Expedient Entry to 1-Aminoadamantane Derivatives via Aza-Prins Cyclization of 7-Methylenebicyclo[33.1]nonan-3-one Oximes

Article abstract of DOI:10.1055/s-0036-1591920

An efficient synthesis of 1-aminoadamantane (amantadine) derivatives is described. This synthesis features acid-promoted aza-Prins cyclization of 7-methylenebicyclo[3.3.1]nonan-3-one oximes, which are readily prepared from 1,3-adamantanediol via a Grob fragmentation and the subsequent oximation, to give various 3-substituted 1-(alkoxyamino)adamantanes. After the reduction of alkoxyamines, not only 3-substituted 1-aminoadamantanes, but also chiral 2,5-disubstituted derivatives were obtained in good yields.

Full text of DOI:10.1055/s-0036-1591920

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
©
Georg Thieme Verlag Stuttgart · New York
2018, 50, A–G
paper
A
en
Synthesis
T. Kuga et al.
Paper
Expedient Entry to 1-Aminoadamantane Derivatives via Aza-Prins
Cyclization of 7-Methylenebicyclo[3.3.1]nonan-3-one Oximes
δ–
Tetsuya Kuga
BnO
LA
O
NOBn
Lewis
acid (LA)
N
Yusuke Sasano
BnONH2
Masaki Tomizawa
Masatoshi Shibuya1
Yoshiharu Iwabuchi*
δ+
0
0
0
0
0-
0
0
2
1-
8
3
0
0-
0
8
2
0
0
0
0
0-
0
0
2
0-
6
7
9
9-
3
9
X
Grob fragmentation
aza-Prins cyclization
nucleophile
NHOBn
Department of Organic Chemistry, Graduate School of
Pharmaceutical Sciences, Tohoku University, 6-3 Aoba,
Aramaki, Aoba-ku, Sendai 980-8578, Japan
y-iwabuchi@m.tohoku.ac.jp
OH
NH2
Zn
OH
Nu
Nu
AcOH
1-aminoadamantanes
Nu = H, OR, N3, Cl, Br, Ph
Received: 05.12.2017
Accepted after revision: 05.01.2018
Published online: 05.02.2018
N
NH2
NH2
HN
DOI: 10.1055/s-0036-1591920; Art ID: ss-2017-f0782-op
CN
O
OH
vildagliptin
Abstract An efficient synthesis of 1-aminoadamantane (amantadine)
derivatives is described. This synthesis features acid-promoted aza-
Prins cyclization of 7-methylenebicyclo[3.3.1]nonan-3-one oximes,
which are readily prepared from 1,3-adamantanediol via a Grob frag-
mentation and the subsequent oximation, to give various 3-substituted
amantadine
memantine
Figure 1 Drugs comprising a 1-aminoadamantane moiety
1-(alkoxyamino)adamantanes. After the reduction of alkoxyamines, not
only 3-substituted 1-aminoadamantanes, but also chiral 2,5-disubsti-
tuted derivatives were obtained in good yields.
ed (or 1-hydroxy-) adamantanes, such as the Ritter reaction
Scheme 1, i),7 and rearrangement reactions from carbox-
b,c
(
7
a,c
ylic acid derivatives (Scheme 1, ii). In particular, the Rit-
ter reaction is most commonly used because the 1-halo- (or
Key words 1-aminoadamantanes, amantadine, 1-(alkoxyamino)-
adamantanes, aza-Prins reaction, oxime
1-hydroxy-) adamantane substrates are readily obtained by
Since its discovery in petroleum in 1933, the cage-
shaped, symmetrically beautiful hydrocarbon adamantane
has fascinated chemists, inspired their imaginations, and
spurred syntheses of derivatives thereof, leading to the de-
C–H functionalization from adamantanes. However, these
reactions are sometimes troublesome for substituted ada-
mantane derivatives because of the somewhat harsh condi-
tions. More significantly, these methods are difficult to ap-
ply to the synthesis of methylene-substituted 1-amino-
adamantanes because they take advantage of the inherent
reactivity of adamantanes: their methine C–H bonds are
2
velopment of diverse domains of organic chemistry. In par-
ticular, the unique physicochemical properties of the ada-
mantane motif confer on the derivatives appropriate lipo-
philicity and stability, resulting in a remarkable ‘success
rate’ in improving or providing pharmacological activity.3
Coupled with some serendipitous incidents, 1-aminoada-
mantane (amantadine) was found to exhibit potent anti-in-
fluenza A activity, expanding the medicinal applications of
8
much more reactive than their methylene C–H bonds. Re-
cently, Vázquez, Naesens, and co-workers disclosed synthe-
sis of 2-substituted 1-aminoadamantanes by combination
of the Ritter reaction with the Wagner–Meerwein rear-
9
rangement from noradamantane alcohols (Scheme 1, iii).
4
adamantane derivatives (Figure 1). Indeed, 3,5-dimethyl-
This synthesis gives 2-alkyl- and 2,2-dialkyl-1-amino-
adamantanes in good yield; however, the substituents on the
adamantane nucleus are limited to only simple alkyl groups.
Our group has long been involved in the chemistry of 2-
1
-aminoadamantane (memantine) has been discovered and
approved for the treatment of Alzheimer’s disease.5
Vildagliptin, consisting of a 1-amino-3-hydroxy-adaman-
tane moiety, is used to treat type 2 diabetes mellitus.6
Notwithstanding the promising properties of 1-amino-
adamantanes in medicinal chemistry, available methods
10
azaadamantane-derived nitroxyl radicals, the synthetic
ventures in which encouraged us to think that a key inter-
mediate, namely bicyclic oxime 1 (see Table 1), would also
be applicable to the synthesis of 1-aminoadamantanes.
Herein, we report a novel method of synthesis of 1-amino-
adamantanes from bicyclic oximes, which are readily
7
that allow access to the structural motif are limited. The
exclusively employed methods for synthesis of 1-amino-
adamantanes are substitution reactions from 1-halogenat-
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–G

