Lewis acid-mediated azidolysis of 2,3-three membered heterocyclic amines

Article abstract of DOI:10.1016/j.tet.2013.09.045

The Lewis acid-catalyzed regioselective azidolysis of 2,3-three membered heterocyclic amines has been investigated. The results obtained demonstrated that using TMSN₃ as a source of azide, the appropriate choice of Lewis acid allowed to obtain

Full text of DOI:10.1016/j.tet.2013.09.045

Tetrahedron 69 (2013) 9557e9565
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Lewis acid-mediated azidolysis of 2,3-three membered heterocyclic
amines
,
b
a
c
Giuliana Righi a , Giorgio Scotti , Francesco Caruso , Miriam Rossi ,
*
Francesco Mecozzi b, Roberto Antonioletti a, Romina Pelagalli b
,
*
a Institute of Biomolecular ChemistrydCNR c/o Department of Chemistry, “Sapienza” University of Rome, p.le A. Moro 5, 00185 Rome, Italy
b Department of Chemistry, “Sapienza” University of Rome, p.le A. Moro 5, 00185 Rome, Italy
c Vassar College, Department of Chemistry, Poughkeepsie, NY 12604-0484, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 6 May 2013
Received in revised form 3 September 2013
Accepted 16 September 2013
Available online 20 September 2013
The Lewis acid-catalyzed regioselective azidolysis of 2,3-three membered heterocyclic amines has been
investigated. The results obtained demonstrated that using TMSN3 as a source of azide, the appropriate
choice of Lewis acid allowed to obtain different regio- and stereocontrolled precursors of aminoalcoholic
and triaminic sequences. Considering the occurrence of these moieties in the structure of many bi-
ologically active compounds, the present methodologies could represent a powerful tool in organic
synthesis for the preparation of interesting molecules.
Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction
sequence described below: (a) epoxidation of allylic alcohol, (b)
transformation of the hydroxyl function into a good leaving group
Epoxides and aziridines are among the most versatile classes of
compounds in organic chemistry on the basis of their facile nu-
cleophilic ring opening, which generally occurs with inversion of
configuration at the reacting carbon atom, as expected in a SN2-
pathway.1 This reactivity has allowed the easy access to a broad
range of 1,2-difunctionalized organic compounds with two ster-
eocontrolled contiguous chiral centers. In this contest, in the last
years, our considerable research interest has been focused on the
regio- and stereoselective opening of 2-functionalized epoxides
and aziridines, mainly by means of metal halides.2 More recently,
our attention turned to the use of azide as the nucleophile,3 one of
the most popular amine precursors, and connected with a project
aimed at the synthesis of new peptidomimetics as enzyme in-
hibitors,4 2,3-three membered heterocyclic amines were consid-
ered the substrates suitable for our purpose. Their ring opening
would provide diaminoalcohols and triamino fragments, moieties
recurrent in many peptidomimetic protease inhibitors, such as HIV
such as the mesylate, (c) nucleophilic substitution with an amine
(Scheme 1).
Recently, we have briefly reported a Lewis acid-mediated
regioselective azidolysis of 2,3-epoxy amines,13 using TMSN3 as
the source of azide in the presence of three different Lewis acids:
BF3$OEt2 (method A), ZnCl2 (method B), and Ti(O-i-Pr)4 (method C),
which were already successfully employed on 2,3-epoxy alcohols or
esters.14 As shown in Table 1, the appropriate choice of Lewis acid
allowed to direct, when NR2 is a tertiary amine, the regioselectivity
of the ring opening in C-3 or C-2 position. In fact, using A or B
methods the expected 3-azido-2-hydroxy amines 5aef were ob-
tained, whereas using the method C the only isolated products
were the 2-azido-3-hydroxy amines 6aec and 6eef.15
It is of interest to note that the C-2 ring opening observed using
TMSN3/Ti(O-i-Pr)4 (method C) was really unexpected, because the
same reaction conditions applied on 2,3-epoxy alcohols has been
reported to give a high C-3 regioselectivity. Therefore we decided to
prepare the 2,3-epoxy amine 4d with a secondary amine at C-1, to
test whether the presence of a proton on the C-1 heteroatom was
crucial for the course of the reaction.
protease,5 renine,6
g b
-secretase,7 human -secretase (BACE1),8
malarial plasmepsins I and II,9 and in [1,4]-benzodiazepines,10 but
also widespread in natural products, such as (ꢀ)-balanol,11 and its
regioisomer ophiocordin12 (Fig. 1).
The 2,3-three epoxy amines were synthesized in satisfactory
yield from the corresponding allylic alcohols through the
Actually, the latter example (entry 8) showed that the presence
of the proton seemed to be important to direct the regioselectivity
of the nucleophilic attach, since in this case only the C-3 derivative
5d was detected. Evidently, there where different orientations
between the epoxides and the source of nucleophile, namely
TMSN3/Ti(O-i-Pr)4, depending on whether NR2 is a tertiary or
* Corresponding authors. E-mail address: giuliana.righi@cnr.it (G. Righi).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.09.045

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G. Righi et al. / Tetrahedron 69 (2013) 9557e9565
Fig. 1. Examples of molecules containing diaminoalcohol and triamino fragments.
Scheme 1. (a) m-CPBA, CH2Cl2, rt, 97e98%; (b) CH3SO2Cl, Et3N, DMAP, CH2Cl2, rt, 88e95%; (c) R2NH, neat, 50 ꢁC, 70e87%.
Table 1
Lewis acid-catalyzed azidolysis of 2,3-epoxy amines
Entry
Epoxide
Methoda
Main product
Yieldb (%)
1
2
4a
4a
A, B
C
5a
6a
85
82
3
4
4b
4b
A, B
C
5b
6b
94
84
5
6
4c
4c
A, B
C
5c
6c
87
97
7
8
4d
4d
A, B
C
5d
5d
98
94
9
10
4e
4e
A, B
C
5e
6e
92
96
11
12
4f
4f
A, B
C
5f
6f
86
92
a
Method A: TMSN3 (1 mmol), BF3$Et2O (2 mmol), CH2Cl2, rt; method B: TMSN3 (1.2 mmol), ZnCl2 (0.04 mmol), neat, 70 ꢁC; method C: TMSN3 (1.04 mmol), Ti(O-i-Pr)4
(1.84 mmol), benzene, 90 ꢁC.
b
The main product was the only product detected (NMR analysis).
secondary amine. In order to rationalize the experimental evidence
molecular calculations are currently under investigation.
The 2,3-epoxy amines were transformed into the corresponding
2,3-aziridine amines through a well known procedure (Scheme 2).17
Different amines, different substituents R0 on the heterocyclic ring,
and different protecting groups of the aziridine nitrogen were used
to investigate the influence of steric hindrance and electronic effects
on the trends of the reaction.
At this point, the same reaction conditions of azidolysis were
applied to the N-protected aziridine amines and, as described
below, gave different products depending on the reagents used
(Table 2).
However, given the interesting results obtained with 2,3-epoxy
amines and the key role played by the azide moiety as an amine
precursor, we decided to extend our studies on 2,3-aziridine
amines, which could give access to triamino sequences. As noted
for 2,3-epoxy amines, despite the rich literature on the chemistry
of aziridine opening, there are, to the best of our knowledge,
only a few reports16 concerning the ring-opening reactions of
2,3-aziridines amines by the azide group.

