β-Aminocarbonates in Regioselective and Ring Expansion Reactions

Article abstract of DOI:10.1021/acs.joc.7b02609

The reactivity of β-aminocarbonates as anisotropic electrophiles has been investigated with several phenols. Products distribution shows that the regioselectivity of the anchimerically driven alkylation reaction depends on the nucleophiles. The results suggest that in the presence of nucleophiles that are also good leaving groups, the reaction takes place under thermodynamic control favoring the attack on the most sterically hindered carbon of the cyclic aziridinium intermediate. Furthermore, when an enantiomerically pure pyrrolidine-based carbonate was used, the reaction with phenols proceeds via a bicyclic aziridinium intermediate leading to the stereoselective synthesis of optically active 3-substituted piperidines via ring expansion reaction. These results were confirmed both by NMR spectroscopy and X-ray diffraction analysis.

Full text of DOI:10.1021/acs.joc.7b02609

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Article
#-Aminocarbonates in regioselective and ring expansion reactions
Fabio Aricò, Alexander S. Aldoshin, Manuele Musolino, Marco Crisma, and Pietro Tundo
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b02609 • Publication Date (Web): 27 Nov 2017
Downloaded from http://pubs.acs.org on December 1, 2017
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βꢀAminocarbonates in regioselective and ring
expansion reactions
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Fabio Aricò,*,a Alexander S. Aldoshin,a Manuele Musolino,a Marco Crismab and Pietro Tundoa
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a Department of Environmental Sciences, Informatics and Statistics, Ca’ Foscari University, Scientific
Campus Via Torino 155 , 30170 Venezia Mestre, Italy; email: fabio.arico@unive.it
b Institute of Biomolecular Chemistry, Padova Unit, CNR, 35131 Padova, Italy.
Abstract: The reactivity of βꢀaminocarbonates as anisotropic electrophiles has been investigated
with several phenols. Products distribution shows that the regioselectivity of the anchimerically
driven alkylation reaction depends on the nucleophiles. The results suggest that in the presence of
nucleophiles that are also good leaving groups, the reaction takes place under thermodynamic
control favoring the attack on the most sterically hindered carbon of the cyclic aziridinium
intermediate. Furthermore, when an enantiomerically pure pyrrolidineꢀbased carbonate was used,
the reaction with phenols proceeds via a bicyclic aziridinium intermediate leading to the
stereoselective synthesis of optically active 3ꢀsubstituted piperidines via ring expansion reaction.
These results were confirmed both by NMR spectroscopy and Xꢀray diffraction analysis.
Keywords: Carbonate chemistry; Anchimeric effect; Ring expansion reaction; Piperidine;
Stereoselective reactions.
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Introduction
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Chlorineꢀbased chemicals are ubiquitous in the chemical industries leading to the production of
solvents, catalysts, building blocks, pesticides, herbicides, additives, polymers and drugs.1 These
compounds are easily prepared, very stable and highly reactive especially when the chlorine ion can
be released as leaving group, however, they also pose concerns for their environmental and health
impact. It is thus not surprising that also several chemical warfare agents (CWA) incorporate the
chlorine moiety. Poignant examples are the notorious mustard gases (Yperite) bis(2ꢀ
chloroethyl)sulfide and bis(2ꢀchloroethyl)ethylamine that, together with their monochloro
derivatives, are lethal CWAs owing to their vesicant and noxious properties (Figure 1).2 Yperites
toxicity is strictly related to their reactivity, enhanced by the presence of a chlorine moiety that can
be readily eliminated by intramolecular nucleophilic substitution promoted by sulfur/nitrogen
anchimeric effect, to form a cyclic episulfonium/aziridinium ion.2
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Despite their lethal properties, mustard gases have attracted a great interest as versatile
electrophiles in inorganic and organic synthesis3 also employed for the preparation of numerous
pharmaceutical intermediates.4
Over the years, our research has been focusing on designing smart, safer chemicals by retaining
the structural motif encompassing the desired properties while substituting the moiety responsible
of the hazard/toxicity of the molecule. In this view the replacement of a chlorine atom by a
carbonate moiety via dialkyl carbonate (DAC) chemistry5 has led to new green synthetic
approaches for industrially appealing compounds, i.e., linear and cyclic carbamates,6 heterocycles,7
intermediates of cosmetic products and antiꢀinflammatory drugs.8
Recently, it was reported the easy preparation of a new class of organic carbonates named sulfur
and nitrogen mustard carbonates (MCs) after their chlorine analogous compounds (Figure 1).9 MCs
reactivity has been investigated with several nucleophiles both in autoclave (180 °C) in absence of
any base, as well as in neat (150 °C) in the presence of a catalytic amount of a K2CO3 as base.