B
Synthesis
T. Kuga et al.
Paper
(
i) Substitution
presence of TMSN at room temperature for 24 hours af-
3
X
NH2
forded 3-azido-1-(hydroxyamino)adamantane (2) in 43%
yield along with recovered substrate (entry 1). In the case of
oxime ether 3, the yield of the adamantane product 4a was
improved to 78%, although the substrate was not complete-
ly consumed (entry 2). Whereas BF ·OEt showed lower ac-
(
a) Ritter reaction, saponification
R
R
(b) azidation, reduction
R
R
R
R
(
X = halogen or OH)
3
2
tivity and gave only 58% yield of product 4a, Sc(OTf) effi-
(
ii) Rearrangement from Carboxylic Acid Derivatives
COX
3
NH2
ciently promoted the cyclization reaction to afford 4a in
93% yield in 3 hours (entries 3 and 4). Brønsted acid TfOH
promoted the cyclization reaction, to give the adamantane
product 4a in 61% yield, accompanied by unproductive
olefin isomerization to the endo-trisubstituted olefin (entry
(
a) Curtius rearrangement
R
R
(b) Hofmann rearrangement
R
R
R
R
(
X = OH or NH2)
5
). The reaction also proceeded with a catalytic amount of
(
(
iii) Combination (Ritter Reaction and Wagner–Meerwein Rearrangement)
Sc(OTf) although the yield was slightly lower (78%) than
R
R
3
NH2
1
2
. ClCH2CN, AcOH, H2SO4
R
that under stoichiometric conditions (entry 6). Note that
the Beckmann rearrangement was never observed any of
the cases investigated, indicating the superiority of the aza-
Prins cyclization.12
OH
R
. thiourea, EtOH, AcOH
reflux
iv) Cyclization of Oxime (This Work)
NH2
1
R
NOR
R
1
2
. acid, nucleophile (Nu)
2
Table 1 Optimization of Substrates and Acids
5
. reduction of hydroxylamine
Nu
NHOR
NOR
(
C3 when R = H)
acid (1.5 equiv), TMSN3 (3 equiv)
(
iv') Olah, G. A. et al. (1990)
O
CH2Cl2 (0.5 M), rt
N3
OH
1
3
: R = H
: R = Bn
2: R = H
4a: R = Bn
Lewis acid, nucleophile (Nu)
Nu
Entry
Substrate
Acid
Time (h)
Product
Yield (%)a
Scheme 1 Synthesis of 1-aminoadamantanes: an overview
1
2
3
4
5
1
3
3
3
3
3
TMSOTf
TMSOTf
BF ·OEt
24
24
24
3
2
43
78
58
93
61
78
4a
4a
4a
4a
4a
prepared from 1,3-adamantanediol (Scheme 1, iv). Treat-
ment of the oximes with acids in the presence of nucleop-
hilic species affords the corresponding 1-(alkoxyamino)ad-
amantanes with various groups at C5 (when R is not H in
Scheme 1, iv) or C3 (when R is H) position, which are re-
duced to 1-aminoadamantanes under standard conditions
in good yield. Moreover, the method enables the synthesis
of optically active 2,5-disubstituted 1-aminoadamantanes
from the corresponding optically active oximes.
3
2
Sc(OTf)
3
TfOH
24
24
6
Sc(OTf) b
3
a
Isolated yield.
b
20 mol%.
With the optimum conditions established, we investi-
Our idea for the synthesis of 1-aminoadamantanes was
inspired by the synthesis of 3-substituted 1-hydroxy-
adamantanes from a bicyclic ketone by acid-promoted
Prins cyclization, which was reported by Olah et al. in 1990
gated the scope of the reaction with respect to nucleophiles
(Table 2). Trifluoroacetic acid and alcohols were efficiently
introduced to afford adamantanes 4b–d in high yields (en-
tries 1–3). Although phenol gave phenyl ether 4e (64%) and
the o-adamantylphenol 4f (32%) as a separable mixture,
thiophenol gave the thioether 4g selectively in 88% yield
(entries 4 and 5). Note that treatment of 4e under the same
conditions as the cyclization did not give any detectable
amount of 4f, indicating that 4e and 4f were generated as
kinetic products. When TMSNCS was used as nucleophile,
thiocyanate 4h was obtained in 83% yield along with a
small amount (2%) of the isothiocyanate 4i (entry 6). Treat-
ment of oxime 3 with aqueous HCl or HBr provided 3-halo-
11
(Scheme 1, iv′). We envisaged that the corresponding
imines and oximes would undergo aza-Prins cyclization to
give the corresponding 1-aminoadamantanes and 1-
(hydroxyamino)adamantanes, respectively, upon treatment
with an appropriate acid, and the subsequent reduction of
the N–O bond of the latter would furnish 1-aminoadaman-
tanes (Scheme 1, iv: oximes are shown).
In our preliminary experiments, oximes 1 and 3 were
chosen as substrates because the corresponding imine was
not obtained (Table 1). Next, the optimum acid with which
to promote the cyclization reaction of the oximes was iden-
tified. Treatment of oxime 1 with Lewis acid TMSOTf in the
adamantanes 4j and 4k without using Sc(OTf) (entries 7
3
and 8). A Friedel–Crafts type reaction in benzene solvent af-
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Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–G

C
Synthesis
T. Kuga et al.
Paper
forded 4l in moderate yield (entry 9). Reductive cyclization
difficulties in isolating the highly polar unprotected prod-
ucts. 1-Alkoxyaminoadamantanes (4) were reduced to 1-
aminoadamantanes (7) in good yields (entries 1–5). The
azido group was reduced under reductive conditions to give
1,3-diaminoadamantane 7n after Boc protection (entry 4).
The trifluoroacetyl group was removed during the two-step
procedure (entry 5). Chiral alkoxyaminoadamantane 6c
was also reduced to 2,5-disubstituted 1-aminoadamantane
in good yield (Scheme 2).
was accomplished using Et SiH as the reductant in HFIP
3
solution to give 4m in 90% yield (entry 10).
Table 2 Scope of the Reaction with Respect to Nucleophiles
NHOBn
NOBn
Sc(OTf)3 (1.5 equiv)
nucleophile (3 equiv)
CH2Cl2 (0.5 M), rt
X
3
4
Table 4 Reduction of Adamantane Alkoxyamines to Amines
Entry Nucleophile
Time (h) Products (yield, %)a
NHOBn
NHBoc
1
2
3
4
5
6
7
8
9
TFAb
8
16
6
4b: X = OTFA (94)
4c: X = OBn (88)
4d: X = OMe (95)
1. (A) H2, Pd/C, MeOH, rt
B) Zn, AcOH–THF, 50 °C
(
BnOH
X
2. (C) Boc2O, Et3N, THF
2
X
MeOHc
PhOH
(D) Boc O, aq NaOH–THF
4
7
2
4e: X = OPh (64), 4f: X = 2-HOC
4g: X = SPh (88)
6 4
H (32)
Entry
Substrate
Conditions
Product (yield, %)a
PhSH
2
TMSNCS
37% aq HClb
48% aq HBrb
PhHc,d
1
4h: X = SCN (83), 4i: X = NCS (8)
4j: X = Cl (69)
1
2
3
4
4g: X = SPh
4k: X = Br
4l: X = Ph
4a: X = N3
(B), (C)
(A), (C)
(B), (C)
(A), (C)
7g: X = SPh (77)
7k: X = Br (79)
24
5
4k: X = Br (71)
7l: X = Ph (61)
24
16
4l: X = Ph (44)
7n: X = NHBoc (71)
7o: X = OH (95)
10
Et
3
SiHe
4m: X = H (90)
5
4b: X = OTFA
Isolated yield.
(A), (D)
a
b
c
a
Isolated yield.
Sc(OTf) was not used.