G. Righi et al. / Tetrahedron 69 (2013) 9557e9565
9559
Scheme 2. (a) TMSN3, BF3, rt, 74e98%; (b) Ph3P, CH3CN, rt then reflux; (c) (i) for Boc: (Boc)2O, DMAP, CH2Cl2, rt, 65e72%; (ii) for CO2Et: ClCO2Et, Et3N, Et2O, 0 ꢁC, 68%; (iii) for Ts: TsCl,
pyr, ꢀ20 ꢁC, 62%.
Table 2
Lewis acid-catalyzed azidolysis of 2,3-aziridine amines
Entry
1
Aziridine
Methoda
A, B
Main product
Yieldb (%)
82
7a
8a
2
3
7a
7b
C
10a
8b
74
98
A, B
4
5
7b
7c
C
10b
8c
74
86
A, B
6
7
7c
C
10c
8d
92
86
7d
A, B
8
7d
C
10d
92
(continued on next page)

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G. Righi et al. / Tetrahedron 69 (2013) 9557e9565
Table 2 (continued )
Entry
Aziridine
Methoda
A, B
Main product
Yieldb (%)
9
7e
8e
83
10
7e
7f
C
C
9eþ10c
90
11
9f
92
a
Method A: TMSN3 (1 mmol), BF3$Et2O (2 mmol), CH2Cl2, rt; method B: TMSN3 (1.2 mmol), ZnCl2 (0.04 mmol), neat, 70 ꢁC; method C: TMSN3 (1.04 mmol), Ti(O-i-Pr)4
(1.84 mmol), benzene, 90 ꢁC.
b
The major regioisomer was the only product detected (NMR analysis).
The methodologies A (TMSN3/BF3$Et2O) and B (TMSN3/ZnCl2)
led to the expected C-3 attack of the heterocyclic ring and gave the
3-azido-2-amine derivatives in satisfactory yield.18 Note that dur-
ing the work-up, the 2,3-aziridine amines were converted into the
corresponding deprotected derivatives due to the acidic conditions
(see Experimental section).19
On the other hand, when the 2,3-aziridine amines were pro-
tected with the acid stable eCOOEt group, the reactions with the
methodologies A and B still afforded only the protected 3-azido-2-
N-(ethoxycarbonyl)-amino derivative (entry 9).
The ring expansion under the reaction conditions C can be ra-
tionalized via an intramolecular rearrangement (Scheme 3) where
the Lewis acid catalyzes the formation of the incipient tertiary
carbocation on eC(CH3)3 with the elimination of a molecule of
isobutene.21 To justify the overall retention of the stereochemistry,
a possible anchimeric assistance of the piperidine/morpholine ring
can be invoked.22
Unexpectedly, the use of TMSN3/Ti(O-i-Pr)4 on the 2,3-aziridine
N-Boc protected amines 7aed did not afford azide derivatives, but
the substrates were quantitatively converted into the correspond-
ing oxazolidin-2-ones. The observed ring expansion proceeded
with complete regio- and stereo-selectivity, giving only trans-5-
aminomethyl-oxazolidin-2-ones (entries 2, 4, 6, 8).
Scheme 3. Rearrangement of N-Boc aziridine to oxazolidin-2-one.
The regiochemistry of the rearrangement was established by
spinespin decoupling experiments. Instead regarding the stereo-
chemistry of the 4,5-disubstituted oxazolidin-2-ones, the coupling
constant J4,5 values were in all cases in accordance with a trans
relationship (5.0e6.0 Hz).20 To confirm further the trans-stereo-
chemistry of the oxazolidin-2-ones, the molecular structure of the
crystalline 10d was studied by X-ray diffraction. The crystallo-
graphic data are consistent with the structure shown in Fig. 2, or
the inverted one, both confirming the trans-stereochemistry of the
HNeC4eC5eO fragment.
The results seemed to suggest that the course of reaction was
independent of the presence of TMSN3; in fact the same product
was also obtained when the reaction was carried out only with
Ti(O-i-Pr)4, although in a longer time.
Utilizing the ethyl carbamate as protecting group the reaction
led to a mixture of the oxazolidin-2-one and the C-2 opening
product in ratio 1:2 (entry 10). Evidently, the lower ability of the
ethyl group to form the incipient carbocation compared with the
tert-butyl one is responsible for the decrease of the ring expansion,
Fig. 2. X-ray structure of the oxazolidin-2-one 10d.

G. Righi et al. / Tetrahedron 69 (2013) 9557e9565
9561
in favor of the C-2 opening one. When we used the N-tosyl aziridine
amine 7f that cannot make oxazolidinone, the reaction gave ex-
clusively the C-2 opening product (entry 11).
25 ꢁC):
d
¼13.7, 19.1, 33.6, 53.7, 55.9, 56.2, 60.6, 66.5. HRMS m/z
calcd for C10H19NO2þHþ: 186.1494; found 186.1491.
In conclusion, we have developed a Lewis acid-mediated
regioselective azidolysis of 2,3-three membered heterocyclic
amines, using TMSN3 as the source of azide.
The peculiarity of these results is due to the possibility to access
to different aminoalcoholic and triaminic fragments (Fig. 3) simply
by choosing appropriately the Lewis acid and, in the case of azir-
idine, the N-functionalization. The products are generally obtained
in high chemical yields and often without requiring any purification.
2.1.3. Diisopropyl-(3-propyl-oxiranylmethyl)-amine 4c. Colorless oil
(167 mg, 84% yield); Rf¼0.52 (silica gel, EtOAc/hexanes 2:8); IR
(neat): 2960, 2720, 1350, 1230, 1110, 975 cmꢀ1; 1H NMR (300 MHz,
CDCl3, 25 ꢁC):
d
¼0.85 (3H, t, J¼7.1 Hz, CH3), 0.91 (12H, d, J¼6.6 Hz,
4CH3), 1.31e1.48 (4H, m), 2.44 (1H, dd, J¼4.8, 14.5 Hz, CHaN), 2.52
(1H, dd, J¼4.3, 14.5 Hz,, CHbN), 2.55e2.67 (2H, m, CHO), 2.95 (2H,
sept, J¼6.6 Hz, CHisopr); 13C NMR (75.4 MHz, CDCl3, 25 ꢁC):
¼13.7,
d
19.1, 20.4, 20.7, 33.8, 46.8, 48.7, 57.9, 59.4. HRMS m/z calcd for
C
12H25NOþHþ: 200.2014; found 200.2012.
2.1.4. Cyclohexyl-(3-propyl-oxiranylmethyl)-amine 4d. Colorless oil
(146 mg, 74% yield); Rf¼0.22 (silica gel, EtOAc/hexanes 2:8); IR
(neat): 3240, 3070, 2640, 1210, 1030, 860 cmꢀ1; 1H NMR (300 MHz,
CDCl3, 25 ꢁC):
d
¼0.95 (3H, t, J¼6.9 Hz, CH3), 0.97e1.95 (15H, m),
2.38e2.43 (1H, m, CHNHcyclohex), 2.63 (1H, dd, J¼6.0,12.5 Hz, CHaN),
2.75e2.79 (1H, m, CHO), 2.80e2.86 (1H, m, CHO), 2.95 (1H, dd,
13
J¼3.5, 12.5 Hz, CHbN); C NMR (75.4 MHz, CDCl3, 25 ꢁC):
d
¼13.9,
19.3, 24.6, 25.7, 33.0, 33.1, 33.5, 48.0, 56.2, 56.7, 57.7. HRMS m/z
calcd for C12H23NOþHþ: 198.1858; found 198.1854.