Reaction mechanism and kinetics have confirmed that these compounds retain the anchimeric effect
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of their mustard gas analogues, without showing any toxic property. Besides, nitrogen MCs have
also been employed in the preparation of new families of azacrowns and polycarbonates.10
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Mustard Gases
Mustard Carbonates
H3C OCO2CH3
H3C
Cl
S
S
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CH3
N
CH3
N
H3C
OCO2CH3
OCO2CH3
H3C
Cl
Cl
Cl
Cl
H3CO2CO
S
S
CH3
N
CH3
N
Cl
H3CO2CO
OCO2CH3
Mustard Carbonates Anchimeric ef fect
CH3
H3C
X
OCO2CH3
CH3OCOO
X
NuH
CH3
Nu
+ CO2 + MeOH
X = NCH3 or S
X
Figure 1. Structure and reactivity of mustard carbonates.
Herein, the reactivity of a new family of nitrogen halfꢀmustard carbonates (HMCs) has been
exploited. Parent alcohols of new HMCs have been selected so that the related aziridinium cyclic
intermediates would be anisotropic electrophiles. Reactions of novel synthesized HMCs with
phenols led to high yielding regioselective, stereoselective and ring expansion reactions for the
preparation of optically active 3ꢀsubstituted piperidines. To the best of our knowledge, the use of
DACs chemistry for the functionalization and subsequent ring expansion reactions of prolinols is
unprecedented.
Results and Discussion
HMCs 1 and 2 have been prepared in good yield by reacting commercially available (rac)ꢀ1ꢀ
dimethylaminoꢀ2ꢀpropanol and (S)ꢀ1ꢀmethylꢀ2ꢀpyrrolidinemethanol, respectively, with DMC in the
presence of K2CO3 via a BAc2 mechanism (Scheme 1). HMC 1 was isolated as a racemic mixture
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while HMC 2 is an enantiomerically pure compound as confirmed by NMR investigation with
optically active shift reagent europium tris[3ꢀ(heptafluoropropylhydroxyl methylene)ꢀ(+)
camphorate].†
CH3 CH3
N
CH3 CH3
N
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H3C
OH
OH
H3C
OCOOCH3
O
K2CO3
r ac 1
(
)-
CH3
N
+
CH3
N
H3C
CH3
O
O
OCOOCH3
(S)-2
Scheme 1. Synthesis of HMCs 1ꢀ2.
The reactivity of HMC 1 was then investigated with a generic nucleophile, i.e., phenol (Scheme
2, Table 1). In a typical reaction, phenol and HMC 1, dissolved into a selected solvent, were
allowed to react in an autoclave in the absence of any base at 180 °C. When the reaction was carried
out in acetonitrile, the substrate was fully converted in two major products, namely the alkylated
derivatives 3 and 4 isolated, both as racemic mixtures, via column chromatography (Table 1).
CH3
O
CH3
O
CH3
N
OH
N
CH3
CH3 CH3
+
3
4
6
CH3
N
OH
O
CH3
O
CH3
N
+
CH3 CH3
CH3
5
CH3
OH
O
CH3
CH
N
O
CH3
3 CH3
OCOOCH3
N
N
+
CH3
CH3
H3C
CH3
tBu
Bu
t
Bu
t
(rac)-1
7
8
CH3
CH3CN, 180 °C
OH
O
CH3
O
CH3
N
N
+
+
CH3
CH3
CH3
tBu
tBu
tBu
tBu
tBu
Bu
t
9
10
CH3
N
OH
O
CH3
O
CH3
N
CH3 CH3
CH3
R
R
R
11 R = OCH3
13 R = Br
12 R = OCH3
14 R = Br
R = OCH3, Br, CN,
NO2
15 R = CN
16 R = CN
17
18
R = NO2
R = NO2
Scheme 2. Synthesis of HMCs 1ꢀ2.
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In these conditions the reaction showed only a minor regioselectivity towards the product 4 as a
result of the preferential attack of the phenol on the less sterically hindered carbon of the cyclic
aziridinium intermediate (Scheme 3).
