Adamantyl aziridines via aza-Michael initiated ring closure (aza-MIRC) reaction

Article abstract of DOI:10.1016/j.tet.2017.01.006

An efficient one-pot synthesis of functionalized adamantylaziridines by aza-Michael initiated ring closure (aza-MIRC) reaction of 1-aminoadamantane with α-halogenated Michael acceptors is described. The reaction goes through an aza-Michael intermediate th

Full text of DOI:10.1016/j.tet.2017.01.006

Accepted Manuscript
Adamantyl aziridines via aza-Michael initiated ring closure (aza-MIRC) reaction
Alena I. Fedotova, Tatiana A. Komarova, Alexey R. Romanov, Igor A. Ushakov, Julien
Legros, Jacques Maddaluno, Alexander Yu. Rulev
PII:
S0040-4020(17)30006-6
10.1016/j.tet.2017.01.006
TET 28376
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 1 November 2016
Revised Date: 23 December 2016
Accepted Date: 4 January 2017
Please cite this article as: Fedotova AI, Komarova TA, Romanov AR, Ushakov IA, Legros J, Maddaluno
J, Rulev AY, Adamantyl aziridines via aza-Michael initiated ring closure (aza-MIRC) reaction,
Tetrahedron (2017), doi: 10.1016/j.tet.2017.01.006.
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ACCEPTED MANUSCRIPT
Graphical Abstract
R
H
H
EWG
AdNH2
base
EWG
R
R
EWG
AdNH
N
X
X
Ad

ACCEPTED MANUSCRIPT
Adamantyl aziridines via aza-Michael initiated ring closure (aza-MIRC) reaction
a,b
a
a
c
Alena I. Fedotova, Tatiana A. Komarova, Alexey R. Romanov, Igor A. Ushakov,
b
b
a
Julien Legros, * Jacques Maddaluno, * and Alexander Yu. Rulev *
a
A. E. Favorsky Institute of Chemistry, Siberian Division of the Russian academy of sciences,
Favorsky Str., Irkutsk, 664033, Russia, E-mail: rulev@irioch.irk.ru
1
b
Normandie Univ, INSA Rouen, UNIROUEN, CNRS, COBRA, 76000 Rouen, France, E-mail:
jmaddalu@crihan.fr; julien.legros@univ-rouen.fr
c
National Research Irkutsk State Technical University, Irkutsk 664074, Russia.
Abstract
An efficient one-pot synthesis of functionalized adamantylaziridines by aza-Michael initiated
ring closure (aza-MIRC) reaction of 1-aminoadamantane with α-halogenated Michael acceptors
is described. The reaction goes through an aza-Michael intermediate that undergoes an
intramolecular nucleophilic substitution. Expectedly, high pressure exerts a beneficial influence
in the case of sterically hindered reagents.
Keywords: aza-Michael addition, aziridines, aminoadamantane
Introduction
Nitrogen-bearing heterocycles are structural fragments found in a large variety of natural
products and drugs, explaining why they are regarded as privileged pharmacophores. Aziridines
are no exception and possess pronounced biological activities such as antibacterial, anti-
inflammatory and cytostatic properties have been evidenced for structures exhibiting this pattern.
These three-membered aza-heterocyclic systems are also known to undergo relatively facile ring
opening, a reaction that can pave new routes toward complex polyfunctional natural and
1
,2
biologically active compounds.
On the other hand the adamantyl moiety, and in particular the 1-aminoadamantane
3
4
5
(
amantadine), is found in several modern drugs possessing anti-viral and anti-diabetic
6
properties, generally mediated by their channel-blocking activities. Those are also used for
7
treating neurodegenerative diseases such as Alzheimer's and Parkinson's diseases. Therefore,
one can expect that the fragment-based combination of adamantane and aziridine moieties would
provide derivatives exhibiting new biological activities.
1

ACCEPTED MANUSCRIPT
O
O
OH
O
O
H
H
N
N
HO
N
N
OH
H
H
N
H
O
O
Miraziridine A
NH
NH2
O
HN
Me
NH2
O
HN
N
Me
Memantine
Tromantadine
Figure 1. Some 1-aminoadamantane and aziridine-derived bioactive compounds.
The potential displayed by these pharmacophores prompted us to explore new routes
toward compounds bearing both the aminoadamantyl and aziridine moieties. To the best of our
knowledge, only one approach to such derivatives has been reported by Johnston and co-authors
who showed that the addition of electron-rich azides including adamantyl azide to methyl vinyl
8
ketone gives acetyl aziridines in good yield under relatively mild conditions. One of the most
convenient and general ways toward aziridine derivatives is the domino-reaction of primary
amines as 1,1-binucleophiles with activated olefins containing a good leaving group at the α-
9
position. In this case, an aza-Michael reaction takes place, immediately followed by a
cyclization triggered by an intramolecular nucleophilic substitution (Scheme 1).
Scheme 1. Domino-assembly of the aziridine core
H NR
EWG
H NR
2
2
R
EWG
EWG
N
H
N
R
X
.
X
RNH HX
2
However, such a strategy does not seem to be appropriate when it comes to
adamantylamine that can be regarded as an exceptionally bulky nucleophile. Herein, we describe
the synthesis of adamantylaziridine derivatives based on the addition of 1-aminoadamantane
onto various halogen-bearing Michael acceptors.
2