Fig. 3. Aminoalcoholic and triaminic fragments accessible with the presented
methodologies.
2.1.5. 1-(3-Cyclohexyl-oxiranylmethyl)-piperidine 4e. Colorless oil
(178 mg, 80% yield); Rf¼0.33 (silica gel, EtOAc/hexanes 3:7); IR
(neat): 3061, 3028, 2960, 1320, 1201, 701 cmꢀ1; 1H NMR (300 MHz,
CDCl3, 25 ꢁC):
d
¼0.92e1.91 (17H, m), 2.27 (1H, dd, J¼6.3, 13.2 Hz,
2. Experimental section
CHaN), 2.31e2.48 (5H, m, CHOþCH2Npiperid), 2.52 (1H, dd, J¼4.0,
13.2 Hz, CHbN), 2.87 (1H, ddd, J¼2.3, 4.0, 6.3 Hz, CHO); 13C NMR
The following compounds 2a and 2b are already known.23
(75.4 MHz, CDCl3, 25 ꢁC):
d
¼23.8, 25.2, 25.3, 25.5, 25.9, 28.6, 29.2,
39.4, 54.5, 55.1, 60.9, 61.1. HRMS m/z calcd for C14H25NOþHþ:
2.1. General procedure for the 2,3-epoxy amines preparation
224.2014; found 224.2009.
To a solution of the appropriate 2,3-epoxy alcohol (1 mmol) in
CH2Cl2 (1.6 mL), Et3N (0.27 mL, 2 mmol) and a catalytic amount of
DMAP were added. After being stirred at 0 ꢁC, methane sulfonyl
chloride (0.08 mL, 1 mmol) was added dropwise. After 2 h (TLC
monitoring), the reaction was quenched with ice cold water, the
organic layers were extracted with CH2Cl2 (20 mL), washed with ice
cold HCl 1 N (5 mL), saturated aqueous NaHCO3 (5 mL, saturated
aqueous), and then brine (15 mL). Organic extracts were dried
(Na2SO4) and then evaporated in vacuo. To the crude mesylate was
then added the suitable amine (2.5 mmol) and the mixture was
stirred at 70 ꢁC for 2 h. After this time the mixture was diluted with
EtOAc (10 mL), washed with brine (5ꢂ3 mL), dried (Na2SO4) and
the solvent removed under reduced pressure. The crude product
was purified by flash chromatography on silica gel (hexane/EtOAc
and/or CHCl3/MeOH).
2.1.6. 4-(3-Cyclohexyl-oxiranylmethyl)-morpholine 4f. Colorless oil
(195 mg, 87% yield); Rf¼0.45 (silica gel, EtOAc/hexanes 1:1); IR
(neat): 3090, 3015, 2970, 1310, 1195, 1050, 711 cmꢀ1 1H NMR
;
(300 MHz, CDCl3, 25 ꢁC):
d
¼0.81e1.35 (6H, m), 1.41e1.92 (5H, m),
2.17 (1H, dd, J¼6.6, 13.1 Hz, CHaN), 2.25e2.43 (5H, m,
CHOþCH2Nmorph), 2.48 (1H, dd, J¼3.7, 13.1 Hz, CHbN), 2.76 (1H, ddd,
J¼2.3, 3.7, 6.1 Hz, CHO), 3.65 (4H, t, J¼4.6 Hz, CH2Omorph); 13C NMR
(75.4 MHz, CDCl3, 25 ꢁC):
d
¼25.2, 25.3, 25.9, 28.6, 29.2, 39.4, 53.7,
54.7, 60.6, 60.7, 66.5. HRMS m/z calcd for C13H23NO2þHþ: 226.1807;
found 226.1804.
2.2. General procedure of the azidolysis
2.2.1. Methodology A. To a stirred solution of the epoxy amine 4
(1 mmol) in dry CH2Cl2 (3 mL) were added dropwise, under argon
atmosphere, TMSN3 (115 mg, 1 mmol) and BF3$OEt2 (283 mg,
0.25 mL, 2 mmol) and the reaction mixture was left stirring at room
temperature. After complete consumption of the substrate (TLC
monitoring), the mixture was diluted with CH2Cl2 (10 mL), washed
with NaHCO3 (3 mL), brine (3ꢂ3 mL), dried (Na2SO4) and the sol-
vent removed under reduced pressure. Often the crude product
was characterized without further purification.
2.1.1. 1-(3-Propyl-oxiranylmethyl)-piperidine
4a. Colorless
oil
(143 mg, 78% yield); Rf¼0.33 (silica gel, EtOAc/hexanes 3:7); IR
(neat): 3040, 2970, 1463, 1240, 1090, 820 cmꢀ1; 1H NMR (300 MHz,
CDCl3, 25 ꢁC):
d
¼0.68 (3H, t, J¼7.4 Hz, CH3), 1.05e1.52 (10H, m), 2.04
(1H, dd, J¼6.4, 13.2 Hz, CHaN), 2.07e2.27 (4H, m, CH2Npiperid), 2.32
(1H, dd, J¼3.9, 13.2 Hz, CHbN), 2.33e2.41 (1H, m, CHO), 2.58 (1H,
ddd, J¼2.2, 3.9, 6.4 Hz, CHO); 13C NMR (75.4 MHz, CDCl3, 25 ꢁC):
d
¼13.4, 18.8, 23.6, 25.4, 33.3, 54.4, 56.0, 56.1, 60.8. HRMS m/z
2.2.2. Methodology B. The epoxy amine 4 (1 mmol), TMSN3
calcd for C11H21NOþHþ: 184.1701; found 184.1698.
(1.2 mmol), and ZnCl2 (0.04 mmol) were stirred at 68 ꢁC for 15 h at
which time an additional of zinc chloride (0.04 mmol) was added.
After a total reaction time of 45 h, the reaction mixture at 20 ꢁC was
treated with THF (0.64 mL), acetic acid (0.064 mL), and HCl concd
(0.027 mL) and then stirred for 30 min. The reaction mixture was
diluted with EtOAc (10 mL) and NaHCO3 (3 mL) and washed with
H2O (4 mL) and the layers were separated. The aqueous phase
was extracted with EtOAc (3ꢂ3 mL). The combined organic
extracts were washed with brine (3ꢂ4 mL), dried (Na2SO4), and
2.1.2. 4-(3-Propyl-oxiranylmethyl)-morpholine 4b. Colorless oil
(130 mg, 70% yield); Rf¼0.40 (silica gel, EtOAc/hexanes 1:1); IR
(neat): 3060, 2980, 2885, 1485, 1380, 1260, 890 cmꢀ1 1H NMR
;
(300 MHz, CDCl3, 25 ꢁC):
d
¼0.87 (3H, t, J¼6.9 Hz, CH3), 1.31e1.52 (4H,
m), 2.23 (1H, dd, J¼6.8,13.1 Hz, CHaN), 2.37e2.57 (4H, m, CH2Nmorph),
2.57e2.67 (2H, m, CHOþCHbN), 2.79 (1H, ddd, J¼2.3, 3.5, 6.8 Hz,
CHO), 3.65 (4H, t, J¼4.7 Hz, CH2Omorph); 13C NMR (75.4 MHz, CDCl3,

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G. Righi et al. / Tetrahedron 69 (2013) 9557e9565
concentrated in vacuo. Often the crude product was characterized
without further purification.