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Table 1. Autoclave reactions between phenol and half mustard carbonates 1 in various solvents and at
different temperature.a
Selectivityc, (%)
Temp
(°C)
P
t
Conv.b
(%)
Entry
Solvent
(bar)
(h)
3
4
1
2
3
4
5
6
7
Acetonitrile
Toluene
180
180
180
180
120
150
210
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2
18
74
39
20
70
22
6
100
96
40
44
41
0
60
56
59
0
THF
19
30
0
96
100d
Methanol
Acetonitrile
Acetonitrile
Acetonitrile
84
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41
58
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59
5
100
100
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a Reaction conditions: PhOH : HMC 3:1 (CHMC 1 = 3 mg/l); b Calculated via GCꢀMS analysis; с Calculated via NMR
analysis; d 75% of 1ꢀ(N,N)ꢀdimethylamino propanolꢀ2 and 25% of anisol were detected on GCꢀMS.
The effects of the solvent and temperature on the products selectivity have been taken into
consideration (Table 1). The results show that the reaction rate increases in polar solvents (# 1ꢀ3,
Table 1). In methanol, however, formation of products 3 and 4 could not be detected, most probably
as the result of transesterification of HMC 1 with the solvent. Notably, the reaction regioselectivity
is not influenced by changes of polarity of the reaction medium. Furthermore, varying the reaction
temperature from 120 to 210 °C (# 5ꢀ7, Table 1), a significant increase of the reaction rate was
observed, however the regioselectivity remained unaffected.
The influence of different types of catalysts has also been investigated.† The presence of weak
(K2CO3) or strong bases (tBuOK, NaH, DBU), as well as, the amphoteric catalyst hydrotalcite
KW2000 did not result in any evident change of products distribution. Reactions conducted with
both homogenous (CH3COOH) and heterogeneous (Amberlyst 15) acidic catalysts did not yield the
alkylated products 3ꢀ4, most probably as they inhibit the formation of the aziridinium intermediate.
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The effect of the nucleophile on the products distribution was then investigated; differently
4
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substituted phenols were selected considering both steric and electronic factors (Scheme 2, Table
2).
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Table 2. Reactivity of HMC 1 with different nucleophiles
#
Substrate Conv.b
%
Selectivityc %
CH3
N
O
CH3
O
CH3
N
Ar
Ar
H3C CH3
CH3
OH
1
2
3
4
5
6
7
8
100
40 (28)
60 (60)
53 (35)
63 (39)
61 (40)
60 (44)
56 (29)
15 (14)
12 (0)
OH
100
47 (32)
37 (24)
39 (20)
40 (27)
44 (35)
85 (85)
OH
100
tBu
tBu
OH
63
tBu
OH
100
H3CO
OH
OH
OH
100
100
100
Br
NC
88 (74)
O2N
a
b
c
Reaction conditions: ArOH : HMC 1 : 1.2 at 180 °C in CH3CN; Conversion determined via GC-MS analysis,
Calculated via NMR analysis on the crude reaction mixture; isolated yields (%) are given in brackets.
Reaction of HMC 1 with naphthol, mono and diꢀtertꢀbutyl phenol showed a regioselectivity
similar to that of phenol. 2,6ꢀDiꢀtertꢀbutyl phenol was the only substrate not completely converted
into the alkylated products 9 and 10, most probably as a result of the substrate steric hindrance.
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Interestingly, the presence of strong electronꢀwithdrawing substituents, such as the pꢀcyano and
pꢀnitro groups, led to the high regioselective formation of alkylated compounds 15 and 17 derived
from the nucleophilic attack on the most sterically hindred site of the cyclic intermediate.
The regioselectivity observed in this reaction can be elucidated according to extensively explored
rearrangement of βꢀamino alcohols via an aziridinium intermediate that usually involves activation
of the hydroxy group followed by the addition of nucleophiles.11 It has been reported that the ratio
of the products formed by the nucleophilic attack at either the Cꢀ1 or Cꢀ2 position of the aziridinium
intermediate varies according to the nature of the nucleophiles and the presence of substituents on
the nitrogen, but also to the solvents and the temperature of the reaction (Scheme 3).12
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CH CH
3
3
CH CH
3
3
DMC
N
N
H C
3
OH
H C
OCOOCH
3
3
intimate ion pair
CH
H C CH
3
CH
3
3
3
Nu
CH
Nu
CH
3
+ Nu
3
+
Nu
CH
N
CH
3
3
N
CH OCOO
3
N
N
CH
N
CH CH
3
CH CH
3
3
3
CH
3
3
H C
3
2
1
Nu
good leaving group
Nu bad leaving group
Nu
Thermodynamic control
Kinetic control
Scheme 3. Proposed reaction mechanism for the regioselective alkylation of acidic nucleophiles.