ACCEPTED MANUSCRIPT
Results and discussion
The simplest access to the target compounds could thus be a tandem sequence involving a
conjugate nucleophilic addition of aminoadamantane followed by an intramolecular substitution
of a halogen leaving group. However, reaction of a very cumbersome nucleophile with Michael
acceptors bearing substituents in the α and/or β positions could appear mostly unrealistic since
9
-12
the aza-Michael reaction is known to be hampered by such substitution patterns.
We thus first
examined the reaction of 1-aminoadamantane with several non-halogenated Michael acceptors,
supposed to be more responsive partners.
Indeed, the activated alkenes 1a-c containing a terminal double bond react readily with 1-
aminoadamantane to give the expected adducts 2a-c (Table 1, entries 1-3). The nature of the
activating group does not affect the selectivity and efficiency of the addition process: in all cases
the reaction proceeds at room temperature and results in the formation of the 1,4-adducts in high
yields.
Table 1. Conjugate addition of 1-aminoadamantane to Michael acceptors
2
1
2
R
R
R
MeOH
EWG
EWG
+
AdNH2
AdNH
1
R
1
a-f
2a-d
Entry
Michael acceptor
Conditions
Product, a
1
2
(Yield, %)
R
R
EWG
1
2
3
4
5
6
7
1a
1b
1c
1d
1d
1e
1f
H
H
H
Me
Me
Me
Ph
H
H
H
H
H
CO Me
CN
rt, 17 h
rt, 17 h
rt, 17 h
rfx, 17 h
2a (79)
2b (82)
2c (92)
0
2
SO Ph
2
CO Me
2
CO Me
rt, 10 kbar, 17 h
rt, 10 kbar, 24 h
rt, 10 kbar, 24 h
2d (28)
2
b
Me
H
CO Me
traces
2
C(O)Me
0
a
b
Isolated yield. Starting ester 1e was recovered only.
Unlike methyl acrylate 1a, the homologous methyl crotonate 1d, bearing an internal
double bond, does not react with 1-aminoadamantane under classical conditions and the starting
materials were recovered after reflux in methanol for 17 hours. High pressure (>10 kbar) is
known to overcome the lack of reactivity of sterically hindered substrates, particularly for this
1
0,11
addition reaction.
Expectedly, the hyperbaric (10 kbar) reaction of aminoadamantane with
methyl crotonate 1d proceeds at room temperature and gives adduct 2d, however in a low 28%
yield (Table 1, entry 5). This result remains worth noting since it provides a particularly bulky
3

ACCEPTED MANUSCRIPT
secondary amine surrounded by quaternary and tertiary substituents. Unfortunately, the
incorporation of a second methyl group at the β-position (methyl senecioate 1e) or the presence
of a terminal aromatic substituent (benzylideneacetone 1f) prevents the amine addition, even
under high pressure (Table 1, entries 6, 7).
We further pursued this study resorting to halogenated electron-deficient alkenes 3. In
this case, the presence of a chloro or a bromo atom in the α-position increases the
2
electrophilicity of the β-sp carbon atom and is, therefore, expected to favor the conjugate
addition. Moreover, these halides behave as good leaving groups and are thus anticipated to
favor the intramolecular nucleophilic substitution.
Initial experiments were run at atmospheric pressure. We observed that 1-
aminoadamantane, similarly to other primary amines, adds efficiently to the halogenated
activated terminal double bond in 3a-c. Thus, the alkenes bearing methoxycarbonyl (3a), acetyl
(3c), or cyano group (3b) gave the target aziridines 5a-c in high yields, however the presence of
additional base was required (Et N: Table 2, entries 1-3). The reaction proceeds easily in protic
3
solvents at room temperature. In contrast to substrates 3a-c, the reaction of bromosulfone 3d
with the amine stops at the aza-Michael adduct 4 (Table 2, entry 4), and all attempts to perform
the ring-closure reaction in a separate step failed in this case.
To our delight, methyl α-chlorocrotonate 3e gives the expected aziridine 5d in good yield
under classical conditions, similarly to unsubstituted acrylates (Table 2, entry 5). The use of
bromine, that has a much weaker electron withdrawing effect and a higher steric hindrance than
chlorine, results in a substantial decrease of reactivity: 1-aminoadamantane does not add to
methyl α-bromocrotonate 3f under the conditions used for terminal alkenes (Table 2, entry 7). It
was shown earlier that the hyperbaric synthesis of aziridinecarboxylates is easily carried out
from β,β-disubstituted bromoacrylates provided that the amines are sufficiently basic and their
1
0
nitrogen atom is sterically available. Comparably, the treatment of methyl α-bromocrotonate 3f
with adamantylamine under 6 kbar forms aziridine 5d (Table 2, entry 6), as a single syn-
diastereomer (vide infra). The moderate yield (44%) of aziridinecarboxylate in this case can be
explained by the occurrence of the competitive oxa-Michael addition of methanol (used as
solvent), giving adduct 6a in 32% yield (Scheme 2). Attempts to avoid this side reaction by
replacing methanol (or ethanol) by non-nucleophilic alcohols (isopropanol or tert-butanol)
remained unsuccessful due to the low solubility of the initial amine in these solvents. Pleasingly,
the 3-bromo-4-phenylbut-3-ene-2-one 3g, absolutely inactive toward amine 1 under classical
conditions, gives, under high pressure, aziridine 5e (39% yield, again as a single syn-
diastereomer) along with 12% of oxa-adduct 6b (Table 2, entries 8, 9; Scheme 2). NMR spectra
4