1.5:8.5); IR (neat): 3560, 3020, 2101, 1230 cmꢀ1; 1H NMR (300 MHz,
CDCl3, 25 ꢁC):
d¼0.80 (3H, t, J¼7.0 Hz, CH3), 0.97 (3H, s, CH3), 0.99
(3H, s, CH3),1.01 (3H, s, CH3),1.04 (3H, s, CH3),1.43 (4H, m), 2.75 (2H,
dd, J1¼J2¼4.4 Hz, CH2N), 3.07 (2H, sept, J¼6.7 Hz, CH(CH3)2), 3.40
(2H, m, CHOHþOH), 3.58 (1H, m, CHN3); 13C NMR (75.4 MHz, CDCl3,
2.2.3. Methodology C. A solution of Ti(O-i-Pr)4 (1.84 mmol) and
TMSN3 (1.04 mmol) in benzene (4 mL) was heated at 90 ꢁC for 4 h.
To the heating yellow solution was added epoxy amines 4 (1 mmol)
in benzene (1 mL) and reflux was continued for 0.8e4 h. The so-
lution was then cooled to 0 ꢁC, H2SO4 15% (8.2 mL) was added, and
the mixture was stirred vigorously for 1 h. Upon cooling the re-
action mixture was diluted with EtOAc (10 mL) and NaHCO3 (3 mL)
and washed with H2O (5ꢂ4 mL) and brine (1 mL), and finally dried
(Na2SO4) before removal of the solvent in vacuo. The resulting
product was characterized without further purification.
25 ꢁC):
d
¼13.4, 19.5, 32.1, 53.0, 59.1, 64.8, 66.2, 68.0; HRMS m/z
calcd for C12H26N4OþHþ: 243.2185; found 243.2188.
2.2.10. (3R*,2S*)-3-Azido-1-cyclohexylamino-hexan-2-ol
5d. Pale
yellow oil (method. A or B: 235 mg, 98% yield; method. C: 225 mg,
94% yield); Rf¼0.49 (silica gel, CHCl3/MeOH 9.2:0.8); IR (neat): 3450,
3022, 2112, 1220, 1020 cmꢀ1 1H NMR (300 MHz, CDCl3, 25 ꢁC):
;
d
¼0.95 (3H, t, J¼7.0 Hz, CH3), 1.01e1.85 (15H, m), 2.31e2.55 (1H, m,
CHcyclo), 2.62 (1H, dd, J¼8.9, 12.2 Hz, CHaN), 2.82 (1H, dd, J¼3.6,
12.2 Hz, CHbN), 2.87e3.05 (1H, br s, OH), 3.31e3.45 (1H, m, CHN3),
3.56 (1H, ddd, J¼3.6, 5.3, 8.9 Hz, CHOH); 13C NMR (75.4 MHz, CDCl3,
2.2.4. (3R*,2S*)-3-Azido-1-piperidin-1-yl-hexan-2-ol 5a. Pale yel-
low oil (192 mg, 85% yield); Rf¼0.44 (silica gel, CHCl3/MeOH 9:1); IR
(neat): 3370, 3020, 2115, 1235, 1021 cmꢀ1
;
1H NMR (300 MHz,
25 ꢁC):
d¼13.8, 2.0, 24.9, 25.9, 32.6, 33.4, 33.7, 47.4, 56.6, 65.6, 71.3;
CDCl3, 25 ꢁC):
d¼0.94 (3H, t, J¼6.9 Hz, CH3), 1.24e1.68 (10H, m),
HRMS m/z calcd for C12H24N4OþHþ: 241.2028; found 241.2031.
2.23e2.47 (5H, m, CH2NpiperidþOH), 2.50e2.68 (2H, m, CH2N),
3.34e3.48 (1H, m, CHN3), 3.67 (1H, ddd, J¼5.12, 5.12, 9.58 Hz,
CHOH); 13C NMR (75.4 MHz, CDCl3, 25 ꢁC): 13.8, 19.6, 24.2, 26.1,
32.5, 54.6, 59.9, 65.5, 68.5; HRMS m/z calcd for C11H22N4OþHþ:
227.1872; found 227.1875.
2.2.11. (1R*,2S*)-1-Azido-1-cyclohexyl-3-piperidin-1-yl-propan-2-ol
5e. Pale yellow oil (245 mg, 92% yield); Rf¼0.43 (silica gel, CHCl3/
MeOH 9.6:0.4); IR (neat): 3350, 3020, 2115, 1215, 1050 cmꢀ1 1H
;
NMR (300 MHz, CDCl3, 25 ꢁC):
d
¼0.99e1.38 (6H, m), 1.40e2.12
(11H, m), 2.24e2.86 (6H, m, CH2NpiperidþCH2N), 3.27 (1H, dd,
J1¼J2¼5.9 Hz, CHN3), 3.65 (1H, br s, OH), 3.74e3.94 (1H, m, CHOH);
2.2.5. (2S*,3R*)-2-Azido-1-piperidin-1-yl-hexan-3-ol 6a. Pale yel-
low oil (192 mg, 82% yield); Rf¼0.51 (silica gel, CHCl3/MeOH 9:1); IR
13C NMR (75.4 MHz, CDCl3, 25 ꢁC):
d¼24.1, 25.8, 25.9, 26.1, 26.2,
(neat): 3620, 3020, 2101, 1230, 1141 cmꢀ1
;
1H NMR (300 MHz,
28.7, 30.4, 38.9, 54.6, 60.3, 65.7, 71.5; HRMS m/z calcd for
CDCl3, 25 ꢁC):
d
¼0.95 (3H, t, J¼7.0 Hz, CH3), 1.30e1.68 (10H, m),
C
14H26N4OþHþ: 267.2185; found 267.2186.
2.24e2.57 (6H, m), 2.63 (1H, br s, OH), 3.53 (1H, ddd, J1¼J2¼5.9,
2.8 Hz, CHN3), 3.64e3.76 (1H, m, CHOH); 13C NMR (75.4 MHz,
2.2.12. (1R*,2S*)-2-Azido-1-cyclohexyl-3-piperidin-1-yl-propan-1-ol
CDCl3, 25 ꢁC):
d
¼14.0, 19.0, 23.8, 25.9, 35.6, 55.4, 60.1, 61.8, 73.0;
6e. Pale yellow oil (255 mg, 96% yield); Rf¼0.37 (silica gel, EtOAc/
HRMS m/z calcd for C11H22N4OþHþ: 227.1872; found 227.1877.
hexanes 4:6); IR (neat): 3320, 3010, 2105, 1220 cmꢀ1 1H NMR
;
(300 MHz, CDCl3, 25 ꢁC):
d
¼0.84e1.80 (16H, m), 1.96e2.11 (1H, m),
2.2.6. (3R*,2S*)-3-Azido-1-morpholin-4-yl-hexan-2-ol 5b. Pale yel-
low oil (214 mg, 94% yield); Rf¼0.23 (silica gel, EtOAc/hexanes 3:7);
2.30e2.48 (3H, m, CH2NpiperidþOH), 2.54e2.63 (2H, m, CH2Npiperid),
2.65 (1H, dd, J¼5.8, 13.6 Hz, CHaN), 2.75(1H, dd, J¼4.0, 13.6 Hz,
CHbN), 3.55 (1H, dd, J¼1.9, 8.2 Hz, CHO), 3.58 (1H, ddd, J¼1.9, 4.0,
IR (neat): 3520, 3020, 2112, 1265, 1120 cmꢀ1 1H NMR (300 MHz,
;
CDCl3, 25 ꢁC):
d
¼0.92 (3H, t, J¼7.0 Hz, CH3), 1.20e1.72 (4H, m),
5.8 Hz, CHN3); 13C NMR (75.4 MHz, CDCl3, 25 ꢁC):
d¼23.9, 25.9, 26.0,
2.34e2.50 (5H, m, CH2NmorphþOH), 2.55e2.82 (2H, m, CH2N),
3.33e3.55 (1H, m, CHN3), 3.58e3.89 (5H, m, CH2OmorphþCHOH);
26.3, 28.9, 29.0, 40.6, 55.6, 60.0, 61.0, 77.5; HRMS m/z calcd for
C
14H26N4OþHþ: 267.2185; found 267.2188.
