A Catalyst-Free, Temperature-Driven One-Pot Synthesis of 1-Adamantylhydrazine Hydrochloride

Article abstract of DOI:10.1055/s-0040-1707353

1-Adamantylhydrazine can be a versatile intermediate for many biologically active compounds as adamantyl possesses a wide spectrum of medicinal properties. Described here is a detailed one-pot synthesis of 1-adamantylhydrazine, carried out on a milligram to gram scale, that steadily delivers a highly stable product used to carry out the synthesis of 1-(adamantan-1-yl)-1 H -pyrazol-3-amine for bacterial studies. The reaction employs inexpensive, catalyst free, readily available starting materials. In the synthesis of 1-(adamantan-1-yl)-1 H -pyrazol-3-amine, the use of a continuous extraction method allows for complete extraction of the target product into the organic layer and increases the overall percentage yield.

Full text of DOI:10.1055/s-0040-1707353

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
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A. Delpe Acharige et al.
PSP
Synthesis
A Catalyst-Free, Temperature-Driven One-Pot Synthesis of
1-Adamantylhydrazine Hydrochloride
Anjana Delpe Acharige
Raul Neri
James Hodgson
Stefan H. Bossmann*
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Department of Chemistry, Kansas State University,
CBC Building 201, Manhattan, KS, 66506-0401,
USA
sbossman@ksu.edu
Received: 30.06.2020
Accepted after revision: 23.07.2020
Published online: 25.08.2020
where an empty ‘p’ orbital of the trivalent carbocation cen-
ter interacts with the sp3 bridgehead C–H orbitals.10 Further
studies suggested that resonance stabilization, such as in
Figure 1b, represents a clear picture of a C–C hyperconjuga-
tion effect.11
DOI: 10.1055/s-0040-1707353; Art ID: ss-2020-m0358-psp
Abstract 1-Adamantylhydrazine can be a versatile intermediate for
many biologically active compounds as adamantyl possesses a wide
spectrum of medicinal properties. Described here is a detailed one-pot
synthesis of 1-adamantylhydrazine, carried out on a milligram to gram
scale, that steadily delivers a highly stable product used to carry out the
synthesis of 1-(adamantan-1-yl)-1H-pyrazol-3-amine for bacterial stud-
ies. The reaction employs inexpensive, catalyst free, readily available
starting materials. In the synthesis of 1-(adamantan-1-yl)-1H-pyrazol-3-
amine, the use of a continuous extraction method allows for complete
extraction of the target product into the organic layer and increases the
overall percentage yield.
iii
(a)
(b)
ii
i
H
H
H
Figure 1 (a) The empty ‘p’ orbital of the carbocation is stabilized with
other three sp3 bridgehead C–H bonds.10 (b) The 1-adamantyl carboca-
tion center is much more stable than other tertiary carbocations due to
these resonance stabilizations. Structures i, ii, and iii are equivalent.11
Key words SN1 substitution, hydrazines, adamantane, 1H-pyrazol-3-
amine, continuous extraction
The polycyclic cage of high symmetry1 and enhanced li-
pophilicity2 of adamantane has been of interest to chemists
since its initial discovery in crude oil in 1933. 1 Most impor-
tantly, various adamantyl derivatives show a very broad
spectrum of medicinal properties such as antiviral,3 antimi-
crobial,4 anticancer,5 antidiabetic (type 2 diabetes),6 and
many more.7 Introduction of the adamantyl functionality to
medicinal compounds can augment therapeutic effects by
increasing the overall effective transportation through bio-
logical membranes as a result of enhanced lipophilicity.8
Adamantyl derivatives are also of importance in material
science applications, for instance as calibration for AFM
tips.9 Commonly, adamantane’s tertiary carbon atoms are
functionalized via halogenation, which is followed by polar
SN1 substitution under electrophilic conditions. Many stud-
ies suggest that the positive charge of the 1-adamantyl car-
bocation can be selectively stabilized with other bridgehead
positions by means of second-order hyperconjugations, al-
lowing SN1 substitution.10 This can be observed in Figure 1a,
Our laboratory needed an efficient and simple synthetic
method for 1-adamantylhydrazine, because it is a mandato-
ry precursor for the synthesis of 1-adamantyl-substituted
pyrazolylthioureas with NNSN-motif.12 This class of novel
antibiotics is activated by copper(I) in activated phago-
somes13 and is very effective against Gram-positive bacte-
ria, such as MRSA (methicillin-resistant Staphylococcus au-
reus).14 After starting this endeavor, we realized the limited
availability of literature describing a feasible methodology.