ACCEPTED MANUSCRIPT
of the crude mixtures suggest that 6a,b are formed as an almost equimolar mixture of
diasteromers.
Table 2. Aziridination of Michael acceptors with 1-aminoadamantane
2
1
2
R
2
R
R
R
AdNH2
Et N
EWG
3
EWG
1
EWG
1
AdNH
R
R
N
X
X
.
Ad
Et N HX
3
4
3
a-h
5a-e
1
2
a
Entry Michael
acceptor
R
R
X
EWG
Conditions
Product b
(yield,%)
1
2
3
4
5
6
7
8
9
3a
3b
3c
3d
3e
3f
H
H
H
H
H
H
H
H
H
H
H
H
Cl
Cl
Br
Br
Cl
Br
Br
Br
Br
CO Me
MeOH, Et N, rt
5a (67)
2
3
CN
EtOH, Et N, rt
5b (58)
5c (82)
4 (81)
3
C(O)Me MeOH, Et N, rt
3
H
SO Ph
EtOH, Et N, rt
2
3
Me
Me
Me
Ph
Ph
CO Me
MeOH, Et N, rt
5d (67)
2
3
CO Me
MeOH, Et N, rt, 6 kbar 5d (44) + 6a (32)
2
3
3f
CO Me
2
EtOH, Et N, rt
3
no reaction
5e (39) + 6b (12)
no reaction
7 (38)
3g
3g
3h
C(O)Me MeOH, rt, 10 kbar
C(O)Me MeOH, Et N, rfx
3
c
1
0
Me Me Br
CO Et
EtOH, rt, 10 kbar
2
a
b
c
The reaction time is 17 h; Isolated yield; The reaction time is 24 h.
Scheme 2. Competitive oxa-Michael reaction
OMe
1
R
EWG
10 kbar
+ MeOH
1
R
EWG
Br
Br
3
f,g
6a,b
1
6
: R = Me, EWG = CO Me (a);
2
1
R = Ph, EWG = C(O)Me (b)
Finally, we carried out the reaction of β,β-disubstituted bromoacrylate 3h with 1-
aminoadamantane. To avoid the transesterification process ethanol was used as solvent. But the
only isolated product turned out to be enoate 7 (38% yield). Its formation can be easily explained
by an initial double bond migration and subsequent substitution of the allylic bromine (Scheme
1
3
3
). Similar transformations proceeding in the presence of strong bases are well known. One can
speculate that the increase of acidity of the methyl allylic protons under high pressure triggers
the double bond migration under the influence of adamantylamine.
5

ACCEPTED MANUSCRIPT
Scheme 3. Reaction of 2-bromo-3-methyl butenoate 3h with 1-aminoadamantane
AdNH2
CO Et
CO Et
2
CO Et
2
2
Br
Br
NHAd
3
h
7
1
The H NMR spectra of aziridines 5a-e exhibit the sharp, well-resolved, signals of three-
3
membered ring. Thus, the J constants of all aziridine protons could be measured with accuracy.
Completed with 2D (NOESY) NMR spectra of 5a-c, these data allowed us to determine
3
unambiguously the relative configuration between protons 2 and 3. The J for cis-aziridine ring
protons reach 6.2-6.6 Hz while these values are known to be in the 2.6-2.8 Hz range for trans-
1
4
2
,3-protons. On these bases, the 2,3-cis configuration was assigned to aziridines 5d,e.
1
Moreover, we have measured the direct coupling constants J(CH) for both methine and
methylene aziridine groups running 2D HSQC experiments. Indeed, these values display
1
5
pronounced stereospecific dependence on the nitrogen lone pair arrangement. Typically, the
1
1
difference between the J (CH) values for the CH moiety reaches 13-15 Hz: the J (CH) values
2
for the cis- and trans-protons belonging to the methylene group of aziridine 5a are 179.7 and
1
65.4 Hz, respectively. This result comes to fully support our conclusions on the stereochemistry
of the aziridines 5 (Figure 2).
NOE
2
.7 Hz
1J(C,H) = 177.9 Hz
H
H
O
1J(C,H) = 165.4 Hz
1J(C,H) = 167.3 Hz
H
N
NOE
NOE
6
.7 Hz
Figure 2. Key NOE interactions and coupling constants for compound 5c
6

