 (3C), 44.2 (3C), 130.1, 130.2, 133.2; ESI-
MS (m/z) = 203.2 ([M+H]+).
4.2.19. 4-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)-1H-pyra-
5.
(a) Breslow, D. S.; Sloan, M. F.; Newburg, N. R.; Renfrow, W.
B. J. Am. Chem. Soc. 1969, 91, 2273-2279. (b) Breslow, D. S.;
Edwards, E. I.; Leone, R.; Schleyer, P. R. J. Am. Chem. Soc. 1968,
90, 7097-7102.
zole (5b). White crystal; m.p. 114-117 ℃; IR (KBr, v, cm-1):
1
3143, 2941, 2843, 1443, 954; H NMR (400MHz, CDCl3) (δ,
ppm): 0.90 (6H, s, Me-H), 1.21 (2H, s, Ad-H), 1.37-1.45 (4H, m,
Ad-H), 1.67-1.82 (4H, m, Ad-H), 2.05 (2H, s, Ad-H), 2.27-2.29
(1H, m, Ad-H), 4.68 (1H, s, N-H), 7.43 (2H, s, pyrazole-H); 13C
NMR (100 MHz, CDCl3) (δ, ppm): 30.0 (2C), 31.1, 32.9, 40.6
(2C), 42.4 (3C), 48.0 (2C), 50.4, 130.0, 130.1, 133.2; ESI-MS
(m/z) = 231.3 ([M+H]+); Anal. Calcd for C15H22N2: C, 78.21; H,
9.63; N, 12.16; Found: C, 78.18; H, 9.54; N, 12.21.
6. (a) Liu, Y. G.; Che, C. M. Chem. Eur. J. 2010, 16, 10494-10501.
(b) Yu, X. Q.; Huang, J. S.; Zhou, X. G.; Che, C. M. Org. Lett.
2000, 2, 2233-2236. (c) Mahy, J. P.; Bedi, G.; Battioni, P.;
Mansuy, D. New J. Chem. 1989, 13, 651-660. (d) Huard, K.;
Lebel, H. Chem. Eur. J. 2008, 14, 6222-6230. (e) Lebel, H.;
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Che, C. M.; Yu, W. Y. J. Org. Chem. 2000, 65, 7858-7864. (g)
Kalita, B.; Lamar, A. A.; Nicholas, K. M. Chem. Commun. 2008,
36, 4291-4293. (h) Kristin, W. F.; Christine, G. E.; Benjamin, H.
B.; Bois, J. D. Tetrahedron 2009, 65, 3042-3051.
4.3 General Procedure for synthesis of compounds 4
A mixture of the appropriate adamantane (1 mmol), 1H-1,2,4-
triazole (2 mmol), AlBr3 (2 mmol) and CBr4 (2 mmol) was
ground in a mortar and pestle at room temperature for 10
minutes. The product of azole derivatives were purified by
column chromatography using ethyl acetate and petroleum ether
mixtures as the mobile phase.
7. (a) Yoshimura, A.; Nemykin, V. N.; Zhdankin, V. V. Chem. Eur.
J. 2011, 17, 10538-10541. (b) Lamar, A. A.; Nicholas, K. M. J.
Org. Chem. 2010, 75, 7644-7650. (c) Ochiai, M.; Miyamoto, K.;
Kaneaki, T.; Hayashi, S.; Nakanishi, W. Science 2011, 332, 448-
451.
8. (a) Belen, R.; Angelika, B.; Toni, R.; Carsten, B. Adv. Synth.
Catal. 2007, 349, 2213-2233. (b) Bruckmann, A.; Krebs, A.;
Bolm, C. Green Chem. 2008, 10, 1131-1141. (c) Stolle, A.;
Szuppa, T.; Leonhardt, S. E. S.; Ondruschka, B. Chem. Soc. Rev.
2011, 40, 2317-2329. (d) Wang, G. W.; Gao J. Green Chem. 2012,
14, 1125-1131.
4.3.1. (1s,3s,5s,7s)-1,3-di(1H-1,2,4-triazol-1-yl)adamantine (4).
White crystal; m.p. 174-176 ℃; IR (KBr, v, cm-1): 3131, 2936,
1
2860, 1501, 1279; H NMR (400MHz, CDCl3) (δ, ppm): 1.84
9.