Halogenation of adamantane is typically performed via bro-
mination; however, chlorination and iodation are also pos-
sible.15,16 Our initial attempts of synthesizing 1-adamantyl-
hydrazine quickly led to the realization that a truly feasible
methodology has not been described in the literature prior
to this study. Daeniker utilized 1-aminoadamantane as the
starting material and performed five subsequent steps via
sydnone to obtain 1-adamantylhydrazine.17 However, this
method proved to be lengthy and not (carbon) economic.
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Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

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A. Delpe Acharige et al.
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Synthesis
The highly strained 1,3-dehydroadamantane may undergo
SN1 type reactions to highly functionalized adamantane de-
rivatives. In this particular study (Scheme 1), 1,3-dehy-
droadamantane (1) was reacted with an excessive amount
(10 equiv) of 2-aminoethan-1-ol (2a) and 3-aminopropan-
1-ol (2b) at 60–70 °C for 1 hour to obtain O- and N-alkyla-
tion products 3a, 3b, 4a, and 4b.18 Unfortunately, 1,3-de-
hydroadamantane is expensive and not readily available for
purchase.
1-Bromoadamantane (purity 99%) and hydrazine monohydrate (puri-
ty 98%) were purchased from Alfa Aesar. 2-Chloroacrylonitrile (99%,
stabilized) was purchased from Acros Organics. Diethyl ether 99%,
ethyl acetate (Certified ACS), potassium carbonate (anhydrous) 99%,
sodium bicarbonate (Powder/Certified ACS), and hydrochloric acid
(12.1 N, certified ACS Plus) were purchased from Fisher Scientific In-
ternational, Inc., and used as received without further purifications.
In-house distilled water was used as the solvent for the pyrazole cy-
clization reaction. 1H (400, 600 MHz) and 13C (100, 151 MHz) spectra
were obtained by using Bruker-Ascend NMR spectrometers. Mass
spectra were obtained on a Waters Acquity UPLC TQD spectrometer.
The UPLC column was CORTECS C18, 90 Å, 2.7 m reversed phase.
Melting points were acquired by using a Mel-Temp 1001D instru-
ment.
OH
n
N
H
4a n = 1
4b n = 2
+
NH2
1-Adamantylhydrazine hydrochloride
+
HO
n
60–70 °C, 1 h
[CAS Reg. No. 16782-39-1]
2a n = 1
2b n = 2
NH2
1
Since 1-bromoadamantane is moisture-sensitive, light-sensitive, and
air-sensitive, it was flushed with argon gas before measuring and
then added to a reaction vessel. If the reaction continues for a pro-
longed period, it is necessary to cover the reaction vessel with a light-
blocking material such as aluminum foil. Ivory-colored (literature
states white to yellow19) 1-bromoadamantane (5 g, 23.24 mmol) was
weighed on weighing paper and transferred to a 500 mL, one-necked,
round-bottom flask with a magnetic stirring bar by using a powder
funnel. Then the round-bottom flask was charged with an excess
amount of hydrazine monohydrate (50 mL, 51.6 g, 1.03 mol), which
acted as the solvent and reactant. 1-Bromoadamantane did not dis-
solve in hydrazine at this point (Figure 2a) and a dispersion occurred
in the reaction vessel. It is noteworthy that vigorous stirring was not
required as it pushed the solid 1-bromoadamantane above the sol-
vent level. Therefore, moderate stirring was crucial to keep all the sol-
ids within the solvent. The round-bottom flask was connected to a
coiled reflux condenser which was connected to continuous water
flow. A mineral oil bath was utilized to reflux the reaction mixture at
125–135 °C. Inside the reaction vessel, the temperature was set to
110 °C. The reflux temperature was crucial, because if the reaction
mixture refluxed below 100 °C, it delivered both the product and un-
reacted 1-bromoadamantyl. The mixture was kept at that tempera-
ture for 8–12 hours. During reflux, 1-bromoadamantane completely
dissolved in hydrazine monohydrate and the reaction mixture even-
tually consisted of a very clear light-yellow colored solution, as shown
in Figure 2b. TLC was performed (EtOAc/hexane 1:1). Spots were visu-
alized with phosphomolybdic acid (PMA), as 1-bromoadamantane is
not visible under the short wavelength of UV. The starting material 1-
bromoadamantane created a dark spot on the light green background
(Rf = 0.90), whereas the product spot was not significantly visible as a
dark spot, which indirectly confirmed the formation of at least one
new product.