13C NMR (75.4 MHz, CDCl3, 25 ꢁC):
d¼13.6, 19.5, 32.3, 53.5, 59.8,
65.1, 66.7, 68.4; HRMS m/z calcd for C10H20N4O2þHþ: 229.1665;
2.2.13. (1R*,2S*)-1-Azido-1-cyclohexyl-3-morpholin-4-yl-propan-2-
ol 5f. Pale yellow oil (230 mg, 86% yield); Rf¼0.32 (silica gel, EtOAc/
hexanes 1:1); IR (neat): 3520, 3023, 2103, 1285, 1123 cmꢀ1; 1H NMR
found 229.1668.
2.2.7. (2S*,3R*)-2-Azido-1-morpholin-4-yl-hexan-3-ol 6b. Pale yel-
low oil (192 mg, 84% yield); Rf¼0.51 (silica gel, EtOAc/hexanes 2:1);
(300 MHz, CDCl3, 25 ꢁC):
d
¼0.93e1.37 (5H, m), 1.37e1.96 (6H, m),
2.19e2.81 (6H, m, CH2NmorphþCH2N), 3.22 (1H, dd, J1¼J2¼5.7 Hz,
IR (neat): 3520, 3025, 2108, 1290, 1120 cmꢀ1 1H NMR (300 MHz,
;
CHN3), 3.70 (5H, br t, J¼4.9 Hz, CH2OmorphþOH), 3.79 (1H, ddd,
CDCl3, 25 ꢁC):
d
¼0.93 (3H, t, J¼7.0 Hz, CH3), 1.36e1.64 (4H, m), 2.59
J¼4.7, 5.7, 9.3 Hz, CHOH); 13C NMR (75.4 MHz, CDCl3, 25 ꢁC):
¼24.6,
d
(4H, t, J¼4.6 Hz, CH2Nmorph), 2.68 (2H, d, J¼6.0 Hz, CH2N), 3.44e3.60
26.8, 27.9, 32.6, 54.4, 60.3, 65.4, 68.3, 71.2; HRMS m/z calcd for
(2H, m, CHN3þOH), 3.60e3.68 (1H, m, CHOH), 3.70 (4H, t, J¼4.5 Hz,
C
13H24N4O2þHþ: 269.1978; found 269.1982.
13
CH2Omorph); C NMR (75.4 MHz, CDCl3, 25 ꢁC):
d¼13.9, 18.9, 36.1,
54.2, 60.1, 62.2, 66.8, 72.6; HRMS m/z calcd for C10H20N4O2þHþ:
2.2.14. (1R*,2S*)-2-Azido-1-cyclohexyl-3-morpholin-4-yl-propan-1-
ol 6f. Pale yellow oil (192 mg, 92% yield); Rf¼0.37 (silica gel, EtOAc/
hexanes 4:6); IR (neat): 3620, 3020, 2101, 1245, 1120 cmꢀ1; 1H NMR
229.1665; found 229.1669.
2.2.8. (3R*,2S*)-3-Azido-1-diisopropylamino-hexan-2-ol
yellow oil (210 mg, 87% yield); Rf¼0.18 (silica gel, EtOAc/hexanes
1.5:8.5); IR (neat): 3420, 3020, 2109, 1215, 1030 cmꢀ1 1H NMR
(300 MHz, CDCl3, 25 ꢁC):
5c. Pale
(300 MHz, CDCl3, 25 ꢁC):
d
¼0.81e1.39 (5H, m), 1.39e2.09 (6H, m),
2.36e2.95 (6H, m, CH2NmorphþCH2N), 3.28 (1H, dd, J¼2.2, 8.1 Hz,
;
CHOH), 3.55e3.86 (1H, m, CHN3), 3e67 (5H, br t, J¼4.4 Hz, CH2O-
13
d
¼0.89 (3H, t, J¼6.9 Hz, CH3), 0.97 (3H, s,
morphþOH); C NMR (75.4 MHz, CDCl3, 25 ꢁC):
d¼25.7, 25.8, 26.1,
CH3), 0.99 (3H s, CH3), 1.01 (3H, s, CH3), 1.03 (3H, s, CH3), 1.28e1.34
(4H, m), 2.68e2.77 (3H, m, CH2NþOH), 3.07 (2H, sept, J¼6.55 Hz,
CH(CH3)2), 3.42 (1H, ddd, J¼3.0, 5.3, 8.3 Hz, CHN3), 3.60 (1H, m,
28.7, 29.1, 40.7, 54.2, 59.6, 60.6, 66.7, 77.0; HRMS m/z calcd for
C
13H24N4O2þHþ: 269.1978; found 269.1980.
CHOH); 13C NMR (75.4 MHz, CDCl3, 25 ꢁC):
d¼13.8, 18.8, 19.9, 20.7,
2.3. General procedure for the aziridine ring formation
36.2, 46.8, 48.3, 64.5, 71.8; HRMS m/z calcd for C12H26N4OþHþ:
243.2185; found 243.2188.
To a stirred solution of the appropriate azido alcohol 5 (1 mmol)
in dry CH3CN (1 mL), PPh3 (1.2 mmol, 314 mg) was added under N2
atmosphere and the flask equipped with a monitoring device for the
nitrogen release. After 2 h the reaction mixture was heated to the
2.2.9. (2S*,3R*)-2-Azido-1-diisopropylamino-hexan-3-ol
6c. Pale
yellow oil (235 mg, 97% yield); Rf¼0.52 (silica gel, EtOAc/hexanes

G. Righi et al. / Tetrahedron 69 (2013) 9557e9565
9563
reflux temperature and stirred for 12 h or until consumption of the
substrate (TLC monitoring). The solvent was then removed under
reduced pressure, the crude dissolved in cold diethyl ether, filtered,
concentrated and used without any purifications in the subsequent
aziridine nitrogen protection with the suitable protecting groups.
at room temperature for 3 h or until consumption of the substrate
(TLC monitoring). The mixture was then filtered through a Celite
pad and the solvent evaporated under reduced pressure to leave
the crude, which was purified by flash chromatography on silica gel
affording 7e as a light yellow oil (235 mg, 80% yield from 5e);
Rf¼0.30 (silica gel, CHCl3/MeOH 9:1); IR (neat): 3060, 2980, 1725,
2.3.1. General procedure for the Boc protection. Under nitrogen at-
mosphere, the appropriate aziridine 5 (1 mmol) was dissolved in of
dry CH2Cl2 (10 mL). The Boc2O (248 mg, 1.1 mmol) and a catalytic
amount of DMAP were then added and the reaction mixture stirred
at room temperature for 12 h or until consumption of the substrate
(TLC monitoring). The solvent was then evaporated under reduced
pressure to leave the crude, which was purified by flash chroma-
tography on silica gel.