ACCEPTED MANUSCRIPT
This stereospecificity suggests that the protonation of the aza-Michael enolate
intermediate occurs in an intermolecular fashion. We believe that the ammonium resulting
directly from the addition is deprotonated by the triethylamine in the medium and that the
+
resulting Et NH acts in turn as the protonating agent for the enolate. These preliminary steps are
3
then followed by a rotation putting the leaving group anti to the amino appendage, allowing the
final formation of aziridines 5 by an intramolecular S 2 that accounts for the observed
N
stereoselectivity (Scheme 4).
Scheme 4. Stereoselective formation of the aziridines 5
Finally, aziridines, by contrast to other cyclic amines, usually exhibit a barrier to nitrogen
1
6
inversion. Therefore, a priori the target aziridines can exist as a mixture of two invertomers. In
this case, the large low-resolved signals of both invertomers in solution at room temperature
1
13
should be observed in both H and C NMR spectra. Only sharp signals were observed in the
NMR spectra of adamantylaziridines 5 suggesting the absence of this inversion due to the
presence of the bulky N-substituent, acting as a conformational anchor.
In conclusion, we have shown that the aza-Michael addition, under both classical and
hyperbaric conditions, followed by intramolecular nucleophilic substitution, allows an efficient
and facile access to adamantylaziridines in one step from adamantylamine and standard α-
halogenated Michael acceptors. The reaction proceeds at room temperature, without catalyst,
leading to the expected heterocycles in good yields. The high-pressure activation reveals itself,
once more here, as a precious tool to overcome the adverse effect of bulkiness in the aza-Michael
addition.
7

ACCEPTED MANUSCRIPT
Experimental
1
13
15
General remarks. H, C, and N NMR spectra were recorded on a Bruker AVANCE 400
MHz (at 400, 100, and 40 MHz, respectively) and Bruker AVANCE 300 MHz (at 300 and 75
MHz, respectively) spectrometers for solution in CDCl . Chemical shifts (
δ
) in ppm are reported
3
1
13
using residual chloroform (7.24 for H and 77.2 for C) as internal reference. The coupling
1
1
constants (J) are given in Hertz. The concerted application of H- H 2D homonuclear
1
13
experiments COSY and NOESY as well as H- C 2D heteronuclear experiments HSQC and
HMBC were used for the distinction of the carbon and proton resonances in all cases. The IR
spectra were measured with Bruker Vertex 70 FT-IR and portable Varian 3100 diamond
ATR/FT-IR instruments. The GC/MS analyses were performed on a Hewlett-Packard HP 5971A
instrument (EI, 70 eV). The silica gel used for flash chromatography was 230-400 Mesh. All
reagents were of reagent grade and were used as such or distilled prior to use. All the solvents
were dried according to standard procedures and freshly distilled prior to use. Haloderivatives
1
7
3
a,b are commercial. 3-Bromobut-3-ene-2-one 3c was prepared as reported previously.
1
8
Bromovinyl phenyl sulfone 3d was prepared according to the known procedure.
General procedure for the reaction of Michael acceptors (1a-c) with adamantylamine
The mixture of 1-aminoadamantane (151 mg, 1 mmol) and Michael acceptor (1a-c) (2 mmol) in
solvent (2 mL) was stirred at room temperature for 17 h. The crude product was purified by
column chromatography (Silica gel, chloroform/methanol 9/1 (for 2a,c); and 95/5 (for 2b)). The
following compounds were prepared according to this procedure.
1
Methyl 3-(adamantan-1-ylamino)propionate 2a. Yellow oil (187 mg, 79%) H NMR (CDCl ,
3
3
6
00 MHz): δ 1.25 (br.s, 1H, NH), 1.48-1.60 (m, 12H, Ad), 1.98-2.05 (m, 3H, Ad), 2.42 (t, J =
1
3
.0 Hz, 2H, CH CO), 2.80 (t, J = 6.0 Hz, 2H, CH N), 3.61 (s, 3H, CH ); C NMR (CDCl , 75
2
2
3
3
MHz): δ 29.6, 36.8, 42.7, 50.4 (Ad), 35.7 (CH CO), 36.0 (CH N), 51.5 (CH ), 173.4 (C=O). IR
2
2
3
-1
(
cm ): ν 1738 (C=O), 3317 (NH). HRMS (ESI, m/z) calcd for C H NO 237.1729; found
14 23 2
2
37.1728.
7
a
3
-(Adamantan-1-ylamino)propionitrile 2b. White solid (168 mg, 82%). m.p. = 48 ºC. Lit.: 48
1
ºC. H NMR (CDCl , 400 MHz): δ 1.00 (br.s, 1H, NH), 1.50-1.70 (m, 12H, Ad), 2.01 (br.s, 3H,
3
13
Ad), 2.40 (t, J = 6.8 Hz, 2H, CH CN), 2.83 (t, J = 6.8 Hz, 2H, CH N); C NMR (CDCl , 100
2
2
3
-1
MHz): δ 20.3 (CH CN), 29.5, 36.6, 42.8, 50.7 (Ad), 36.8 (CH N), 119.0 (CN). IR (cm ): ν 2247
2
2
+
(
CN), 3310 (NH). MS (EI) m/z (relative intensity): m/z (%): 204 (17, M ), 164 (50), 147 (69),
1
9
35 (62), 106 (100), 79 (21). Calcd for C H N : C 76.42; H 9.87; N 13.71. Found: C 76.46; H
13 20 2
.87; N 13.81.
8