The nucleophile was used as the solvent (0.5 M).
3
d
e
8
0 °C.
NHOBn
NH2
Ph
Ph
HFIP was used as the solvent (0.5 M).
H
H
Zn
OBn
OBn
AcOH–THF, 50 °C, 6 h
We then investigated the applicability of the optically
6
c
8c (68%)
13
active bicyclic oxime 5 as substrate. The Sc(OTf) -promot-
3
Scheme 2 Reduction of alkoxyamine 6c
ed cyclization with various nucleophiles afforded 2,5-
disubstituted 1-alkoxyaminoadamantanes in good yields
(Table 3).
In summary, we have developed an expedient synthetic
method for 1-aminoadamantane derivatives from readily
Table 3 Cyclization of Optically Active Oxime 5
available bicyclic ene-oximes through Sc(OTf) -promoted
3
aza-Prins cyclization and reduction of the resulting 1-
(alkoxyamino)adamantane intermediates. The method de-
veloped herein provides not only 3-substituted 1-aminoad-
amantanes, but also chiral 2,5-disubstituted derivatives in
good yields. We believe that this method will improve the
availability of 1-aminoadamantane derivatives and facili-
tate the development of pharmaceuticals.
Ph
Ph
NHOBn
NOBn
Sc(OTf)3 (1.5 equiv)
nucleophile (3 equiv)
H
H
CH2Cl2 (0.5 M), rt
X
5
6
Entry
Nucleophile
Time (h)
X
Product
Yield (%)a
1
2
3
4
TMSN
BnOH
3
8
4
N
3
6a
6c
64
76
62
84
OBn
Br
All reactions were carried out with anhydrous solvents under argon
atmosphere, unless otherwise noted. Anhydrous THF and CH Cl were
TMSBr
Et
SiHb
Isolated yield.
3
6k
6m
2
2
3
16
H
purchased from Kanto Chemical Co., Inc. Other solvents were dried
and distilled according to standard protocols. Reagents were obtained
from commercial suppliers and used without further purification,
unless otherwise noted. Reactions were monitored by thin-layer
chromatography (TLC) carried out on silica gel plates (Merck Kieselgel
60 F254). Column chromatography was carried out with Silica gel 60
N (Kanto Chemical Co., Inc., spherical, neutral, 63–210 μm, or 40–50
μm). All melting points were determined with a Yazawa Micro Melt-
ing Point BY-2. Optical rotations were measured with a JASCO P-2200
a
b
HFIP was used as the solvent (0.5 M).
Finally, we demonstrated that 1-alkoxyaminoadaman-
tanes were reduced to 1-aminoadamantanes (Table 4). The
yields of 1-aminoadamantanes were determined by isolat-
ing the corresponding Boc-protected products because of
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Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–G

D
Synthesis
T. Kuga et al.
Paper
1
3
Polarimeter at r.t., using the sodium D line. IR spectra were recorded
with a JASCO FT/IR-410 Fourier Transform Infrared Spectrophotome-
C NMR (100 MHz, CDCl ): δ = 138.0, 128.3, 128.2, 127.7, 77.5, 73.3,
3
58.4, 48.2, 43.6, 40.3, 39.5, 35.6, 30.2.
1
13
ter. H NMR (400 MHz) and C NMR spectra (100 MHz) were record-
ed with JEOL JNM-AL-400 spectrometers. EI mass spectra were re-
corded with JEOL JMS-DX303, JEOL JNM-AL500, and JEOL JMS-700.
ESI mass spectra were recorded with a Thermo Scientific Exactive
mass spectrometer.
+
MS (EI): m/z (%) = 287 [M] , 91 (100).
+
HRMS (EI): m/z [M] calcd for C18H25NO : 287.1885; found: 287.1899.
2
O-Benzyl-N-(3-phenoxyadamantan-1-yl)hydroxylamine (4e)
Yield 44.9 mg (0.129 mmol, 64%); colorless oil.
IR (neat): 2911 cm–1
.
Aza-Prins Cyclization of Oximes; Typical Procedure for 4a
To a solution of 3 (51.4 mg, 0.211 mmol) in CH Cl (0.4 mL) were add-
1
2
2
H NMR (400 MHz, CDCl ): δ = 7.36–7.23 (m, 7 H), 7.09 (t, J = 7.4 Hz,
3
ed Sc(OTf) (148 mg, 0.301 mmol) and TMSN (78.6 μL, 0.600 mmol)
3
3
1 H), 6.98 (d, J = 8.8 Hz, 2 H), 5.20 (br s, 1 H), 4.67 (s, 2 H), 2.30 (br s,
2
at 0 °C. After stirring 3 h at r.t., the reaction was quenched with satu-
H), 1.83 (m, 6 H), 1.61 (br s, 4 H), 1.52 (br s, 2 H).
rated aqueous NaHCO , and the mixture was extracted with EtOAc.
3
13
C NMR (100 MHz, CDCl ): δ = 153.8, 137.9, 128.8, 128.30, 128.27,
3
The combined organic layers were washed with brine and dried over
MgSO4. Concentration and flash column chromatography (hex-
ane/EtOAc, 10:1) provided 4a.
1
27.7, 124.9, 123.8, 78.5, 77.4, 58.7, 45.5, 42.0, 39.2, 35.3, 30.5.
+
MS (EI): m/z (%) = 349 [M] , 256 (100).
+
HRMS (EI): m/z [M] calcd for C23H NO : 349.2042; found: 349.2024.
Yield: 55.5 mg (0.186 mmol, 93%); colorless oil.
27
2
IR (neat): 2088 cm–1
.
2
-(3-((Benzyloxy)amino)adamantan-1-yl)phenol (4f)
Yield 22.6 mg (0.065 mmol, 32%); colorless crystals; mp 162 °C
CH Cl –hexane).
1
H NMR (400 MHz, CDCl ): δ = 7.35–7.28 (m, 5 H), 5.18 (br s, 1 H),
3
4.67 (s, 2 H), 2.29 (br s, 2 H), 1.77 (br s, 2 H), 1.74 (br s, 4 H), 1.66 (br d,
(
2
2
J = 12.1 Hz, 2 H), 1.61–1.58 (m, 4 H).
IR (neat): 2910 cm–1
1H NMR (400 MHz, CDCl
1.4 Hz, 1 H), 7.04 (dd, J = 7.9, 7.6 Hz, 1 H), 6.87 (dd, J = 7.6, 7.6 Hz,
H), 6.61 (d, J = 7.9 Hz, 1 H), 5.55 (br s, 1 H), 4.74 (s, 2 H), 2.27 (br s,
2 H), 2.15–2.11 (m, 4 H), 2.02 (br d, J = 12.1 Hz, 2 H), 1.82 (br d, J =
1.6 Hz, 2 H), 1.74–1.64 (m, 4 H).
.
1
3
C NMR (100 MHz, CDCl ): δ = 137.7, 128.23, 128.18, 127.7, 77.5,
3
5
9.9, 57.5, 44.4, 40.8, 39.0, 35.1, 29.9.