1310, 965 cmꢀ1; 1H NMR (300 MHz, CDCl3, 25 ꢁC):
d
¼0.97e1.12 (5H,
m), 1.16 (3H, t, J¼7.2 Hz, CH3), 1.25e1.71 (12H, m), 2.01e2.07 (1H, m,
CHNazir), 2.11 (1H, dd, J¼6.3, 13.2 Hz, CHaN), 2.37e2.46 (5H, m,
CH2NpiperidþCHNazir), 2.72 (1H, dd, J¼4.2, 13.2 Hz, CHbN), 4.04 (2H,
q, J¼7.2 Hz, OCH2). 13C NMR (75.4 MHz, CDCl3, 25 ꢁC):
¼13.6, 24.9,
d
25.2, 25.4, 29.9, 38.7, 40.9, 43.8, 54.1, 61.0, 61.6, 160.9. HRMS m/z
calcd for C17H30N2O2þHþ: 295.2386; found 295.2382.
2.3.7. Synthesis of (2R*,3R*) N-tosyl-2-(piperidin-1-ylmethyl)-3-
cyclohexyl-aziridine (7f). Under N2 atmosphere, the aziridine 5e
(1 mmol) was dissolved in dry pyridine (1.5 mL) and TsCl (1.1 mmol,
190 mg) was then added. After being stirred at room temperature
for 12 h (TLC monitoring), the reaction was diluted with Et2O
(15 mL) and washed with a saturated solution of CuSO4. The organic
layers were washed with brine, dried over Na2SO4, and then
evaporated in vacuo to leave the crude product that was purified by
flash chromatography on silica gel affording 7f as a light yellow oil
(329 mg, 87% yield from 5e). Rf¼0.35 (silica gel, EtOAc/hexanes
40:60); IR (neat): 3040, 2969, 1710, 1655, 1603, 1234, 965 cmꢀ1; 1H
2.3.2. (2R*,3R*) N-tert-Butoxycarbonyl-2-(piperidin-1-ylmethyl)-3-
propyl-aziridine 7a. Pale yellow oil (220 mg, 78% yield from 5a);
Rf¼0.45 (silica gel, EtOAc/hexanes 6:4); IR (neat): 3060, 2980, 2110,
1718,1312, 980 cmꢀ1; 1H NMR (300 MHz, CDCl3, 25 ꢁC):
d¼0.93 (3H,
t, J¼7.3 Hz, CH3), 1.18e1.32 (2H, m), 1.42 (9H, br s, C(CH3)3),
1.35e1.68 (8H, m), 2.15 (1H, ddd, J¼3.2, 4.9, 5.0 Hz, CHNazir), 2.22
(1H, dd, J¼6.0, 12.5 Hz, CHaN), 2.31 (1H, ddd, J¼3.2, 5.0, 6.0 Hz,
CHNazir), 2.36e2.55 (4H, m, CH2Npiperid), 2.60 (1H, dd, J¼5.0,
12.5 Hz, CHbN). 13C NMR (75.4 MHz, CDCl3, 25 ꢁC):
d
¼13.6, 20.1,
25.6, 27.7, 27.9, 32.7, 40.8, 42.8, 54.3, 60.0, 80.6, 160.4. HRMS m/z
calcd for C16H30N2O2þHþ: 283.2386; found 283.2383.
NMR (300 MHz, CDCl3, 25 ꢁC):
d
¼0.74e1.97 (17H, m), 2.40 (3H, s,
CH3), 2.24e2.70 (6H, m, CH2NpiperidþCHaNþCHNazir), 2.78 (1H, ddd,
J¼4.0, 4.4, 8.2 Hz, CHNazir), 3.04 (1H, dd, J¼3.9, 13.0 Hz, CHbN), 7.27
(2H, d, J¼8.4 Hz, CHarom), 7.81 (2H, d, J¼8.4 Hz, CHarom). 13C NMR
2.3.3. (2R*,3R*) N-tert-Butoxycarbonyl-2-(morpholin-1-ylmethyl)-3-
propyl-aziridine 7b. Pale yellow oil (220 mg, 70% yield from 5b);
Rf¼0.40 (silica gel, EtOAc/hexanes 1:1); IR (neat): 2990, 2975, 2210,
(75.4 MHz, CDCl3, 25 ꢁC):
d
¼21.5, 24.0, 25.3, 25.5, 25.8, 25.9, 30.1,
1725, 1309, 975 cmꢀ1
;
1H NMR (300 MHz, CDCl3, 25 ꢁC):
d¼0.87
30.6, 38.9, 47.1, 53.4, 54.7, 57.3, 127.6, 129.1, 129.2, 143.8. HRMS m/z
(3H, t, J¼7.2 Hz, CH3), 1.03e1.26 (2H, m), 1.36 (9H, br s, C(CH3)3),
1.41e1.75 (2H, m), 2.04e2.18 (1H, m, CHNazir), 2.19e2.31 (1H, m,
CHNazir), 2.32e2.71 (6H, m, CH2NmorphþCH2N), 3.63 (4H, t, J¼4.6 Hz,
calcd for C21H32N2O2SþHþ: 377.2263; found 377.2259.
2.3.8. (1S*,2R*)-2-Azido-1-piperidin-1-ylmethyl-pentylammina
8a. Light yellow oil (method. A or B: 184 mg, 82% yield); Rf¼0.24
(silica gel, CHCl3/MeOH 9.2:0.8, two runs); IR (neat): 3380, 3020,
2115, 1240, 1025, 1009, 860 cmꢀ1; 1H NMR (300 MHz, CDCl3, 25 ꢁC):
CH2Omorph). 13C NMR (75.4 MHz, CDCl3, 25 ꢁC):
d¼13.5, 20.1, 27.7,
32.5, 40.6, 42.4, 53.5, 59.7, 66.6, 80.6, 160.2. HRMS m/z calcd for
C
15H28N2O3þHþ: 285.2178; found 285.2175.
d
¼0.94 (3H, t, J¼7.0 Hz, CH3), 1.31e1.83 (10H, m), 2.34e2.78 (6H, m,
2.3.4. (2R*,3R*) N-tert-Butoxycarbonyl-2-(piperidin-1-ylmethyl)-3-
cyclohexyl-aziridine 7c. Yellow oil (252 mg, 78% yield from 5e);
Rf¼0.40 (silica gel, EtOAc/hexanes 1:1); IR (neat): 3100, 3060, 2975,
CH2NpiperidþCH2N), 3.09 (1H, ddd, J¼4.4, 4.4, 9.0 Hz, CHNH2),
3.35e3.45 (1H, m, CHN3), 3.80 (2H, br s); 13C NMR (75.4 MHz,
CDCl3, 25 ꢁC):
d¼13.7, 19.4, 23.7, 25.2, 32.8, 50.9, 54.7, 60.4, 66.1.