ACCEPTED MANUSCRIPT
1
Adamantan-1-yl-(2-benzenesulfonylethyl)amine 2c. Colorless oil (294 mg, 92%). H NMR
CDCl , 400 MHz): δ 1.36 (br.s, 1H, NH), 1.50-1.68 (m, 12H, Ad), 1.98-2.05 (m, 3H, Ad), 2.87-
(
3
3
7
5
.00 (m, 2H, CH N), 3.12-3.37 (m, 2H, CH SO ), 7.42-7.50 (m, 2H, Ar), 7.60-7.68 (m, 1H, Ar),
2 2 2
1
3
.85-7.95 (m, 2H, Ar); C NMR (CDCl , 100 MHz): δ 29.6, 36.7, 42.6, 50.8 (Ad), 34.6 (CH N),
3
2
-1
7.6 (CH SO ), 128.1, 129.4, 133.8, 139.6 (Ph). IR (cm ): ν 1143, 1307 (SO ), 3317 (NH). MS
2
2
2
+
(
EI) m/z (relative intensity): m/z (%): 319 (6, M ), 263 (24), 262 (100), 177 (67), 135 (57), 120
(
82), 93 (46), 77 (74). Calcd for C H NO S: C 67.68; H 7.89; N 4.38; S 10.04. Found: C 67.44;
18
25
2
H 7.90; N 4.31, S 9.78.
Methyl 3-(adamantan-1-ylamino)butanoate 2d: The mixture of aminoadamantane (151 mg, 1
mmol), and methyl crotonate (200 mg, 2 mmol) in methanol (1.0 mL) was placed in a Teflon
reaction vessel and pressurized to 10 kbar at room temperature for 17 h. After that, the pressure
was released and the mixture was concentrated in vacuo. The crude product 2d was purified by
1
column chromatography (Silica gel, eluent Ether). Colorless oil (70 mg, 28%). H NMR (CDCl ,
3
3
2
3
4
3
00 MHz): δ 0.97 (br.s, 1H, NH), 1.08 (d, J = 6.4 Hz, 3H, CH C), 1.50-1.63 (m, 12H, Ad), 1.98-
3
.03 (m, 3H, Ad), 2.26 (dd, J = 15.1, 6.1 Hz, 1H, CH ), 2.36 (dd, J = 15.1, 6.4 Hz, 1H, CH ),
2
2
1
3
.24-3.35 (m, 1H, CH), 3.63 (s, 3H, CH ); C NMR (CDCl , 75 MHz): δ 25.0 (CH ), 29.8, 36.8,
3
3
3
-1
3.2, 51.2 (Ad), 43.2 (CH ), 45.3 (CH), 51.5 (CH O), 173.0 (C=O). IR (cm ): ν 1732 (C=O),
2
3
319 (NH). HRMS (ESI, m/z) calcd for C H NO 252.1964; found 252.1962.
1
5
26
2
General procedure for the synthesis of aziridines (5a-f) and aza-adduct 4:
Under classical conditions. The mixture of 1-aminoadamantane (151 mg, 1 mmol), Michael
acceptor (3a-e) (2 mmol), and triethylamine (111 mg, 1.1 mmol) in the corresponding solvent (2
mL) was stirred at room temperature for 17 h. Then the mixture was concentrated in vacuo. The
crude product was purified by column chromatography (Silica gel, chloroform/methanol 98/2
(
for 4); 9/1 (for 5a), 95/5 (for 5c), ether (for 5d); or Al O , chloroform (for 5b)). The following
2 3
compounds were prepared according to this procedure.
1
Methyl (1-adamantan-1-yl)aziridine-2-carboxylate 5a. Light yellow oil (158 mg, 67%). H
NMR (CDCl , 400 MHz): δ 1.40-1.60 (m, 12H, Ad), 1.86 (dd, J = 2.8, 1.3 Hz, 1H, CH ), 1.92
3
2
(
dd, J = 6.3, 1.3 Hz, 1H, CH ), 1.97-2.05 (m, 3H, Ad), 2.39 (dd, J = 6.3, 2.8 Hz, 1H, CH), 3.65
2
1
3
(
s, 3H, CH ); C NMR (CDCl , 100 MHz): δ 26.2 (CH ), 28.9 (CH), 29.4, 36.6, 40.0, 53.5 (Ad),
3 3 2
15
-1
5
2.2 (CH ), 172.5 (C=O); N NMR (CDCl , 40 MHz): δ -332.4. IR (cm ): ν 1732 (C=O). MS
3 3
+
(
EI) m/z (relative intensity): m/z (%): 235 (7, M ), 136 (12), 135 (100), 107 (15), 93 (23), 79
(
28), 41 (21). Calcd for C H NO : C 71.46; H 8.99; N 5.95. Found: C 71.49; H 8.94; N 5.97.
14
21
2
9