O
n
4a n = 1
4b n = 2
Scheme 1 Reaction of 1,3-dehydroadamantane 1 with 2-aminoethan-
1-ol (2a) and 3-aminopropan-1-ol 2b, leading to four different O- and
N-alkylation products 3a, 3b, 4a, and 4b
In 1968, the synthesis of 1-adamantylhydrazine and its
derivatives was patented by Thomas and Shetty; the au-
thors reacted a halogenated adamantane with anhydrous
hydrazine under a continuously supplied inert atmosphere
and sustained heating.19 An important drawback of this
patent is that the compounds were identified by means of
their melting points only. When we reproduced the original
procedure, drawbacks were encountered such as the neces-
sity of using anhydrous hydrogen chloride and inefficient
drying methods. Most importantly, we always obtained
mixtures of the target compounds and multiple byproducts.
Here we report modifications of the original synthetic
procedures by Thomas and Shetty, which were designed to
obtain a significantly higher yield of 1-adamantylhydrazine
(Scheme 2), which was used to subsequently synthesize the
target 1-(1-adamantyl)pyrazol-3-amine as shown in
Scheme 3.
NH2-NH2·H2O
NH-NH2
Br
110–125 °C
Scheme 2 Synthetic strategy towards 1-adamantylhydrazine
The reaction mixture was cooled to room temperature, followed by
the addition of 45% (w/w) aq KOH solution (50 mL). When the mix-
ture cooled, the clear solution turned cloudy due to the adamantyl
product featuring low solubility in hydrazine monohydrate. Further
addition of 45% (w/w) aq KOH solution (125 mL) facilitated the sepa-
ration of excessive hydrazine from the crude 1-adamantylhydra-
zine.19 At this point, the previously cloudy reaction mixture turned
into an opaque dispersion. It was transferred to a separatory funnel
and extracted with Et2O (3 × 50 mL). Due to the hydrophobic adaman-
tyl moiety, the product could be found in the organic layer (Et2O). The
organic layer was dried over anhydrous sodium sulfate. Note that the
original literature stated using anhydrous magnesium sulfate.19 Upon
Cl
K2CO3/NaHCO3
(1:2)
NH2
+
N
NH-NH2·HCl
N
H2O, rt
overnight
CN
2-chloro-
acrylonitrile
Scheme 3 Synthesis of 1-(adamantan-1-yl)-1H-pyrazol-3-amine using
1-adamantylhydrazine
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–D

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A. Delpe Acharige et al.
PSP
Synthesis
IR: 2891 (w,s), 2709 (w,s), 2549 (m,b), 1480 (m,s), 1085 (m,s) cm–1
.
1H NMR (400 MHz, DMSO-d6):  = 2.11 (s, 3 H), 1.78 (s, 6 H), 1.59 (m,
6 H).
13C NMR (101 MHz, DMSO-d6):  = 45.72, 37.05, 35.88, 30.50, 28.65.