2205, 1725, 1315, 982 cmꢀ1
;
1H NMR (300 MHz, CDCl3, 25 ꢁC):
HRMS m/z calcd for C11H23N5þHþ: 226.2032; found 226.2028.
d
¼0.98e1.31 (4H, m), 1.42 (9H, br s, C(CH3)3), 1.48e1.89 (13H, m),
1.92e2.03 (1H, m, CHNazir), 2.07 (1H, dd, J¼6.7, 13 Hz, CHaN), 2.37
(1H, ddd, J¼3.7, 7.1, 7.1 Hz, CHNazir), 2.48e2.65 (4H, m, CH2Npiperid),
2.78 (1H, dd, J¼4.4, 13 Hz, CHbN). 13C NMR (75.4 MHz, CDCl3, 25 ꢁC):
2.3.9. (4R*,5R*)-5-Piperidin-1-ylmethyl-4-propyl-oxazolidin-2-one
10a. Light yellow oil (method. C: 167 mg, 74% yield); Rf¼0.29 (silica
gel, CHCl3/MeOH 9.6:0.4); IR (neat): 3100, 2850, 1720, 1593, 1465,
d
¼24.4, 25.7, 25.8, 26.1, 27.9, 30.7, 39.5, 39.6, 54.5, 59.5, 80.5, 160.5.
1332, 1210, 830, 750 cmꢀ1 1H NMR (300 MHz, CDCl3, 25 ꢁC):
;
HRMS m/z calcd for C19H34N2O2þHþ: 323.2699; found 323.2696.
d
¼1.04 (3H, t, J¼7.3 Hz, CH3), 1.26e1.95 (10H, m), 2.48e2.98 (6H, m,
CH2NpiperidþCH2N), 3.56e3.74 (1H, m, CHNH), 3.48e3.69 (1H, m,
CHO), 6.50 (1H, br s, NH); 13C NMR (75.4 MHz, CDCl3, 25 ꢁC):
¼13.6,
2.3.5. (2R*,3R*) N-tert-Butoxycarbonyl-2-(morpholin-1-ylmethyl)-3-
cyclohexyl-aziridine 7d. Yellow oil (227 mg, 70% yield from 5f);
Rf¼0.38 (silica gel, EtOAc/hexanes 1:1); IR (neat): 3075, 2980, 2210,
d
18.3, 21.8, 24.9, 36.7, 54.6, 56.3, 61.4, 79.5,158.9; HRMS m/z calcd for
C
12H22N2O2þHþ: 227.1760; found 227.1759.
1720, 1310, 980 cmꢀ1
;
1H NMR (300 MHz, CDCl3, 25 ꢁC):
d
¼1.01e1.35 (6H, m), 1.42 (9H, br s, C(CH3)3), 1.55e1.83 (5H, m),
2.3.10. (1S*,2R*)-2-Azido-1-morpholin-4-ylmethyl-pentylamine
8b. Light yellow oil (method. A or B: 222 mg, 98% yield); Rf¼0.24
(silica gel, CHCl3/MeOH 9.2:0.8, two runs); IR (neat): 3510, 3030,
2110, 1230, 1120, 980, 870 cmꢀ1; 1H NMR (300 MHz, CDCl3, 25 ꢁC):
2.07e2.31 (1H, m, CHNazir), 2.18 (1H, dd, J¼8.5, 12.6 Hz, CHaN),
2.34e2.64 (4H, m, CH2Nmorph), 2.71e2.87 (1H, m, CHNazir), 2.73 (1H,
dd, J¼2.3, 12.6 Hz, CHbN), 3.73 (4H, t, J¼4.6 Hz, CH2Omorph). 13C NMR
(75.4 MHz, CDCl3, 25 ꢁC):
d¼24.9, 25.1, 25.5, 27.3, 29.7, 30.2, 38.7,
d
¼0.92 (3H, t, J¼7.0 Hz, CH3), 1.09e1.66 (4H, m), 2.12e2.67 (6H, m,
38.9, 47.4, 53.1, 58.6, 66.1, 79.8, 159.7. HRMS m/z calcd for
C
CH2NmorphþCH2N), 2.75e3.15 (3H, m, CHNþNH2), 3.25e3.46 (1H,
18H32N2O3þHþ: 325.2491; found 325.2488.
m, CHN3), 3.66 (4H, br t, J¼4.3 Hz, CH2Omorph); 13C NMR (75.4 MHz,
CDCl3, 25 ꢁC):
d¼13.7, 19.5, 32.7, 50.8, 53.9, 60.4, 65.7, 66.8. HRMS
2.3.6. (2R*,3R*) N-Ethoxycarbonyl-2-(piperidin-1-ylmethyl)-3-
cyclohexyl-aziridine 7e. Under N2 atmosphere, the aziridine 5e
(1 mmol) was dissolved in of anhydrous diethyl ether (3 mL). The
Et3N (1.2 mmol,121 mg, 0.2 mL) and ethyl chloroformate (1.2 mmol,
130 mg, 0.1 mL) were then added and the reaction mixture stirred
m/z calcd for C10H21N5OþHþ: 228.1824; found 228.1821.
2.3.11. (4R*,5R*)-5-Morpholin-4-ylmethyl-4-propyl-oxazolidin-2-one
10b. Light yellow oil (method. C: 168 mg, 74% yield); Rf¼0.34 (silica
gel, CHCl3/MeOH 9.2:0.8); IR (neat): 3100, 2860, 1720, 1590, 1460,

9564
G. Righi et al. / Tetrahedron 69 (2013) 9557e9565
1350, 1200, 830 cmꢀ1
;
1H NMR (300 MHz, CDCl3, 25 ꢁC):
d
¼0.92
60% yield); Rf¼0.84 (silica gel, EtOAc/hexanes 4:6); IR (neat): 3060,
(3H, t, J¼7.2 Hz, CH3), 1.26e1.63 (4H, m), 2.19e2.73 (6H, m,
CH2NmorphþCH2N), 3.49 (1H, ddd, J1¼J2¼J3¼6.0 Hz, CHN), 3.65 (4H,
t, J¼4.6 Hz, CH2Omorph), 4.28 (1H, ddd, J1¼J2¼J3¼6.2 Hz, CHO), 6.76
2980, 2100, 1735, 1315, 980 cmꢀ1; 1H NMR (300 MHz, CDCl3, 25 ꢁC):
d
¼1.17 (3H, t, J¼7.1 Hz, CH3), 0.87e1.89 (17H, m), 2.13e2.71 (6H, m,
CH2NpiperidþCH2N), 3. 34 (1H, ddd, J¼1.3, 8.7, 10.2 Hz, CHNH), 3.78
(1H, ddd, J¼1.3, 4.2, 9.1 Hz, CHN3), 4.04 (2H, q, J¼7.2 Hz, CH2O), 4.77
(1H, br s, NH); 13C NMR (75.4 MHz, CDCl3, 25 ꢁC):
d¼13.7, 18.6, 37.3,
54.2, 56.2, 61.6, 66.7, 80.6, 159.3. HRMS m/z calcd for
(1H, br d, J¼10.2 Hz, NH); 13C NMR (75.4 MHz, CDCl3, 25 ꢁC):
¼14.3,
d
C
11H20N2O3þHþ: 229.1552; found 229.1552.
21.5, 24.0, 25.3, 25.5, 25.8, 25.9, 30.1, 30.6,40.2, 54.8, 54.9, 59.0, 60.8,
61.6, 156.5. HRMS m/z calcd for C17H31N5O2þHþ: 338.2556; found
338.2554.