In our case study, the HMC 1 due to its anchimeric effect is able to form the aziridinium
intermediate via SNi in neutral condition. The cyclic intermediate is trapped in a intimate ion pair
together with the methoxycarbonate anion, i.e., the leaving group.13 In the presence of phenol, or
nucleophiles with similar moderate acidity, the alkylated products form under kinetic control as the
nucleophiles is not a good leaving group. Thus, the regioselectivity observed (#1ꢀ6; Table 1) is
justified by the preferential attack on the less sterically hindered C2 carbon.
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On the other hand, the presence of a strong electron withdrawing group (#7ꢀ8; Table 1) in the
nucleophile enhances its ability as leaving group. In this case, the reaction proceeds under
thermodynamic control and the attack on the sterically hindered C1 position is favored.
In order to have a further insight on the stereochemistry of the reaction the reactivity of carbonate
pyrrolidine HMC 2 derived from the enantiomerically pure (S)ꢀparent alcohol was then
investigated.
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In this case, reaction of a phenol with HMC 2 could lead to three distinct products, i.e., a
substituted (S)ꢀpyrrolidine and the two enantiomers of the substituted piperidine formed via ring
expansion (Scheme 4). In fact, only the nucleophilic attack on the more sterically hindered tertiary
carbon of the bicyclic aziridinium intermediates would affect the stereogenic center of the
pyrrolidine.
This latter reaction is particularly interesting as might lead to the formation of optically active 3ꢀ
substituted piperdines that are very common building blocks both in natural and bioactive
compounds.14 Several synthetic approaches to these compounds have been reported in the
literature, including hydrogenation of substituted pyridines followed by enantiomeric resolution of
their related ammonium salts,15 enantioselective hydrogenation of tetrahydropyridines,15
diastereoselective alkylation and reduction of oxazolopiperidines and/or the separation of the
diastereomers,16 cyclization of optically active linear azido sulfonate derivatives after reduction of
the azido group17 and enantioselective ring expansion of prolinols.18 Over the years, the latter
synthetic approach led to the efficient synthesis of several C3ꢀsubstituted piperidines including 3ꢀ
haloꢀ, 3ꢀhydroxyꢀ, 3ꢀamino, 3ꢀthio, 3ꢀcyano and 3ꢀarylpiperidines.19
CH3
N
CH3
N
CH3
N
H3C
N
OAr
+
HO Ar
OCO2CH3
(S or R)
OAr
(S)
(S)
Scheme 4. Reaction of HMC 2 with a phenol.
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Scheme 5. Reaction of phenols with HMC 2. Conversion was 100% for all substrates. Products distribution
was calculated via NMR analysis on the reaction crude mixture.
In our case study, a substituted phenol was reacted with HMC 2 in 1:1 mol. ratio at 180 °C in
acetonitrile. Results, reported in Scheme 5, are consistent with the regioselectivity observed for
HMC 1. Alkylation of less acidic nucleophiles led mainly to substituted pyrrolidines (kinetically
controlled reaction). Conversely, more acidic pꢀcyano and pꢀnitro phenol formed preferably the
related piperidines as a result of the thermodynamically controlled mechanism.
Products 19ꢀ27 have been isolated as pure compounds and both NMR spectroscopy and mass
spectrometry have confirmed the proposed structures.†
Ring expansion of Nꢀalkylated prolinols is generally highly stereoselective, however, to the best
of our knowledge this is the first example based on carbonate derivatives. Thus, in order to assess
the stereoselectivity of the reaction, an NMR investigation was firstly carried out. In particular,
slow addition of europium tris[3ꢀ(heptafluoropropylhydroxyl methylene)ꢀ(+) camphorate] to a
chloroformꢀd solution of piperidines 25 or 27, isolated as pure compounds, did not lead to any
peaks splitting in the spectra, indicating the presence of only one enantiomer, at least within the
detection limits of the NMR analysis.