): δ = 7.36–7.25 (m, 5 H), 7.19 (dd, J = 7.6,
3
+
MS (EI): m/z (%) = 298 [M] , 91 (100).
1
+
HRMS (EI): m/z [M] calcd for C 7H N O: 298.1794; found: 298.1776.
1
22
4
1
3
-((Benzyloxy)amino)adamantan-1-yl 2,2,2-Trifluoroacetate (4b)
13
C NMR (100 MHz, CDCl ): δ = 154.8, 137.9, 135.2, 128.3, 128.2,
3
Yield: 69.7 mg (0.189 mmol, 94%); colorless oil.
IR (neat): 1776 cm–1
127.7, 126.9, 126.8, 120.3, 116.5, 77.2, 56.9, 42.5, 39.8, 39.7, 38.4,
.
36.2, 29.7.
1
+
H NMR (400 MHz, CDCl ): δ = 7.37–7.27 (m, 5 H), 5.19 (br s, 1 H),
MS (EI): m/z (%) = 349 [M] , 227 (100).
3
4
2
.67 (s, 2 H), 2.36 (br s, 2 H), 2.15–2.08 (m, 6 H), 1.72 (br d, J = 11.6 Hz,
H), 1.65–1.55 (m, 4 H).
+
HRMS (EI): m/z [M] calcd for C23H27NO : 349.2042; found: 349.2041.
2
13
C NMR (100 MHz, CDCl ): δ = 155.6 (q, J = 41.2 Hz), 137.7, 128.2,
O-Benzyl-N-(3-(phenylthio)adamantan-1-yl)hydroxylamine (4g)
3
1
27.8, 127.7, 114.2 (q, J = 286.7 Hz), 86.9, 77.5, 58.6, 43.9, 39.9, 38.8,
Yield: 64.2 mg (0.175 mmol, 88%); colorless oil.
35.0, 30.5.
IR (neat): 2911 cm–1
.
+
MS (EI): m/z (%) = 369 [M] , 91 (100).
HRMS (EI): m/z [M]+ calcd for C19H22F NO : 369.1552; found:
1
H NMR (400 MHz, CDCl ): δ = 7.50 (d, J = 7.2 Hz, 2 H), 7.37–7.24 (m,
3
3
3
8 H), 5.13 (br s, 1 H), 4.65 (s, 2 H), 2.17 (br s, 2 H), 1.76–1.74 (m, 4 H),
369.1559.
1.71 (br d, J = 12.6 Hz, 2 H), 1.58–1.57 (m, 4 H), 1.53 (br s, 2 H).
13
C NMR (100 MHz, CDCl ): δ = 137.9, 137.7, 130.2, 128.7, 128.4,
3
O-Benzyl-N-(3-(benzyloxy)adamantan-1-yl)hydroxylamine (4c)
1
28.3, 128.2, 127.7, 77.5, 57.3, 48.1, 46.3, 42.7, 39.1, 35.3, 30.3.
Yield: 64.3 mg (0.177 mmol, 88%); colorless oil.
+
MS (EI): m/z (%) = 365 [M] , 166 (100).
IR (neat): 2911 cm–1
.
+
HRMS (EI): m/z [M] calcd for C23H27NOS: 365.1813; found: 365.1830.
1
H NMR (400 MHz, CDCl ): δ = 7.35–7.23 (m, 10 H), 5.21 (br s, 1 H),
3
4
.69 (s, 2 H), 4.50 (s, 2 H), 2.30 (br s, 2 H), 1.82–1.79 (m, 6 H), 1.66 (br
O-Benzyl-N-(3-thiocyanatoadamantan-1-yl)hydroxylamine (4h)
d, J = 12.1 Hz, 2 H), 1.61 (br d, J = 12.1 Hz, 2 H), 1.56 (br s, 2 H).
Yield: 52.5 mg (0.167 mmol, 83%); colorless prisms; mp 66 °C (petro-
leum ether).
13
C NMR (100 MHz, CDCl ): δ = 139.8, 138.0, 128.3, 128.24, 128.22,
3
127.7, 127.4, 127.1, 77.4, 74.0, 62.7, 58.4, 44.4, 41.0, 39.5, 35.6, 30.3.
IR (neat): 2148 cm–1
.
+
MS (EI): m/z (%) = 363 [M] , 91 (100).
1
H NMR (400 MHz, CDCl ): δ = 7.37–7.38 (m, 5 H), 5.18 (br s, 1 H),
3
+
HRMS (EI): m/z [M] calcd for C 4H NO : 363.2198; found: 363.2208.
2
29
2
4.67 (s, 2 H), 2.32 (br s, 2 H), 2.32–1.94 (m, 6 H), 1.70 (br d, J = 12.1 Hz,
2
13
H), 1.63–1.60 (m, 4 H).
O-Benzyl-N-(3-methoxyadamantan-1-yl)hydroxylamine (4d)
4.5 mg (0.190 mmol, 95%); colorless oil.
C NMR (100 MHz, CDCl ): δ = 137.7, 128.3, 127.8, 110.5, 77.5, 57.5,
3
5
53.7, 46.4, 42.7, 38.5, 34.7, 30.5.
IR (neat): 2909 cm–1
.
+
HRMS (ESI+): m/z [M + Na] calcd for C18H22N OSNa: 337.1345; found:
337.1333.
2
1
H NMR (400 MHz, CDCl ): δ = 7.34–7.27 (m, 5 H), 5.22 (br s, 1 H),
3
4.68 (s, 2 H), 3.23 (s, 3 H), 2.29 (br s, 2 H), 1.70–1.56 (m, 10 H), 1.54
(m, 2 H).
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–G

E
Synthesis
T. Kuga et al.
Paper
+
O-Benzyl-N-(3-isothiocyanatoadamantan-1-yl)hydroxylamine (4i)
MS (EI): m/z (%) = 257 [M] , 91 (100).
+
Yield: 4.88 mg (0.0155 mg, 8%); colorless prisms; mp 64 °C (petro-
leum ether).
HRMS (EI): m/z [M] calcd for C17H23NO: 257.1780; found: 257.1780.
IR (neat): 2091 cm–1
.
N-((1R,2S,5R)-5-Azido-2-benzyladamantan-1-yl)-O-benzylhydrox-
1
ylamine (6a)
H NMR (400 MHz, CDCl ): δ = 7.37–7.28 (m, 5 H), 5.15 (br s, 1 H),
3
Yield: 49.5 mg (0.127 mmol, 64%); colorless solid; mp 65 °C; [α] 27
4.66 (s, 2 H), 2.26 (m, 2 H), 1.96 (br s, 2 H), 1.94–1.89 (m, 4 H), 1.67 (br
D
d, J = 11.6 Hz, 2 H), 1.61–1.54 (m, 4 H).
+38.8 (c = 0.54, CHCl ).