(a) Lee, B.; Kang, P.; Lee, K. H.; Cho, J.; Nam, W.; Lee, W. K.;
Hur, N. H. Tetrahedron Lett. 2013, 54, 1384-1388. (b) Sato, K.;
Ozu, T.; Takenaga, N. Tetrahedron Lett. 2013, 54, 661-664. (c)
Schmidt, R.; Stolle, A.; Ondruschka, B. Green Chem. 2012, 14,
(2H, s, Ad-H), 2.21-2.32 (8H, m, Ad-H), 2.61 (4H, s, Ad-H),
7.96 (2H, s, triazole-H), 8.16 (2H, s, triazole-H); 13C NMR (100
MHz, CDCl3) (δ, ppm): 29.6 (2C), 34.5, 41.2 (4C), 47.2, 59.4

6
Tetrahedron
1673-1679. (d) Chuang, C. P.; Chen, K. P. Tetrahedron 2012,
Ciminale, F.; Nacci, A. Eur. J. Org. Chem. 2012, 16, 3105-3111.
(b) Chiappe, C.; Piccioli, P.; Pieraccini, D. Green Chem. 2006, 8,
ACCEPTED MANUSCRIPT
68, 1401-1406. (e) Choudhary, G.; Peddinti, R. K. Green Chem.
2011, 13, 276-282. (f) Kumar, A.; Sharma, S. Green Chem. 2011,
13, 2017-2020. (g) Carlier, L.; Baron, M.; Chamayou, A.;
Couarraze, G. Tetrahedron Lett. 2011, 52, 4686-4689. (h)
Ghahremanzadeh, R.; Ahadi, S.; Shakibaei, G. I.; Bazgir, A.
Tetrahedron Lett. 2010, 51, 499-502.
277-281.
12. Full details have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication no.
CCDC-947577 (4). Copies of the data can be obtained, free of
charge, on application to CCDC, 12 Union Road, Cambridge CB2
10. (a) Akhrem, I. S.; Orlinkov, A. V. Chem. Rev. 2007, 107, 2037-
2079. (b) Orlinkov, A. V.; Kagramanov, N. D.; Petrovskii, P. V.;
Akhrem, I. S. Tetrahedron Lett. 2010, 51, 259-263. (c) Akhrem, I.
S.; Orlinkov, A. V.; Afanaseva, L. V.; Mysov, E. I.; Volpin, M. E.
Tetrahedron Lett. 1995, 36, 9365-9368. (d) Akhrem, I. S.;
Avetisyan, D. V.; Afanas'eva, L. V. Tetrahedron Lett. 2012, 53,
3493-3496. (e) Akhrem, I. S.; Afanas'eva, L. V.; Kagramanov, N.
D.; Petrovskii, P. V. Tetrahedron Lett. 2012, 53, 4221-4224.
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1EZ,
UK,
(fax:
+44-(0)1223-336033
or
e-mail:
deposit@ccdc.cam.ac.Uk).
Supplementary Material
Experimental procedures and compound characterization data
are available. Supplementary data related to this article can be
found at xxxxxx .

ACCEPTED MANUSCRIPT
Supporting Information
Solvent-free and direct sp3 C-H
amination of unfunctionalized adamantanes
promoted by grinding
Zhen Wei, Jiarong Li, Ning Wang, Qi Zhang, Daxin Shi* and Kening Sun*
School of Chemical Engineering and Environment, Beijing Institute of Technology, Beijing 100081,
China
E-mail: shidaxin@bit.edu.cn (D. Shi)
sunkn@bit.edu.cn (K. Sun)
Contents
General Information
General Procedure for synthesis of compounds
Spectra Data for the Products
1H NMR and 13C NMR Spectra of products
S1

ACCEPTED MANUSCRIPT
General Information
All the reactions were carried out at room temperature that is 15-20 . Unless otherwise noted,
all reagents were purchased from commercial suppliers and used without purification. All reactions
were conducted by grinding in a mortar and pestle. Melting points were determined using XT4
microscope melting point apparatus (uncorrected). Infrared (IR) spectra were recorded on a Perkin
1
Elmer FT-IR spectrophotometer with KBr pellets. H and 13C NMR spectra were recorded at a
Bruker 400 (400 MHz) spectrometer with TMS as the internal standard. Mass spectra were recorded
on a ZAB-HS mass spectrometer using ESI ionization. Elemental analyses were performed on an
Elementar Vario EL.