However, having established the enantioselectivity of the ring expansion reaction, the absolute
stereochemistry of the product remained yet to be assessed. Luckily, Nꢀmethylꢀ3ꢀ(4ꢀ
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cyanophenoxy)piperidine 25 gave single crystals amenable to an Xꢀray diffraction analysis, which
unambiguously proved the R configuration of the product.† In the structure (Figure 2), the
piperidine ring adopts a chair conformation, with the O1 and C6 substituents occupying the
equatorial positions. The angle between normals to the average planes of the piperidine and the
phenyl ring is 59.0°.
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Figure 2. XꢀRay diffraction structure of (R)ꢀNꢀmethylꢀ3ꢀ(4ꢀcyanophenoxy)piperidine 25. Anisotropic
displacement ellipsoids are drawn at the 30% probability level.
These results confirm that in case of nucleophiles which could be good leaving groups the
reaction proceeds under thermodynamic control via a stereoselective ring expansion reaction
leading to optically active 3ꢀsubstituted piperidines (Scheme 6).
Scheme 6. Stereoselective ringꢀexpansion reaction of (S)ꢀHMC 2 leading to (R)ꢀNꢀmethylꢀ3ꢀ(4ꢀ
nitrophenoxy)piperidine 27.
An additional experiment was conducted so to assess the thermodynamic behavior of the ringꢀ
expansion reaction when performed in the presence of a nucleophile that can also operate as a good
leaving group. Thus, a pure sample of (S)ꢀ4ꢀ((1ꢀmethylpyrrolidinꢀ2ꢀyl)methoxy)benzonitrile 26
dissolved in acetonitrile was heated at 180 °C in autoclave. Samples taken at time interval showed
an increasing conversion of the substituted (S)ꢀpyrrolidine 26 into the related optically active
piperidine, i.e., (R)ꢀNꢀmethylꢀ3ꢀ(4ꢀcyanophenoxy)piperidine 25 (Scheme 7).† This result is perfectly
in accordance with the proposed thermodynamically controlled mechanism.
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CH3
N
H3C
CN
CN
O
N
N
CH3
O
O
NC
26
(S)-
(R)-25
9
Scheme 7. Thermodynamic behavior of the ringꢀexpansion reaction: conversion of the substituted (S)ꢀ
pyrrolidine 26 into the related (R)ꢀpiperidine 25.
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Conclusions
In summary, alkylation of several substituted phenols via anchimeric effect of nitrogen HMC 1
and 2 has been investigated. A possible mechanism accounting for the reaction regioselectivity has
been proposed. Nucleophiles that are also good leaving group attack preferably the most sterically
hindered carbon as the products are in equilibrium with the aziridinium cyclic intermediate and this
ultimately favors the formation of the most thermodynamically stable compound.
According to the results obtained on the reactivity of HMC 2 with substituted phenols, it was
demonstrated that, when the nucleophile attacks the electrophilic site bearing the stereocenter, the
anchimerically driven alkylation is also stereoselective with inversion of configuration as
demonstrated by the Xꢀray diffraction analysis.
As a result this synthetic approach can be employed for the synthesis of enantiomerically pure 3ꢀ
substituted piperidine via ringꢀexpansion reaction of pyrrolidines. This is quite appealing as the
piperidine moiety is present in numerous alkaloids, biologically active molecules and therapeutic
agents and numerous studies have been devoted to their synthesis especially focusing on the
possibility to control the stereoselectivity of this scaffold.20
Experimental Section
All reagents were purchased by Sigma Aldrich and used without any further purification. Mass
spectra were run on GCꢀMS Agilent Technologies (GC System 6890N Network, Agilent
1
Technologies Mass Selective Detector 5973, capillary column of silica HPꢀ5). H NMR spectra
were recorded at 400 MHz on a Bruker AscendTM 400. The chemical shifts are reported in ppm
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from the solvent resonance as the internal standard (CDCl3: 7.26 ppm) and regarding the
tetramethylsilane (TMS). Data are reported as follows: chemical shift, integration multiplicity (s =
singlet, d = doublet, t = triplet, q = quartet, qui = quintet, sext = sextet, sept = septet, m = multiplet,)
13
and coupling constants (Hz). C NMR spectra were recorded at 100 MHz on a Bruker AscendTM
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400. Chemical shift are reported in ppm from the solvent resonance as internal standard
(CDCl3: 77 ppm).