3
13
IR (neat): 2925, 2089 cm–1
.
C NMR (100 MHz, CDCl ): δ = 137.8, 130.8, 128.34, 128.29, 127.8,
3
7
7.5, 59.3, 56.9, 46.5, 43.0, 38.7, 34.8, 29.4.
1
H NMR (400 MHz, CDCl ): δ = 7.36–7.26 (m, 7 H), 7.24–7.14 (m, 3 H),
3
+
MS (EI): m/z (%) = 314 [M] , 165 (100).
HRMS (EI): m/z [M]+ calcd for C18H22N OS: 314.1453; found:
5.34 (s, 1 H), 4.73 (s, 2 H), 3.06 (dd, J = 12.6, 3.4 Hz, 1 H), 2.41 (dd,
J = 12.6, 11.9 Hz, 1 H), 2.27 (s, 1 H), 2.09 (d, J = 11.9 Hz, 1 H), 2.01–1.87
2
(m, 3 H), 1.76–1.74 (m, 4 H), 1.55–1.43 (m, 4 H).
314.1447.
13
C NMR (100 MHz, CDCl ): δ = 140.8, 137.9, 128.9, 128.29, 128.26,
3
O-Benzyl-N-(3-chloroadamantan-1-yl)hydroxylamine (4j)
1
3
28.2, 127.7, 125.8, 77.0, 59.9, 59.8, 46.2, 41.4, 41.3, 38.5, 36.5, 35.3,
2.6, 31.1, 30.4.
Yield: 40.5 mg (0.139 mmol, 69%); colorless oil.
IR (neat): 2912 cm–1
.
+
MS (EI): m/z (%) = 388 [M] , 83 (100).
1
H NMR (400 MHz, CDCl ): δ = 7.37–7.27 (m, 5 H), 5.18 (br s, 1 H),
+
3
HRMS (EI): m/z [M] calcd for C24H28N O: 388.2263; found: 388.2232.
4
4
.68 (s, 2 H), 2.27 (br s, 2 H), 2.12 (br s, 2 H), 2.09–2.03 (m, 4 H), 1.69
(
1
br d, J = 12.1 Hz, 2 H), 1.64–1.54 (m, 4 H).
O-Benzyl-N-((1R,2S,5R)-2-benzyl-5-(benzyloxy)adamantan-1-
yl)hydroxylamine (6c)
Yield: 68.9 mg (0.152 mmol, 76%); colorless oil; [α]D27 +36.9 (c = 0.43,
CHCl3).
3
C NMR (100 MHz, CDCl ): δ = 137.8, 128.3, 128.2, 127.7, 77.5, 67.9,
3
5
8.7, 50.5, 46.8, 38.7, 34.8, 31.5.
+
MS (EI): m/z (%) = 291 [M] , 91 (100).
HRMS (EI): m/z [M]+ calcd for C17H22ClNO: 291.1390; found:
IR (neat): 2925 cm–1
.
291.1403.
1
H NMR (400 MHz, CDCl ): δ = 7.37–7.23 (m, 12 H), 7.19–7.15 (m,
3
3
H), 5.39 (br s, 1 H), 4.75 (s, 2 H), 4.51 (s, 2 H), 3.08 (dd, J = 12.8,
O-Benzyl-N-(3-bromoadamantan-1-yl)hydroxylamine (4k)
3.4 Hz, 1 H), 2.47 (dd, J = 12.8, 12.8 Hz, 1 H), 2.29 (br s, 1 H), 2.12–2.04
Yield: 50.9 mg (0.143 mmol, 71%); colorless oil.
(m, 2 H), 1.97 (br d, J = 12.1 Hz, 1 H), 1.90 (br s, 1 H), 1.81–1.71 (m,
4 H), 1.61–1.50 (m, 3 H), 1.43 (br d, J = 13.0 Hz, 1 H).
IR (neat): 2911 cm–1
.
13C NMR (100 MHz, CDCl
): δ = 141.3, 139.6, 138.1, 129.1, 128.32,
28.29, 128.24, 128.15, 127.7, 127.5, 127.2, 125.7, 76.9, 74.1, 62.7,
1
3
H NMR (400 MHz, CDCl ): δ = 7.37–7.28 (m, 5 H), 5.17 (br s, 1 H),
3
1
6
4.67 (s, 2 H), 2.34 (br s, 2 H), 2.30–2.23 (m, 6 H), 1.72 (br d, J = 12.1 Hz,
0.7, 46.5, 41.8, 41.4, 38.5, 37.0, 35.7, 32.7, 31.5, 30.8.
2
H), 1.68–1.61 (m, 4 H).
+
13
MS (EI): m/z (%) = 453 [M] , 91 (100).
C NMR (100 MHz, CDCl ): δ = 137.9, 128.33, 128.27, 127.8, 77.5,
3
+
64.2, 58.9, 52.0, 48.3, 38.5, 34.8, 32.2.
HRMS (EI): m/z [M] calcd for C31H35NO : 453.2668; found: 453.2686.
2
+
MS (EI): m/z (%) = 335 [M] , 91 (100).
HRMS (EI): m/z [M]+ calcd for C17H22BrNO: 335.0885; found:
O-Benzyl-N-((1R,2S,5R)-2-benzyl-5-bromoadamantan-1-yl)hy-
droxylamine (6k)
Yield: 53.0 mg (0.124 mmol, 62%); colorless oil; [α]D23 +46.1 (c = 1.06,
335.0893.
CHCl3).
O-Benzyl-N-(3-phenyladamantan-1-yl)hydroxylamine (4l)
IR (neat): 2913 cm–1
1H NMR (400 MHz, CDCl
.33 (br s, 1 H), 4.73 (s, 2 H), 3.07 (dd, J = 13.5, 3.9 Hz, 1 H), 2.54–2.45
.
Yield: 29.1 mg (0.087 mmol, 44%); colorless oil.
IR (neat): 2905 cm–1
3
): δ = 7.36–7.24 (m, 7 H), 7.19–7.14 (m, 3 H),
.
5
1
H NMR (400 MHz, CDCl ): δ = 7.37–7.27 (m, 9 H), 7.20 (m, 1 H), 5.27
3
(m, 2 H), 2.33–2.20 (m, 4 H), 2.12–2.08 (m, 2 H), 2.05 (m, 1 H), 1.96
(br s, 1 H), 4.72 (s, 2 H), 2.28 (br s, 2 H), 1.90–1.86 (m, 4 H), 1.82 (br d,
(br d, J = 12.6 Hz, 1 H), 1.85–1.80 (m, 2 H), 1.61 (m, 1 H), 1.48 (br d, J =
J = 12.1 Hz, 2 H), 1.76–1.73 (m, 4 H), 1.67 (br d, J = 13.0 Hz, 2 H).