General Procedure for synthesis
General Procedure for synthesis of compounds 3 and 5
A mixture of the appropriate adamantane/norbornane (1 mmol), azole/heteroarylamine/arylamine
(1 mmol), AlBr3 (0.5 mmol) and CBr4 (0.5 mmol) was ground in a mortar and pestle at room
temperature till the completion of reaction as indicated by TLC (5-10 min). The product of azole
derivatives were purified by recrystallisation from ethyl alcohol, and the heteroaryl/ arylamine
derivatives were purified by column chromatography using ethyl acetate and petroleum ether
mixtures as the mobile phase.
General Procedure for synthesis of compound 4
A mixture of the appropriate adamantane (1 mmol), 1H-1,2,4-triazole (2 mmol), AlBr3 (2 mmol)
and CBr4 (2 mmol) was ground in a mortar and pestle at room temperature for 10 minutes. The
product of azole derivatives were purified by column chromatography using ethyl acetate and
petroleum ether mixtures as the mobile phase.
Spectra Data for the Products
1-((3s,5s,7s)-adamantan-1-yl)-1H-tetrazole (3a)
White crystal; m.p. 135-136 ℃; IR (KBr, v, cm-1): 3348, 3148, 3121, 2913, 2855, 1626, 1556, 1453; 1H NMR
(400MHz, CDCl3) (δ, ppm): 1.83 (6H, s, Ad-H), 2.27 (6H, s, Ad-H), 2.31 (3H, s, Ad-H), 8.63 (1H, s, tetrazole-H);
13C NMR (100 MHz, CDCl3) (δ, ppm): 29.23 (3C), 35.61 (3C), 42.59 (3C), 59.72, 139.30; ESI-MS (m/z) = 205.2
([M+H]+).
1-((3s,5s,7s)-adamantan-1-yl)-1H-benzo[d][1,2,3]triazole (3b)
S2

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1
White crystal; m.p. 164-165 ℃; IR (KBr, v, cm-1): 3051, 2918, 2849, 1671, 1620, 1454, 740; H NMR
(400MHz, CDCl3) (δ, ppm): 1.91 (6H, s, Ad-H), 2.38 (3H, s, Ad-H), 2.56 (6H, s, Ad-H), 7.36 (1 H, td, J = 7.6, 1.6
Hz, benzotriazole-H), 7.45 (1 H, td, J = 7.2, 0.8 Hz, benzotriazole-H), 7.85 (1 H, d, J = 8.0 Hz, benzotriazole-H),
8.11 (1 H, d, J = 9.2 Hz, benzotriazole-H); 13C NMR (100 MHz, CDCl3) (δ, ppm): 29.31 (3C), 35.70 (3C), 42.84
(3C), 61.67, 112.50, 120.43, 123.43, 126.31, 131.74, 147.06; ESI-MS (m/z) = 254.2 ([M+H]+).
1-((3s,5s,7s)-adamantan-1-yl)-1H-1,2,4-triazole (3c)
1
White crystal; m.p. 87-88 ℃; IR (KBr, v, cm-1): 3119, 2909, 2861, 1742, 1498, 1276; H NMR (400MHz,
CDCl3) (δ, ppm): 1.78 (6H, s, Ad-H), 2.17 (6H, s, Ad-H), 2.24 (3H, s, Ad-H), 7.93 (1H, s, triazole-H), 8.12 (1H, s,
triazole-H); 13C NMR (100 MHz, CDCl3) (δ, ppm): 29.39 (3C), 36.04 (3C), 42.68 (3C), 58.63, 139.49, 151.31;
ESI-MS (m/z) = 204.2 ([M+H]+).
1-((3s,5s,7s)-adamantan-1-yl)-1H-1,2,4-triazol-3-amine (3d)
1
White crystal; m.p. 223-225 ℃; IR (KBr, v, cm-1): 3349, 3183, 2909, 2855, 1646, 1557; H NMR (400MHz,
DMSO-d6) (δ, ppm): 1.68 (6H, s, Ad-H), 2.01 (6H, s, Ad-H), 2.13 (3H, s, Ad-H), 5.15 (2H, s, N-H), 7.94 (1H, s,
azole-H); 13C NMR (100 MHz, DMSO-d6) (δ, ppm): 28.71 (3C), 35.57 (3C), 41.83 (3C), 56.41, 138.74, 162.26;
ESI-MS (m/z) = 219.2 ([M+H]+).