MS: m/z = 167.15 [M + 1].
1-(Adamantan-1-yl)-1H-pyrazol-3-amine (Scheme 3)
[CAS Reg. No. 128315-61-7]
A previously published protocol was used for the synthesis of the de-
sired adamantyl-substituted heterocyclic product with slight modifi-
cations to the workup process.20 2-Chloroacrylonitrile (202.4 mg, 2.31
mmol) was measured into a 150 mL round-bottom flask and dis-
persed with distilled water (5 mL). Separately, K2CO3 (168 mg, 1.21
mmol) and NaHCO3 (204 mg, 2.48 mmol) were dissolved in distilled
water (5–7 mL) and mixed, followed by the addition to the 2-chloro-
acrylonitrile solution. Then 1-adamantylhydrazine hydrochloride salt
(2.31 mmol, 466.0 mg) was dissolved in distilled water (15 mL) and
transferred to the original mixture, which was stirred continuously
overnight. According to the original protocol, the product was meant
to be extracted with EtOAc (3×). However, from previous experience,
it was both convenient and effective to perform a continuous ex-
traction (Figure 4) to collect the desired product from the aqueous
layer, as pyrazole derivatives tend to show considerable hydrophilic
behavior. Finally, the organic layer was dried under vacuum and puri-
fied via flash column chromatography (EtOAc/hexane 5:95 to 25:75);
this gave a thick dark orange oil-like liquid.
Figure 2 (a) 1-Bromoadamantyl was not readily dissolved in hydrazine
at lower temperature; (b) 1-bromoadamantyl dissolved as the internal
temperature was elevated to 110 °C
the addition of anhydrous sodium sulfate, the product solution
turned clear. The product solution was then concentrated under vacu-
um to approximately a quarter of the solvent volume. Then the con-
centrated reaction mixture was charged with concentrated hydro-
chloric acid (3–5 mL), lowering the pH to 2.0, to obtain the 1-ada-
mantylhydrazine chloride salt, which is more stable than 1-
adamantylhydrazine. Upon the addition of hydrochloric acid, a white
solid product crashed out of the Et2O solution, as shown in Figure 3a.
The solid product was isolated via gravity-driven filtration and dried
under high vacuum (Figure 3b). Original literature stated to conduct
recrystallization of this white solid using 2-propanol. Although this
purification step was reproduced, it led to considerable loss of prod-
uct due to solubility of the reaction product in 2-propanol.19 Without
recrystallization, the yield was >88% (4.13 g) of 1-adamantylhydra-
zine hydrochloride. After recrystallization, it was diminished to ~53%.
It should be noted that the reaction product was pure according to
NMR and TLC characterization before and after recrystallization from
2-propanol.
Yield: 216 mg (43%).
IR: 3318.16 (w,b), 2904 (m, s), 2849 (m,s), 1683 (w,s), 1542 (w.s), 743
(m,s) cm–1
.
1H NMR (400 MHz, CDCl3):  = 7.47 (d, J = 14.3 Hz, 1 H), 6.36 (d,
J = 14.3 Hz, 1 H), 6.06 (s, 1 H), 2.23 (m, 3 H), 1.77 (m, 6 H), 1.28 (s, 6
H).
13C NMR (101 MHz, CDCl3):  = 160.39, 146.58, 106.20, 42.73, 40.20,
36.32, 29.55.
Funding Information
The work was supported by the National Institutes of Health (NIH)
(NIH/DHHS 1R01Al121364-01A1).
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ati
o
n
a
lInstitutesof
H
e
a
l
th(N
I
H/D
H
H
S
1
R
0
1
A
l
1
2
1
3
6
4-0
1
A
1)
Supporting Information
Supporting Information for this article is available online at
https://doi.org/10.1055/s-0040-1707353.
S
u
p
p
orit
n
gInformati
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n
S
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Figure 3 (a) White solid crashed out during the addition of concd aq
HCl; (b) final dried product of 1-adamantylhydrazine hydrochloride salt
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© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–D