12.6 Hz, 1 H).
13
C NMR (100 MHz, CDCl ): δ = 150.0, 138.1, 128.3, 128.24, 128.15,
13
3
C NMR (100 MHz, CDCl ): δ = 140.9, 137.9, 129.0, 128.3, 128.2,
3
127.6, 125.7, 124.9, 77.5, 56.6, 45.8, 42.4, 39.7, 38.1, 35.9, 29.7.
127.8, 125.8, 64.3, 61.2, 49.0, 45.9, 45.8, 42.8, 40.8, 36.1, 33.5, 32.67,
+
MS (EI): m/z (%) = 333 [M] , 91 (100).
32.65.
+
+
HRMS (EI): m/z [M] calcd for C23H27NO: 333.2093; found: 333.2091.
MS (EI): m/z (%) = 425 [M] , 91 (100).
HRMS (EI): m/z [M]+ calcd for C24H28BrNO: 425.1354; found:
N-(Adamantan-1-yl)-O-benzylhydroxylamine (4m)
425.1344.
Yield: 46.4 mg (0.180 mmol, 90%); colorless oil.
IR (neat): 2916 cm–1
.
O-Benzyl-N-((1R,2S,5S)-2-benzyladamantan-1-yl)hydroxylamine
1
(6m)
H NMR (400 MHz, CDCl ): δ = 7.35–7.27 (m, 5 H), 4.69 (s, 2 H), 2.08
3
Yield: 58.1 mg (0.167 mmol, 84%); colorless oil; [α]D24 +6.9 (c = 0.35,
CHCl3).
(
1
br s, 3 H), 1.70–1.61 (m, 12 H).
3
C NMR (100 MHz, CDCl ): δ = 138.2, 128.24, 128.15, 127.6, 77.4,
3
IR (neat): 2909 cm–1
.
5
5.5, 40.5, 36.7, 29.2.
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–G

F
Synthesis
T. Kuga et al.
Paper
1
HRMS (EI): m/z [M – Br]+ calcd for C15H24NO : 250.1807; found:
H NMR (400 MHz, CDCl ): δ = 7.37–7.23 (m, 7 H), 7.18–7.16 (m, 3 H),
3
2
5.33 (br s, 1 H), 4.76 (s, 2 H), 3.07 (dd, J = 12.9, 3.4 Hz, 1 H), 2.49 (dd,
250.1835.
J = 12.9, 12.1 Hz, 1 H), 2.19 (d, J = 12.1 Hz, 1 H), 2.05 (br s, 3 H), 1.95
(
1
d, J = 12.6, Hz, 1 H), 1.77 (m, 1 H), 1.70–1.66 (m, 5 H), 1.50 (d, J =
1.6 Hz, 1 H), 1.45–1.35 (m, 2 H).
tert-Butyl (3-Phenyladamantan-1-yl) Carbamate (7l)
To a solution of 4l (25.2 mg, 0.0756 mmol) in AcOH–THF (3:2, 1 mL)
was added activated Zn (47 mg, 0.69 mmol) at 50 °C. After stirring for
1
3
C NMR (100 MHz, CDCl ): δ = 142.0, 138.4, 129.1, 128.3, 128.2,
3
1
2
28.1, 127.6, 125.5, 76.9, 57.5, 47.2, 42.8, 38.2, 37.5, 34.3, 32.8, 30.9,
9.7, 29.5, 29.0.
1.5 h at 50 °C, the reaction was quenched with 28% aqueous NH OH at
4
0 °C and the mixture was extracted with CHCl . The combined organ-
3
+
ic layers were dried over K CO and concentrated under reduced pres-
MS (EI): m/z (%) = 347 [M] , 91 (100).
2 3
sure. To the residue were added THF (1 mL), Et N (49 μL, 0.35 mmol),
+
3
HRMS (EI): m/z [M] calcd for C24H29NO: 347.2249; found: 347.2236.
and Boc O (48 μL, 0.21 mmol) at 0 °C. After stirring for 40 min at r.t.,
2
the reaction was quenched with saturated aqueous NaHCO3 and the
mixture was extracted with EtOAc. The combined organic layers were
tert-Butyl (3-(Phenylthio)adamantan-1-yl) Carbamate (7g)
To a solution of 4g (25.7 mg, 0.0703 mmol) in AcOH–THF (3:2, 1 mL)
washed with brine and dried over MgSO . Concentration and flash
4
was added activated Zn (46 mg, 0.70 mmol) at 50 °C. After stirring for
column chromatography (hexane/EtOAc, 20:1) provided 7l.
1
0
h at 50 °C, the reaction was quenched with 28% aqueous NH OH at
4
Yield: 15.1 mg (0.0460 mmol, 61%); colorless solid; mp 125 °C (color-
less crystals, CH Cl –hexane).
°C and the mixture was extracted with CHCl . The combined organ-
3
2
2
ic layers were dried over K CO and concentrated under reduced pres-
sure. To the residue were added THF (1 mL), Et N (49 μL, 0.35 mmol),
and Boc O (48 μL, 0.21 mmol) at 0 °C. After stirring overnight at r.t.,
2
3
IR (neat): 2908, 1719, 1168 cm–1
.
3
1
H NMR (400 MHz, CDCl ): δ = 7.37–7.29 (m, 4 H), 7.18 (m, 1 H), 4.45
2
3
the reaction was quenched with saturated aqueous NaHCO3 and the
mixture was extracted with EtOAc. The combined organic layers were
(s, 1 H), 2.27 (br s, 2 H), 2.01 (s, 2 H), 1.99 (br d, J = 13.0 Hz, 2 H), 1.95–
1.87 (m, 4 H), 1.84 (br d, J = 12.2 Hz, 2 H), 1.69 (m, 2 H), 1.43 (s, 9 H).
washed with brine and dried over MgSO . Concentration and flash
column chromatography (hexane/EtOAc, 8:1) provided 7g.
13
4
C NMR (100 MHz, CDCl ): δ = 154.2, 149.7, 128.2, 125.8, 124.9, 78.8,
3
51.5, 47.2, 42.0, 41.2, 38.3, 35.6, 29.9, 28.5.
Yield: 19.5 mg (0.0542 mmol, 77%); colorless solid; mp 134 °C (color-
less crystals, CH Cl –hexane).
+
MS (EI): m/z (%) = 327 [M] , 271 (100).
2
2
+
HRMS (EI): m/z [M] calcd for C21H29NO : 327.2198; found: 327.2208.
2
IR (neat): 2910, 1717, 1166 cm–1
.
1
H NMR (400 MHz, CDCl ): δ = 7.49 (d, J = 6.8 Hz, 2 H), 7.48–7.29 (m,
H), 4.36 (s, 1 H), 2.16 (br s, 2 H), 1.93–1.89 (m, 3 H), 1.78–1.73 (m,
H), 1.58–1.53 (m, 3 H), 1.41 (s, 9 H).