1-((3s,5s,7s)-adamantan-1-yl)-1H-imidazole (3e)
White crystal; m.p. 110-112 ℃; IR (KBr, v, cm-1): 3052, 2914, 2832, 1432, 933; 1H NMR (400MHz, CDCl3) (δ,
ppm): 1.77 (6H, s, Ad-H), 2.08 (6H, s, Ad-H), 2.24 (3H, s, Ad-H), 7.06 (1H, s, imidazole-H), 7.08 (1H, s,
imidazole-H), 7.64 (1H, s, imidazole-H); 13C NMR (100 MHz, CDCl3) (δ, ppm): 29.51 (3C), 36.07 (3C), 43.87
(3C), 55.02, 115.34, 128.81, 133.63; ESI-MS (m/z) = 203.2 ([M+H]+).
(3s,5s,7s)-N-(p-tolyl)adamantan-1-amine (3f)
S3

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White crystal; m.p. 95-96 ℃; IR (KBr, v, cm-1): 3408, 2909, 2848, 1609, 1517, 1449, 803; 1H NMR (400MHz,
CDCl3) (δ, ppm): 1.66 (6H, s, Ad-H), 1.82 (6H, s, Ad-H), 2.09 (3H, s, Ad-H), 2.26 (1H, s, Me-H), 6.74-6.77 (2H,
m, phenyl-H), 6.97-7.00 (2H, m, phenyl-H); 13C NMR (100 MHz, CDCl3) (δ, ppm): 20.64, 29.76 (3C), 36.51 (3C),
43.65 (3C), 52.47, 120.96 (2C), 129.28 (3C), 143.20; ESI-MS (m/z) = 242.3 ([M+H]+).
(3s,5s,7s)-N-(4-nitrophenyl)adamantan-1-amine (3g)
1
Yellow crystal; m.p. 169-170 ℃; IR (KBr, v, cm-1): 3371, 2919, 2850, 1595, 1535, 1450, 1275; H NMR
(400MHz, DMSO-d6) (δ, ppm): 1.64-1.69 (6H, m, Ad-H), 1.96 (6H, s, Ad-H), 2.09 (3H, s, Ad-H), 6.84 (2H, d, J =
9.2 Hz, phenyl-H), 7.92 (2H, d, J = 9.2 Hz, phenyl-H); 13C NMR (100 MHz, DMSO-d6) (δ, ppm): 29.63 (3C),
36.58 (3C), 41.71 (3C), 53.38, 112.55 (2C), 126.11 (2C), 137.34, 150.03; ESI-MS (m/z) = 273.0 ([M+H]+).
(3s,5s,7s)-N-(3-nitrophenyl)adamantan-1-amine (3h)
1
Yellow crystal; m.p. 125-126 ℃; IR (KBr, v, cm-1): 3413, 2906, 2849, 1621, 1577, 1529, 1338; H NMR
(400MHz, CDCl3) (δ, ppm): 1.63 (6H, s, Ad-H), 1.86 (6H, s, Ad-H), 2.08 (3H, s, Ad-H), 6.89-6.92 (1H, m,
phenyl-H), 7.13-7.19 (1H, m, phenyl-H), 7.43-7.45 (1H, m, phenyl-H), 7.48-7.49 (1H, m, phenyl-H); 13C NMR
(100 MHz, CDCl3) (δ, ppm): 29.67 (3C), 36.39 (3C), 42.92 (3C), 53.08, 110.43, 112.26, 122.52, 129.43, 149.23,
150.59; ESI-MS (m/z) = 273.3 ([M+H]+).
2-((3s,5s,7s)-adamantan-1-ylamino)benzonitrile (3i)
1
White crystal; m.p. 153-154 ℃; IR (KBr, v, cm-1): 3395, 2917, 2846, 2209, 1603, 1579, 1519, 1465, 741; H
NMR (400MHz, CDCl3) (δ, ppm): 1.70 (6H, s, Ad-H), 1.99 (6H, s, Ad-H), 2.15 (3H, s, Ad-H), 4.38 (1H, s, N-H),
6.61-6.65 (1H, m, phenyl-H), 7.01 (1H, d, J = 9.6 Hz, phenyl-H), 7.28-7.32 (1H, m, phenyl-H), 7.36 (1H, d, J =
8.0 Hz, phenyl-H); 13C NMR (100 MHz, CDCl3) (δ, ppm): 29.66 (3C), 36.36 (3C), 42.61 (3C), 52.76, 97.79,
114.73, 116.44, 118.31, 133.20, 133.45, 149.18; ESI-MS (m/z) = 253.2 ([M+H]+).