ACCEPTED MANUSCRIPT
(
1-Adamantan-1-yl)-aziridine-2-carbonitrile 5b. White solid (119 mg, 58%), m.p. 48-49 ºC.
1
H NMR (CDCl , 400 MHz): δ 1.40-1.69 (m, 12H, Ad), 1.95-2.05 (m, 2H, CH ), 2.02-2.10 (m,
3
2
1
3
3
H, Ad), 2.24-2.29 (m, 1H, CH); C NMR (CDCl , 100 MHz): δ 15.5 (CH ), 26.4 (CH), 29.4,
3 2
-1
3
6.5, 39.8, 53.8 (Ad), 119.9 (CN). IR (cm ): ν 2245 (CN). MS (EI) m/z (relative intensity): m/z
+
(
%): 319 (6, M ), 263 (24), 262 (100), 177 (67), 135 (57), 120 (82), 93 (46), 77 (74). Calcd for
C H N : C 77.18; H 8.97; N 13.85. Found: C 76.86; H 8.95; N 13.83.
13
18
2
8
1
-(1-Adamantan-1-yl-aziridin-2-yl)ethanone 5c. White solid (180 mg, 82%), m.p. 48-49 ºC.
1
H NMR (CDCl , 400 MHz): δ 1.45-1.56 (m, 9H, Ad), 1.57-1.67 (m, 3H, Ad), 1.81 (dd, J = 2.7,
3
1
.3 Hz, CH, CH ), 1.96-2.00 (m, 1H, CH ), 1.99 (s, 3H, CH ), 2.00-2.07 (m, 3H, Ad), 2.41 (dd, J
2 2 3
1
3
=
6.7, 2.7 Hz, 1H, CH); C NMR (CDCl , 100 MHz): δ 24.8 (CH ), 26.9 (CH ), 29.5, 36.8, 40.3,
3 3 2
1
5
-1
5
3.4 (Ad), 36.7 (CH), 209.4 (C=O); N NMR (CDCl , 40 MHz): δ -320.2. IR (cm ): ν 1700
3
+
(
C=O). MS (EI) m/z (relative intensity): m/z (%): 219 (4, M ), 178 (16), 135 (100), 93 (10), 79
(
31), 67 (14), 41 (22). Calcd for C H NO: C 76.67; H 9.65; N 6.39. Found: C 76.31; H 9.56; N
1
4
21
6
.24.
Methyl (1-adamantan-1-yl)-3-methylaziridine-2-carboxylate 5d. Colorless oil (167 mg,
1
6
1
3
7%). H NMR (CDCl , 300 MHz): δ 1.18 (d, J = 5.5 Hz, 3H, CH CH), 1.37-1.70 (m, 13H, Ad),
3
3
.97-2.10 (m, 3H, Ad), 2.18-2.26 (m, 1H, CHCH ), 2.47 (d, J = 6.6 Hz, 1H, CHC=O), 3.68 (s,
3
1
3
H, CH O); C NMR (CDCl , 75 MHz): δ 14.5 (CH C), 29.4, 38.8, 40.1, 53.5 (Ad), 32.7
3
3
3
-1
(
CHCH ), 34.3 (CHC=O), 52.0 (CH O) 171.5 (C=O). IR (cm ): ν 1748 (C=O). HRMS (ESI,
3
3
m/z) calcd for C H NO 250.1807; found 250.1806.
1
5
24
2
1
Adamantan-1-yl-(2-benzenesulfonyl-2-bromoethyl)amine 4: Yellow oil (324 mg, 81%). H
NMR (CDCl , 400 MHz): δ 1.30 (br. s, 1H, NH); 1.50-1.69 (m, 12H, Ad); 2.03 (br.s, 3H, Ad);
3
3
.10 (dd, J = 13.3, 8.4 Hz, 1H, CH ); 3.50 (dd, J = 13.3, 4.4 Hz, 1H, CH ); 4.80 (dd, J = 8.4, 4.4
2 2
13
Hz, 1H, CH); 7.54-7.58 (m, 2H, C H ); 7.65-7.70 (m, 1H, C H ); 7.92-7.95 (m, 2H, C H ); C
6
5
6
5
6
5
NMR (CDCl , 100 MHz): δ 29.5, 36.5, 42.8, 50.9 (Ad); 42.4 (C-N); 66.7 (C-S); 129.1, 129.9,
3
-1
1
34.6, 135.9 (C H ). IR (cm ): ν 1150, 1310 (SO ); 3325 (N-H). MS, (EI) m/z (relative
6 5 2
+
+
intensity): m/z (%): 399 (1, M + 1); 297(1, M - 1); 342 (18); 340 (18); 164 (100); 135 (95).
Calcd. for C H BrNO S: C 54.27; H 6.07; N 3.52; S 8.05. Found: C 54.44; H 6.21; N 3.55; S
1
8
24
2
7
.94.
Under high pressure: The mixture of 1-aminoadamantane (151 mg, 1 mmol), Michael acceptor
3f-h) (2 mmol), and triethylamine (111 mg, 1.1 mmol) in solvent (2 mL) was placed in a Teflon
(
reaction vessel and pressurized to 10 kbar at room temperature for the corresponding time. After
that, the pressure was released and the mixture was concentrated in vacuo. The crude product
1
0