2.3.12. (1S*,2R*)-2-Azido-2-cyclohexyl-1-piperidin-1-ylmethyl-eth-
ylamine 8c. Light yellow oil (method. A or B: 230 mg, 86% yield);
Rf¼0.20 (silica gel, CHCl3/MeOH 4:1); IR (neat): 3430, 3015, 2109,
2.3.18. (1S*,2R*)-2-Azido-1-cyclohexyl-3-piperidin-4-yl-(N-tosyl)-
propylamine 9f. Light yellow oil (method. C: 385 mg, 92% yield);
Rf¼0.84 (silica gel, EtOAc/hexanes 4:6); IR (neat): 3055, 2970, 2098,
1210, 1030, 980, 880 cmꢀ1 1H NMR (300 MHz, CDCl3, 25 ꢁC):
;
d
¼1.18e1.98 (17H, m), 2.08e2.95 (8H, m, CH2NpiperidþCH2NþNH2),
2.98e3.19 (1H, m, CHNH2), 3.48e3.71 (1H, m, CHN3). 13C NMR
1650, 1603, 1235, 1100, 990, 975 cmꢀ1 1H NMR (300 MHz, CDCl3,
;
(75.4 MHz, CDCl3, 25 ꢁC):
d
¼25.6, 25.9, 26.5, 30.9, 31.3, 33.7, 48.3,
25 ꢁC):
d
¼0.72e1.89 (17H, m), 2.40 (3H, s, CH3), 2.42e2.78 (4H, m,
54.1, 61.1, 67.1. HRMS m/z calcd for C14H27N5þHþ: 266.2345; found
CH2Npiperid), 3.08e3.15 (1H, m, CHNH), 3.21 (1H, dd, J¼5.2, 12.4 Hz,
CHaN), 3.31(1H, dd, J¼7.6, 12.4 Hz, CHbN), 3.57e3.56 (1H, m, CHN3),
4.65 (1H, br d, J¼9.7 Hz, NH), 7.28 (2H, d, J¼8.2 Hz, CHarom), 7.71 (2H,
266.22342.
2.3.13. (4R*,5R*)-4-Cyclohexyl-5-piperidin-1-ylmethyl-oxazolidin-2-
one 10c. Light yellow oil (method. C: 245 mg, 92% yield); Rf¼0.32
(silica gel, EtOAc/hexanes 4:1, two runs); IR (neat): 3095, 2855,
d, J¼8.2 Hz, CHarom); 13C NMR (75.4 MHz, CDCl3, 25 ꢁC):
¼21.0, 21.7,
d
24.1, 25.2, 25.3, 25.7, 25.9, 31.1, 31.6, 39.5, 54.7, 58.8, 61.0, 126.7,
130.2, 137.1, 142.1. HRMS m/z calcd for C21H33N5O2SþHþ: 420.2433;
found 420.2430.
2700, 1720, 1595, 1470, 1345, 1210, 810 cmꢀ1 1H NMR (300 MHz,
;
CDCl3, 25 ꢁC):
d
¼1.03e1.94 (17H, m), 2.32e2.51 (4H, m, CH2Npiperid),
2.44 (1H, dd, J¼4.6, 13.5 Hz, CHaN), 2.56 (1H, dd, J¼6.9, 13.6 Hz,
CHbN), 3.22 (1H, dd, J1¼J2¼5.9 Hz, CHNH), 4.40 (1H, ddd, J¼4.7, 5.9,
6.7 Hz, CHO), 7.05 (1H, br s, NH); 13C NMR (75.4 MHz, CDCl3, 25 ꢁC):
Acknowledgements
We thank for financial support MIUR (Ministry of University and
ResearchdRome) (PRIN 2010e2011: Design and stereoselective
synthesis of compounds active toward proteic targets involved in
viral and tumoral pathologies), Italian Ministry for Education,
University and Research in the framework of the Flagship Project
NanoMAX, and US National Science Foundation, through the grant
0521237 for the X-ray diffractometer.
d
¼23.9, 25.5, 25.6, 25.7, 26.0, 28.0, 28.4, 41.9, 55.1, 61.0, 62.7, 78.3,
159.6. HRMS m/z calcd for C15H26N2O2þHþ: 267.2073; found
267.2070.
2.3.14. (1S*,2R*)-2-Azido-2-cyclohexyl-1-morpholin-4-ylmethyl-eth-
ylamine 8d. Light yellow oil (method. A or B: 230 mg, 86% yield);
Rf¼0.15 (silica gel, EtOAc/hexanes 3:1, two runs); IR (neat): 3440,
3020, 2115, 1225, 1020, 980, 850 cmꢀ1 1H NMR (300 MHz, CDCl3,
;
Supplementary data
25 ꢁC):
d
¼0.95e1.32 (5H, m), 1.52e1.93 (6H m), 2.32 (1H, dd, J¼6.3,
12.8 Hz, CHaN), 2.41 (1H, dd, J¼5.3, 12.8 Hz, CHbN), 2.45e2.61 (6H,
m, CH2NmorphþNH2), 3.04 (1H, m, CHNH2), 3.62e3.67 (1H, m,
CHN3), 3.68 (4H, t, J¼4.7 Hz, CH2Omorph). 13C NMR (75.4 MHz, CDCl3,
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2013.09.045.
25 ꢁC):
d¼25.9, 26.0, 26.5, 28.8, 30.9, 39.8, 48.1, 53.8, 62.8, 66.7, 72.6.
References and notes
HRMS m/z calcd for C13H25N5OþHþ: 268.2137; found 268.2135.
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2-one 10d. Yellow solid, mp¼99.8e101.9 (method. C: 247 mg, 92%
yield); Rf¼0.39 (silica gel, CHCl3/MeOH 96:4); IR (neat): 3105, 2900,
2. Righi, G.; Bovicelli, P.; Barontini, M.; Tirotta, I. Green Chem. 2012, 2, 495e502
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2710, 1722, 1601, 1460, 1350, 1200, 850 cmꢀ1 1H NMR (300 MHz,
;
CDCl3, 25 ꢁC):
d
¼1.03e1.47 (6H, m), 1.53e1.86 (5H, m), 2.36e2.72
(6H, m, CH2NmorphþCH2N), 3.23 (1H, dd, J1¼J2¼6.5 Hz, CHNH), 3.65
(4H, t, J¼4.1 Hz, CH2Omorph), 4.40 (1H, ddd, J¼4.1, 5.7, 6.5 Hz, CHO),
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d
¼25.5, 25.6,
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280 mg, 83% yield) Rf¼0.75 (silica gel, EtOAc/hexanes 4:6); IR
(neat): 3060, 2980, 2100, 1730, 1320, 980 cmꢀ1; 1H NMR (300 MHz,
CDCl3, 25 ꢁC):
d
¼1.15 (3H, t, J¼7.1 Hz, CH3), 0.95e1.88 (17H, m),
2.09e2.81 (6H, m, CH2NpiperidþCH2N), 3.38e3.45 (1H, m, CHNH),
3.78 (1H, dd, J¼1.3, 8.5 Hz, CHN3), 4.05 (2H, q, J¼7.2 Hz, CH2O), 4.77
(1H, br d, J¼10.2 Hz, NH); 13C NMR (75.4 MHz, CDCl3, 25 ꢁC):
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d
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61.6, 158.2. HRMS m/z calcd for C17H31N5O2þHþ: 338.2556; found
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