N-((3s,5s,7s)-adamantan-1-yl)pyridin-2-amine (3j)
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1
White crystal; m.p. 171-172 ℃; IR (KBr, v, cm-1): 3372, 3011, 2904, 2847, 1602, 1507, 1485; H NMR
(400MHz, CDCl3) (δ, ppm): 1.70 (6H, s, Ad-H), 2.04 (6H, s, Ad-H), 2.12 (3H, s, Ad-H), 4.48 (1H, s, N-H),
6.48-6.53 (2H, m, pyridine-H), 7.32-7.37 (1H, m, pyridine-H), 8.03 (1H, d, J=3.6 Hz, pyridine-H); 13C NMR (100
MHz, CDCl3) (δ, ppm): 29.10 (3C), 35.63 (3C), 41.77 (3C), 56.43, 112.31, 114.54, 138.40, 147.82, 156.97;
ESI-MS (m/z) = 229.2 ([M+H]+).
2-((3s,5s,7s)-adamantan-1-ylamino)nicotinonitrile (3k)
White crystal; m.p. 169-170 ℃; IR (KBr, v, cm-1): 3359, 3003, 2902, 2849, 2219, 1591, 1576, 1506, 1461,
1415; 1H NMR (400MHz, CDCl3) (δ, ppm): 1.73 (6H, s, Ad-H), 2.13 (3H, s, Ad-H), 2.16 (6H, s, Ad-H), 4.93 (1H,
s, N-H), 6.51-6.54 (1H, m, pyridine-H), 7.58-7.60 (1H, m, pyridine-H), 8.22-8.24 (1H, m , pyridine-H); 13C NMR
(100 MHz, CDCl3) (δ, ppm): 29.73 (3C), 36.56 (3C), 41.81 (3C), 53.28, 91.93, 111.29, 117.87, 141.30, 152.10,
158.54; ESI-MS (m/z) = 254.2 ([M+H]+).
N2,N6-di((3s,5s,7s)-adamantan-1-yl)pyridine-2,6-diamine (3l)
1
Green crystal; m.p. 144-145 ℃; IR (KBr, v, cm-1): 3393, 3323, 2905, 2849, 1591, 1498, 1452; H NMR
(400MHz, CDCl3) (δ, ppm): 1.67 (12H, s, Ad-H), 2.05 (12H, s, Ad-H), 2.09 (6H, s, Ad-H), 4.13 (2H, s, N-H),
5.73 (2H, d, J = 7.6 Hz, pyridine-H), 7.07 (1H, t, J = 7.6 Hz, pyridine-H); 13C NMR (100 MHz, CDCl3) (δ, ppm):
29.73 (6C), 36.58 (6C), 42.60 (6C), 49.37, 51.30, 97.29 (2C), 137.94, 157.01 (2C); ESI-MS (m/z) = 378.5
([M+H]+); Anal. Calcd for C25H35N3: C, 79.53; H, 9.34; N, 11.13; Found: C, 79.31; H, 9.27; N, 11.08.
1-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)-1H-benzo[d][1,2,3]triazole (3m)
1
White crystal; m.p. 104-105 ℃; IR (KBr, v, cm-1): 3103, 2915, 2848, 1611, 1454, 750; H NMR (400MHz,
CDCl3) (δ, ppm): 0.98 (6H, s, Me-H), 1.35 (2H, s, Ad-H), 1.46-1.58 (4H, m, Ad-H), 2.10-2.20 (4H, m, Ad-H),
2.35 (2H, s, Ad-H), 2.37-2.39 (1H, m, Ad-H), 7.32 (1 H, td, J = 7.2, 0 Hz, benzotriazole-H), 7.41 (1 H, td, J = 7.4,
1.2 Hz, benzotriazole-H), 7.78 (1 H, d, J = 8.0 Hz, benzotriazole-H), 8.07 (1 H, d, J = 8.4 Hz, benzotriazole-H);
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13C NMR (100 MHz, CDCl3) (δ, ppm): 30.10 (2C), 32.90, 40.67 (2C), 42.49 (3C), 48.02 (2C), 50.43, 63.11,
112.36, 120.33, 123.34, 126. 25, 131.66, 146.89; ESI-MS (m/z) = 282.1 ([M+H]+); Anal. Calcd for C18H23N3: C,
76.83; H, 8.24; N, 14.93; Found: C, 76.65; H, 8.12; N, 14.81.