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was purified by column chromatography (Silica gel, pentane/ether, 9/1 (for 5d, 6a, 7), 7/3 (for
5
e, 6b), The following compounds were prepared according to this procedure.
1
1
-(1-Adamantan-1-yl)-3-phenylaziridin-2-yl)ethanone 5e: Colorless oil (115 mg, 39%). H
NMR (CDCl , 300 MHz): δ 1.50-1.70 (m, 12H, Ad), 1.56 (s, 3H, CH ), 2.00-2.15 (m, 3H, Ad),
3
3
2
.79 (d, J = 6.4 Hz, 1H, CHC(O)), 3.38 (d, J = 6.4 Hz, 1H, CHPh), 7.15-7.27 (m, 3H, Ph), 7.34-
13
7
.38 (m, 2H, Ph); C NMR (CDCl , 75 MHz): δ 28.3 (CH ), 29.5, 36.8, 40.4, 53.4 (Ad), 40.6
3
3
-1
(
CHPh), 44.6 (CHC(O)), 127.4, 128.2, 128.3, 136.9 (Ph), 208.6 (C=O). IR (cm ): ν 1699 (C=O).
HRMS (ESI, m/z) calcd for C H NO 296.2014; found 296.2010.
2
0
26
Methyl 2-bromo-3-methoxybutanoate 6a: Dark brown oil (68 mg, 32%). (53:47) Mixture of
1
two diastereomers. Major isomer: H NMR (CDCl , 300 MHz): δ 1.26 (d, J = 6.2 Hz, 3H, CH ),
3
3
3
.34 (s, 3H, CH O), 3.60-3.75 (m, 1H, CHBr), 3.77 (s, 3H, CH OC(O)), 4.32 (d, J = 6.5 Hz, 1H,
3 3
13
CH); C NMR (CDCl , 75 MHz): δ 16.4 (CH ), 48.2 (CHBr), 53.0 (CH O), 57.4 (CH C(O)),
3
3
3
3
1
7
3
8
7.3 (CHO), 168.8 (C=O). Minor isomer: H NMR (CDCl , 300 MHz): δ 1.33 (d, J = 6.2 Hz,
3
H, CH ), 3.10 (s, 3H, CH O), 3.60-3.75 (m, 1H, CHBr), 3.77 (s, 3H, CH OC(O)), 4.18 (d, J =
3
3
3
13
.3 Hz, 1H, CH ); C NMR (CDCl , 75 MHz): δ 16.7 (CH ), 49.9 (CHBr), 53.1 (CH O), 57.5
3
3
3
-1
(
CH C(O)), 77.5 (CHO), 169.5 (C=O). IR (cm ): ν 1743 (C=O). HRMS (ESI, m/z) calcd for
3
C H BrO 211.9892; found 211.9898.
6
11
3
3
-Bromo-4-methoxy-4-phenylbutan-2-one 6b: Pale yellow oil (31 mg, 12%). (51:49) Mixture
1
of two diastereomers. Major isomer: H NMR (CDCl , 300 MHz): δ 2.37 (s, 3H, CH C(O)), 3.18
3
3
(
s, 3H, CH O), 4.43 (d, J = 7.6 Hz, 1H, CH), 4.55 (d, J = 7.6 Hz, 1H, CHBr), 7.25-7.40 (m, 5H,
3
1
3
Ph); C NMR (CDCl , 75 MHz): δ 28.6 (CH C(O)), 57.3 (CH O), 57.7 (CHBr), 84.1 (CHO),
3
3
3
1
1
2
1
28.1, 128.9, 129.1, 137.3 (Ph), 201.1 (C=O). Minor isomer: H NMR (CDCl , 300 MHz): δ
3
.15 (s, 3H, CH C(O)), 3.26 (s, 3H, CH O), 4.23 (d, J = 9.5 Hz, 1H, CH), 4.52 (d, J = 9.5 Hz,
3
3
1
3
H, CHBr), 7.25-7.40 (m, 5H, Ph); C NMR (CDCl , 75 MHz): δ 26.8 (CH C(O)), 54.4
3
3
-1
(
CH3O), 57.6 (CHBr), 82.7 (CHO), 127.9, 128.7, 129.1, 137.2 (Ph), 201.0 (C=O). IR (cm ): ν
1
720 (C=O). HRMS (ESI, m/z) calcd for C H BrO 258.0106; found 258.0106.
1
1
14
2
1
Ethyl (1-adamantan-1-ylamino)-3-methylbut-3-enoate 7: Colorless oil (105 mg, 38%). H
NMR (CDCl , 300 MHz): δ 1.26 (t, J = 7.2 Hz, 3H, CH CH ), 1.47-1.70 (m, 12H, Ad), 1.77 (s,
3
3
2
3
H, CH ), 1.81 (s, 1H, NH), 2.00-2.05 (m, 3H, Ad), 3.90 (s, 1H, CH), 4.17 (q, J = 7.2 Hz, 2H,
3
1
3
CH ), 4.84-4.87 (m, 1H, CH =), 4.93-4.96 (m, 1H, CH =); C NMR (CDCl , 75 MHz): δ 14.3
2
2
2
3
(
CH CH ), 20.0 (CH C), 29.8, 36.7, 43.1, 51.2 (Ad), 59.3 (CH), 61.1 (CH ), 112.9 (CH =), 144.7
3 2 3 2 2
1
1