3
Di-tert-butyl (Adamantane-1,3-diyl) Dicarbamate (7n)
3
6
To a solution of 4a (20.7 mg, 0.0695 mmol) in MeOH (1 mL) was add-
ed 10% Pd/C (4 mg) under Ar atmosphere, then the reaction flask was
purged with H (three times). After stirring for 12 h under H atmo-
13
C NMR (100 MHz, CDCl ): δ = 154.2, 137.7, 130.2, 128.8, 128.4, 79.0,
3
2
2
sphere (balloon), the mixture was filtered through Celite® and the fil-
trate was concentrated under reduced pressure. To the residue were
added THF (1 mL), Et N (49 μL, 0.35 mmol), and Boc O (48 μL, 0.21
5
2.0, 48.0, 47.8, 42.5, 40.6, 34.9, 30.5, 28.4.
+
MS (EI): m/z (%) = 359 [M] , 194 (100).
HRMS (EI): m/z [M]+ calcd for C21H29NO S: 359.1919; found:
3
3
2
2
mmol) at 0 °C. After stirring for 3 h at r.t., the reaction was quenched
59.1902.
with saturated aqueous NaHCO at 0 °C and the mixture was extract-
3
ed with EtOAc. The combined organic layers were washed with brine
tert-Butyl (3-Bromoadamantan-1-yl) Carbamate (7k)
and dried over MgSO . Concentration and flash column chromatogra-
4
To a solution of 4k (25.1 mg, 0.0745 mmol) in MeOH (1 mL) was add-
phy (hexane/EtOAc, 8:1) provided 7n.
ed 10% Pd/C (5 mg) under Ar atmosphere, then the reaction flask was
Yield: 18.2 mg (0.0497 mmol, 71%); colorless solid.
purged with H2 (three times). After stirring for 4 h under H atmo-
2
IR (neat): 2910, 1700, 1166 cm–1
.
®
sphere (balloon), the mixture was filtered through Celite and the fil-
1
trate was concentrated under reduced pressure. To the residue were
H NMR (400 MHz, CDCl ): δ = 4.43 (s, 2 H), 2.20 (s, 2 H), 2.10 (s, 2 H),
3
added THF (1 mL), Et N (49 μL, 0.35 mmol), and Boc O (48 μL, 0.21
1.87 (br s, 8 H), 1.57 (s, 2 H), 1.42 (s, 18 H).
3
2
mmol) at 0 °C. After stirring for 3 h at r.t., the reaction was quenched
13
C NMR (100 MHz, CDCl ): δ = 154.2, 78.9, 51.8, 40.8, 35.2, 29.8, 28.4.
3
with saturated aqueous NaHCO at 0 °C and the mixture was extract-
3
+
MS (EI): m/z (%) = 366 [M] , 254 (100).
HRMS (EI): m/z [M]+ calcd for
ed with EtOAc. The combined organic layers were washed with brine
and dried over MgSO . Concentration and flash column chromatogra-
C H N O : 366.2519; found:
20 34 2 4
4
phy (hexane/EtOAc, 15:1) provided 7k.
366.2520.
Yield: 19.6 mg (0.0593 mmol, 79%); colorless solid; mp 97 °C (color-
less crystals, hexane).
tert-Butyl (3-Hydroxyadamantan-1-yl) Carbamate (7o)
IR (neat): 3343, 1698 cm–1
To a solution of 4b (25.3 mg, 0.0686 mmol) in MeOH (1 mL) was add-
ed 10% Pd/C (5 mg) under Ar atmosphere, then the reaction flask was
purged with H2 (three times). After stirring for 6 h under H2 atmo-
sphere (balloon), the mixture was filtered through Celite and the fil-
trate was concentrated under reduced pressure. To the residue were
.
1
H NMR (400 MHz, CDCl ): δ = 4.45 (s, 1 H), 2.55 (s, 2 H), 2.26 (br s,
3
4
H), 2.21 (br s, 2 H), 1.99 (br d, J = 12.2 Hz, 2 H), 1.85 (br d, J = 12.2 Hz,
®
2
H), 1.64 (br s, 2 H), 1.43 (s, 9 H).
13
C NMR (100 MHz, CDCl ): δ = 154.0, 79.2, 63.3, 53.2, 52.7, 47.9, 40.1,
added THF (0.5 mL), 2 M aqueous NaOH (0.5 mL), and Boc O (48 μL,
3
2
34.4, 32.3, 28.4.
0.21 mmol) at 0 °C. After stirring for 16 h at r.t., the mixture was di-
+
+
luted with H O and extracted with EtOAc. The combined organic lay-
MS (EI): m/z (%) = 250 [M – Br] , 213 [M – NHBoc] , 194 (100).
2
ers were washed with brine and dried over MgSO . Concentration and
4
flash column chromatography (hexane/EtOAc, 2:1 to 1:1) provided 7o.
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–G

G
Synthesis
T. Kuga et al.
Paper
Yield: 17.6 mg (0.0678 mmol, 94%); colorless solid; mp 116 °C (color-
(2) (a) Lenda, S.; Mackaek, V. Collect. Czech. Chem. Commun. 1933, 5,
1. (b) Fort, R. C.; Schleyer, P. v. R. Chem. Rev. 1964, 64, 277.
(c) Gunawan, M. A.; Hierso, J.-C.; Poinsot, D.; Fokin, A. A.; Folina,
N. A.; Trachenko, B. A.; Schreiner, P. R. New J. Chem. 2014, 38, 28.
less crystals, CHCl –hexane).
3
IR (neat): 3349, 2913, 1694, 1166 cm–1
.
1
H NMR (400 MHz, CDCl ): δ = 4.45 (s, 1 H), 2.25 (br s, 2 H), 1.91 (s,
3
(3) (a) Wanka, L.; Iqbal, K.; Schreiner, P. R. Chem. Rev. 2013, 113,
2
H), 1.84 (br s, 4 H), 1.67 (m, 5 H), 1.53 (m, 2 H), 1.43 (s, 9 H).
3516. (b) Liu, J.; Obando, D.; Liao, V.; Lifa, T.; Codd, R. Eur. J. Med.
13
C NMR (100 MHz, CDCl ): δ = 154.1, 79.0, 69.3, 53.0, 49.4, 44.1, 40.6,
Chem. 2011, 46, 1949. (c) Lamoureux, G.; Artavia, G. Curr. Med.
Chem. 2010, 17, 2967. (d) Spasov, A. A.; Khamidova, T. V.;
Bugaeva, L. I.; Morozov, I. S. Pharm. Chem. J. 2000, 34, 1.
4) Davis, W. L.; Grunert, R. R.; Haff, R. F.; McGahen, J. W.;
Neumayer, E. M.; Paulshock, M.; Watts, J. C.; Wood, T. R.;
Hermann, E. C.; Hoffmann, C. E. Science 1964, 144, 862.