2-(((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)amino)benzonitrile (3n)
1
White crystal; m.p. 75-76 ℃; IR (KBr, v, cm-1): 3403, 2945, 2893, 2205, 1605, 1576, 1514, 1463; H NMR
(400MHz, CDCl3) (δ, ppm): 0.90 (6H, s, Me-H), 1.20 (2H, s, Ad-H), 1.33-1.42 (4H, m, Ad-H), 1.57-1.68 (4H, m,
Ad-H), 1.85 (2H, s, Ad-H), 2.21-2.23 (1H, m, Ad-H), 4.45 (1H, s, N-H), 6.64-6.68 (1H, m, phenyl-H), 7.00 (1H,
d, J = 8.8 Hz, phenyl-H), 7.30-7.34 (1H, m, phenyl-H), 7.38 (1H, d, J = 8.0 Hz, phenyl-H); 13C NMR (100 MHz,
CDCl3) (δ, ppm): 30.31 (2C), 32.79, 41.08 (2C), 42.65 (3C), 48.73 (2C), 50.62, 54.56, 95.35, 114.92, 116.67,
120.94, 133.20, 133.47, 152.02; ESI-MS (m/z) = 281.1 ([M+H]+); Anal. Calcd for C19H24N2: C, 81.38; H, 8.63; N,
9.99; Found: C, 81.25; H, 8.52; N, 9.91.
2-(((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)amino)nicotinonitrile (3o)
1
White crystal; m.p. 70-71 ℃; IR (KBr, v, cm-1): 3398, 2941, 2843, 2215, 1591, 1575, 1416; H NMR
(400MHz, CDCl3) (δ, ppm): 0.88 (6H, s, Me-H), 1.18-1.20 (2H, m, Ad-H), 1.30-1.44 (4H, m, Ad-H), 1.73-1.84
(4H, m, Ad-H), 2.00 (2H, s, Ad-H), 2.17-2.19 (1H, m, Ad-H), 4.93 (1H, s, N-H), 6.51-6.54 (1H, m, pyridine-H),
7.57-7.59 (1H, m, pyridine-H), 8.22-8.24 (1H, m , pyridine-H); 13C NMR (100 MHz, CDCl3) (δ, ppm): 30.23 (2C),
32.59, 40.16 (2C), 42.75 (3C), 47.73 (2C), 50.69, 54.77, 100.71, 111.23, 117.29, 141. 19, 152.24, 160.53; ESI-MS
(m/z) = 282.3 ([M+H]+); Anal. Calcd for C18H23N3: C, 76.83; H, 8.24; N, 14.93; Found: C, 76.65; H, 8.32; N,
14.91.
1-((1R,4S)-bicyclo[2.2.1]heptan-2-yl)-1H-benzo[d][1,2,3]triazole (3p)
1
White crystal; m.p. 75-76 ℃; IR (KBr, v, cm-1): 3062, 2960, 2867, 1613, 1453, 741; H NMR (400MHz,
CDCl3) (δ, ppm): 1.31-1.47 (4H, m, norbornane-H), 1.61-1.77 (2H, m, norbornane-H), 1.96-2.03 (2H, m,
norbornane-H), 2.55-2.70 (2H, m, norbornane-H), 4.56-4.59 (1H, m, norbornane-H), 7.35 (1 H, td, J = 7.6, 0.0 Hz,
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benzotriazole-H), 7.45 (1 H, td, J = 7.2, 0.8 Hz, benzotriazole-H), 7.53 (1 H, d, J = 9.2 Hz, benzotriazole-H), 8.04
(1 H, d, J = 8.0 Hz, benzotriazole-H); 13C NMR (100 MHz, CDCl3) (δ, ppm): 27.11, 28.76, 35.95, 36.00, 37.36,
42.96, 61.93, 109.76, 119.91, 123.88, 126.81, 133.02, 146.26; ESI-MS (m/z) = 214.1 ([M+H]+).