DIPꢀEIꢀMS spectra were recorded on a largeꢀscale tandem mass spectrometer (Waters AutoSpec 6F
– Organic Synthesis and Mass Spectrometry Lab – University of Mons, Belgium) combining six
sectors of E1B1c1E2c2E3B2c3E4 configuration (E stands for electric sector, B for magnetic sector
and c for collision cell). General conditions were 8 kV accelerating voltage, 70 eV ionizing electron
energy and 200 °C ion source temperature. The PEI samples (1 mg), introduced in small Pyrex
capillaries, were directly introduced into the ion source without any external heating. The ions were
obtained under electron ionization in positive ion mode (200 ꢁA trap current). The full scan mass
spectra were recorded by scanning the field of the first magnetic sector and collecting the ions with
an offꢀaxis photomultiplier detector. Accurate mass measurements were acquired using
perfluorokerosene (PFK) as the internal standard.
General procedure for the synthesis of nitrogen half mustard carbonates HMC 1 and 2. In a
typical experiment, 1ꢀdimethylaminoꢀ2ꢀpropanol or (S)ꢀ(ꢀ)ꢀ1ꢀmethylꢀ2ꢀpyrrolidinemethanol (1.0 eq.
mol), DMC (20.0 eq. mol) and dried potassium carbonate (1.0 mol eq.) were placed into a roundꢀ
bottomed flask equipped with a reflux condenser. While being stirred magnetically, the mixture was
heated at the reflux temperature (90 °C) for 43 and 27 hours respectively. The progress of the
reactions was monitored by GCꢀMS until consumption of the starting amino alcohol. The methanol
formed as byꢀproduct in the transesterification reaction was being removed during the reaction by a
DeanꢀStark apparatus. The reaction mixture was then cooled, filtered and the solvent evaporated
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under vacuum. Half mustard carbonates 1 and 2 were obtained pure and did not need any further
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purification.
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1-(dimethylamino)propan-2-yl methyl carbonate 1. Brown liquid; 62 % yield (9.64 g). GCꢀMS
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Calcd for C7H15NO3 161.2 g.molꢀ1; Found 161.1 g.molꢀ1. HRMS (EI) m/z: [M]+ Calcd for C7H15NO3
1
161.1051; Found 161.1049. H NMR (400 MHz, CDCl3): δ = 1.20 (d, 3H), 2.20 (s, 6H), 2.20 (q,
13
1H), 2.47 (q, 1H), 3.7 (s, 3H), 4.82 (sext, 1H) ppm. C NMR (100 MHz, CDCl3): δ = 18.4, 46.0,
54.5, 64.2, 72.7, 155.4 ppm.
(S)-methyl (1-methylpyrrolidin-2-yl)methyl carbonate 2. Brown liquid; 81 % yield (4.64 g). GCꢀMS
Calcd for C8H15NO3 173.2 g.molꢀ1; Found 173.1 g.molꢀ1. HRMS (EI) m/z: [M]+ Calcd for C8H15NO3
1
173.1051; Found 173.1052. H NMR (400 MHz, CDCl3): δ=1.52ꢀ1.80 (m, 3H), 1.83ꢀ1.94 (m, 1H),
2.15ꢀ2.23 (m, 1H), 2.35 (s, 3H), 2.40ꢀ2.48 (m, 1H), 2.97ꢀ3.04 (m, 1H), 3.71 (s, 3H), 3.98ꢀ4.05 (m,
13
1H), 4.06ꢀ4.12 (m, 1H) ppm. C NMR (100 MHz, CDCl3): δ = 22.9, 28.4, 41.4, 54.7, 57.6, 63.7,
70.1, 155.9 ppm.
Reaction of nitrogen half mustard carbonates 1 with different nucleophiles. In a typical
experiment, a solution of selected nucleophile (1.0 mol eq.) and HMC 1 (1.2 mol eq.) in 100.0 mL
of acetonitrile was placed into a steel autoclave and heated at 180 °C for 5ꢀ24 hours under pressure
while being stirred. The autoclave was then cooled and vented and the solvent was evaporated
under vacuum. The pure products were isolated as pure by column chromatography.