5) (a) Gerzon, K.; Krumkalns, E. V.; Brindle, R. L.; Marshall, F. J.;
Root, M. A. J. Med. Chem. 1963, 6, 760. (b) Witt, A.; Macdonald,
N.; Kirkpatric, P. Nat. Rev. Drug Discovery 2004, 3, 109. (c) Alam,
S.; Lingenfelter, K. S.; Bender, A. M.; Lindsley, C. W. ACS Chem.
Neurosci. 2017, 8, 1823.
3
34.9, 30.6, 28.4.
+
MS (EI): m/z (%) = 267 [M] , 211 (100).
(
(
+
HRMS (EI): m/z [M] calcd for C15H25NO : 267.1834; found: 267.1817.
3
(1R,2S,3R,5R,7R)-2-Benzyl-5-(benzyloxy)adamantan-1-amine (8c)
To a solution of 6c (34.5 mg, 0.0761 mmol) in AcOH–THF (3:2, 1 mL)
was added activated Zn (25 mg, 0.38 mmol) at 50 °C. After stirring for
6
0
h at 50 °C, the reaction was quenched with 28% aqueous NH OH at
4
°C and the mixture was extracted with CHCl . The combined organ-
3
ic layers were dried over K CO . Concentration and flash column chro-
(6) (a) Villhauer, E. B.; Brinkman, J. A.; Naderi, G. B.; Burkey, B. F.;
Dunning, B. E.; Prasad, K.; Mangold, B. L.; Russell, M. E.; Hughes,
T. E. J. Med. Chem. 2006, 46, 2774. (b) Keating, G. M. Drugs 2014,
2
3
matography (hexane/EtOAc, 1:1 to CHCl /MeOH, 10:1) provided 8c.
3
Yield: 18.0 mg (0.0520 mmol, 68%); colorless oil; [α]D25 +77.8 (c =
74, 587.
0.34, CHCl3).
(
7) For selected examples, see: (a) Jasys, V. J.; Lombardo, F.;
Applenton, T. A.; Bordner, J.; Ziliox, M.; Volkmann, R. A. J. Am.
Chem. Soc. 2000, 122, 466. (b) Jirgensons, A.; Kauss, V.; Kalvinsh,
I.; Gold, M. R. Synthesis 2000, 1709. (c) Forkin, A. A.; Merz, A. M.;
Schwertfeger, H.; Liu, S. L.; Dahl, J. E. P.; Carlson, R. K. M.;
Schreiner, P. R. Synthesis 2009, 909.
IR (neat): 3358 cm–1
.
1
H NMR (400 MHz, CDCl ): δ = 7.38–7.24 (m, 7 H), 7.19–7.17 (m, 3 H),
3
4
1
2
.54 (s, 2 H), 3.06 (dd, J = 12.7, 3.9 Hz, 1 H), 2.52 (dd, J = 12.7, 12.7 Hz,
H), 2.26 (br s, 1 H), 2.04–1.98 (m, 2 H), 1.88 (br s, 1 H), 1.79 (br s,
H), 1.71 (br d, J = 11.1 Hz, 1 H), 1.65–1.43 (m, 8 H).
13
C NMR (100 MHz, CDCl ): δ = 141.2, 139.7, 129.0, 128.3, 127.5,
(8) Recently, few examples of palladium-catalyzed adamantane
methylene C–H functionalization have been reported, see:
(a) Lao, Y.-X.; Wu, J.-Q.; Chen, Y.; Zhang, S.-S.; Li, Q.; Wang, H.
Org. Chem. Front. 2015, 2, 1374. (b) Fan, Z.; Shu, S.; Ni, J.; Yao, Q.;
Zhang, A. ACS Catal. 2016, 6, 769. (c) Larrosa, M.; Heiles, S.;
Becker, J.; Spengler, B.; Hrdina, R. Adv. Synth. Catal. 2016, 358,
3
127.2, 125.8, 74.3, 62.8, 52.9, 51.6, 47.2, 45.0, 40.9, 37.1, 34.7, 33.1,
31.7, 31.1.
+
MS (EI): m/z (%) = 347 [M] , 91 (100).
+
HRMS (EI): m/z [M] calcd for C 4H29NO: 347.2249; found: 347.2244.
2
2163.
(
9) Torres, E.; Fernández, R.; Miquet, S.; Font-Bardia, M.;
Funding Information
Vanderlinden, E.; Naesens, L.; Vázquez, S. ACS Med. Chem. Lett.
2012, 3, 1065.
This work was partly supported by a Grant-in-Aid for Scientific Re-
search on Innovative Areas ‘Advanced Molecular Transformations by
Organocatalysis’ (No. 23105011) from MEXT, ‘Precisely Designed Cat-
alysts with Customized Scaffolding’ (No. JP16H00998) from JSPS, and
Life Science Research (Platform for Drug Discovery, Informatics, and
Structural Life Science) from the Japan Agency for Medical Research
(
(
10) (a) Shibuya, M.; Tomizawa, M.; Suzuki, I.; Iwabuchi, Y. J. Am.
Chem. Soc. 2006, 128, 8412. (b) Shibuya, M.; Sasano, Y.;
Tomizawa, M.; Hamada, T.; Kozawa, M.; Nagahama, N.;
Iwabuchi, Y. Synthesis 2011, 3418. (c) Iwabuchi, Y. Chem. Pharm.
Bull. 2013, 61, 1197.
11) (a) Olah, G. A.; Krishnamurti, R.; Prakash, G. K. S. Synthesis 1990,
and Development (AMED), Japan.
M
n
isitry
of
E
d
u
coaitn
,
Cutler,
S
p
or,ts
Secince
a
n
d
Tech
n
o
lg
y
2(
3
1
0
5
0
1
1aJ)p
a
n
S
o
ecity
o
f
r
hte
P
or
m
o
itn
of
S
ecin
c
e
P
J(1
6
H
0
0
9
9
8)
6
1
46. (b) Messmer, A.; Glléri, D.-C. A. Angew. Chem. 1965, 77,
71. (c) Stetter, H.; Gärtner, J. Chem. Ber. 1966, 99, 925.
(
d) Serguchev, Y. A.; Ponomarenko, M. V.; Lourie, L. F.; Chenega,
Supporting Information
A. N. J. Fluorine Chem. 2013, 123, 207. (e) Jung, M. E.; Lee, G. S.
J. Org. Chem. 2014, 79, 10544.
Supporting information for this article is available online at
https://doi.org/10.1055/s-0036-1591920.
(
12) The Ts- and Bz-esters of oxime 1 underwent Beckmann rear-
rangement without acids.
S
u
p
p
ortioIgnfrm oaitn
S
u
p
p
ortioIgnfrm oaitn
(13) Shibuya, M.; Taniguchi, T.; Takahashi, M.; Ogasawara, K. Tetrahe-
dron Lett. 2002, 43, 4145.
References
(1) New address: Department of Basic Medicinal Sciences, Gradu-
ate School of Pharmaceutical Sciences, Nagoya University, Furo-
cho, Chikusa-ku, Nagoya 464-8601, Japan.
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–G