(1R,4S)-N-(3-nitrophenyl)bicyclo[2.2.1]heptan-2-amine (3q)
1
Yellow crystal; m.p. 65-66 ℃; IR (KBr, v, cm-1): 3413, 2960, 2867, 1621, 1571, 1534, 1332; H NMR
(400MHz, CDCl3) (δ, ppm): 1.18-1.23 (4H, m, norbornane-H), 1.43-1.56 (3H, m, norbornane-H), 1.77-1.82 (1H,
m, norbornane-H), 2.19-2.25 (2H, m, norbornane-H), 3.19 (1H, m, norbornane-H), 3.87 (1H, s, NH), 6.72-6.75
(1H, m, phenyl-H), 7.15-7.19 (1H, m, phenyl-H), 7.39-7.41 (1H, m, phenyl-H), 7.46-7.47 (1H, m, phenyl-H); 13
C
NMR (100 MHz, CDCl3) (δ, ppm): 26.42, 28.45, 35.56, 35.75, 41.02, 41.24, 56.59, 106.70, 111.52, 119.05,
129.73, 148.30, 149.68; ESI-MS (m/z) = 233.2 ([M+H]+).
(1s,3s,5s,7s)-1,3-di(1H-1,2,4-triazol-1-yl)adamantine (4)
N
N
N
N
N
N
4
White crystal; m.p. 174-176 ℃; IR (KBr, v, cm-1): 3131, 2936, 2860, 1501, 1279; 1H NMR (400MHz, CDCl3)
(δ, ppm): 1.84 (2H, s, Ad-H), 2.21-2.32 (8H, m, Ad-H), 2.61 (4H, s, Ad-H), 7.96 (2H, s, triazole-H), 8.16 (2H, s,
triazole-H); 13C NMR (100 MHz, CDCl3) (δ, ppm): 29.69 (2C), 34.59, 41.22 (4C), 47.23, 59.48 (2C), 139.45,
151.67; ESI-MS (m/z) = 271.2 ([M+H]+); Anal. Calcd for C14H18N6: C, 62.20; H, 6.71; N, 31.09; Found: C, 62.18;
H, 6.64; N, 31.15.
4-((3s,5s,7s)-adamantan-1-yl)-1H-pyrazole (5a)
White crystal; m.p. 208-210 ℃; IR (KBr, v, cm-1): 3155, 2902, 2846, 1449, 958; 1H NMR (400MHz, CDCl3) (δ,
ppm): 1.76 (6H, s, Ad-H), 1.86 (6H, s, Ad-H), 2.04 (3H, s, Ad-H), 4.73 (1H, s, N-H), 7.44 (2H, s, pyrazole-H);
13C NMR (100 MHz, CDCl3) (δ, ppm): 28.78 (3C), 31.27, 36.84 (3C), 44.28 (3C), 130.14, 130.25, 133.29;
ESI-MS (m/z) = 203.2 ([M+H]+).
4-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)-1H-pyrazole (5b)
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N
NH
5b
White crystal; m.p. 114-117 ℃; IR (KBr, v, cm-1): 3143, 2941, 2843, 1443, 954; 1H NMR (400MHz, CDCl3) (δ,
ppm): 0.90 (6H, s, Me-H), 1.21 (2H, s, Ad-H), 1.37-1.45 (4H, m, Ad-H), 1.67-1.82 (4H, m, Ad-H), 2.05 (2H, s,
Ad-H), 2.27-2.29 (1H, m, Ad-H), 4.68 (1H, s, N-H), 7.43 (2H, s, pyrazole-H); 13C NMR (100 MHz, CDCl3) (δ,
ppm): 30.08 (2C), 31.17, 32.92, 40.69 (2C), 42.43 (3C), 48.00 (2C), 50.41, 130.09, 130.15, 133.27; ESI-MS (m/z)
= 231.3 ([M+H]+); Anal. Calcd for C15H22N2: C, 78.21; H, 9.63; N, 12.16; Found: C, 78.18; H, 9.54; N, 12.21.
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1H NMR and 13C NMR Spectra of products
N
N
N
N
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N
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N
N
N
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N
NH2
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N
H
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NC
N
H
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Ad
Ad
N
N
N
H
H
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Ad
Ad
N
N
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N
N
N
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N
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NC
N
H
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N
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NC
N
H
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NC
N
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N
N
N
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N
N
N
N
N
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N
NH
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H
N
NH
H
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NH
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