ACCEPTED MANUSCRIPT
-1
(
=C), 175.2 (C=O). IR (cm ): ν 1736 (C=O), 3327 (NH). HRMS (ESI, m/z) calcd for C H NO
17 27 2
2
78.2120; found 278.2114.
Acknowledgement
The authors are grateful to the French Ministry of Foreign Affairs for the fellowship of A.F.
program Metchnikov), the CNRS (PICS 6293), and RFBR (Grant N14-03-91051) through joint
program HP2O. Labex SynOrg (ANR-11- LABX-0029), the Region Haute-Normandie, and the
European France (Manche)−England cross-border cooperation program INTERREG IV A “AI-
(
́
CHEM CHANNEL” co-financed by ERDF are also thanked for financial support. Some spectral
and analytical data were obtained using the equipment of the Baykal analytical center for
collective use SB RAS which is also acknowledged.
References and notes
1
2
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14, 7954-8015.
. (a) Spilovska K., Korabecny J., Kral J., Horova A., Musilek K., Soukup O., Drtinova L.,
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G. Curr. Med. Chem. 2010, 17, 2967-2978.
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. Klimochkin Yu. N., Moiseev I. K., Boreko E. I. Khim-Farm. Zh. 1989, 23, 418-421 (in
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(
b) M. K. Indulen, V. A. Kalninya I., Rjazantseva G. M., Bubovitch V. I. Mechanism of antiviral
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. Mahoney J. M., Smith C. R., Johnston J. N. J. Amer. Chem. Soc. 2005, 127, 1354-1355.
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9
Blazewska K. M. Synthesis 2016, 48, 2681-2704.
1
2

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1
0. (a) Rulev A. Yu., Maddaluno J. Eur. J. Org. Chem. 2001, 2001, 2569-2576; (b) Rulev A.
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1
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1
6
1
1
1
5. Yonezawa T., Morishima I., Fukuta K., Ohmori Y. J. Mol. Spectroscopy 1969, 31, 341-345.
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