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N,N-dimethyl-2-phenoxypropan-1-amine 3. Reaction time 18 h. The pure compound was obtained
in 28% (96 mg) yield as a brown oil by column chromatography on silica gel using diethyl ether :
methanol (9 : 1) as elution mixture. GCꢀMS Calcd for C11H17NO 179.3 g.molꢀ1; Found 179.1
1
g.molꢀ1. HRMS (EI) m/z: [M]+ Calcd for C11H17NO 179.1310; Found 179.1310. H NMR (400
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MHz, CDCl3): δ = 1.33 (d, 3H), 2.34 (s, 6H), 2.42ꢀ2.49 (m, 1H), 2.64ꢀ2.71 (m, 1H), 4.53 (sext, 1H),
6.92ꢀ6.96 (m, 3H), 7.26ꢀ7.32 (m, 2H) ppm. 13C NMR (100 MHz, CDCl3): δ = 18.4, 46.2, 64.8, 72.0,
116.0, 120.7, 129.5, 157.8 ppm.
N,N-dimethyl-1-phenoxypropan-2-amine 4. The pure compound was obtained in 60 % (204 mg) as
a brown oil by column chromatography on silica gel using diethyl ether : methanol (9 : 1) as
elution mixture. GCꢀMS Calcd for C11H17NO 179.3 g.molꢀ1; Found 179.1 g.molꢀ1. HRMS (EI) m/z:
1
[M]+ Calcd for C11H17NO 179.1310; Found 179.1310. H NMR (400 MHz, CDCl3): δ = 1.18 (d,
3H), 2.40 (s, 6H), 3.00 (sext, 1H), 3.85ꢀ3.91 (m, 1H), 4.05ꢀ4.10 (m, 1H), 6.93ꢀ6.98 (m, 3H), 7.28ꢀ
13
7.33 (m, 2H) ppm. C NMR (100 MHz, CDCl3): δ = 12.5, 41.5, 58.4, 69.8, 114.6, 120.7, 129.4,
158.9 ppm.
N,N-dimethyl-2-(naphthalen-2-yloxy)propan-1-amine 5. The pure compound was obtained in 32%
(138 mg) yield as a brown oil by column chromatography on silica gel using diethyl ether :
methanol (9 : 1) as elution mixture. GCꢀMS Calcd for C15H19NO 229,3 g.molꢀ1; Found 229.1
1
g.molꢀ1. HRMS (EI) m/z: [M]+ Calcd for C15H19NO 229,1466; Found 229.1470. H NMR (400
MHz, CDCl3): δ = 1.31 (d, 3H), 2.29 (s, 6H), 2.42ꢀ2.48 (m, 1H), 2.63ꢀ2.70 (m, 1H), 4.63 (sext, 1H),
13
7.05ꢀ7.13 (m, 2H), 7.21ꢀ7.29 (m, 1H), 7.31ꢀ7.39 (m, 1H), 7.60ꢀ7.71 (m, 3H) ppm. C NMR (100
MHz, CDCl3): δ = 18.3, 46.1, 64.6, 72.0, 108.6, 119.8, 123.6, 126.3, 126.7, 127.6, 129.0, 129.5,
134.6, 155.6 ppm.
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N,N-dimethyl-1-(naphthalen-2-yloxy)propan-2-amine 6. The pure compound was obtained in 32%
(138 mg) yield as a brown oil by column chromatography on silica gel using diethyl ether :
methanol (9 : 1) as elution mixture. GCꢀMS Calcd for C15H19NO 229.3 g.molꢀ1 ; Found 229.1
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g.molꢀ1. HRMS (EI) m/z: [M]+ Calcd for C15H19NO 229,1466; Found 229.1468. H NMR (400
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MHz, CDCl3): δ = 1.13 (d,3H), 2.36 (s, 6H), 3.02 (sext, 1H), 3.90ꢀ3.96 (m, 1H), 4.08ꢀ4.14 (m, 1H),
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7.05ꢀ7.10 (m, 2H), 7.22ꢀ7.30 (m, 1H), 7.32ꢀ7.40 (m, 1H), 7.62ꢀ7.72 (m, 3H) ppm. C NMR (100
MHz, CDCl3): δ = 12.5, 41.5, 58.5, 69.7, 106.7, 119.0, 123.6, 126.4, 126.7, 127.6, 129.0, 129.4,
134.5, 156.8 ppm.
2-(2-(tert-butyl)phenoxy)-N,N-dimethylpropan-1-amine 7. 24 % yield (105 mg) as a brown oil by
column chromatography on silica gel using diethyl ether as elution mixture. GCꢀMS Calcd for
C15H25NO 235.37 g.molꢀ1; Found 235.2 g.molꢀ1. HRMS (EI) m/z: [M]+ Calcd for C15H25NO
1
235.1936; Found 235.1936. HꢀNMR (400 MHz, CDCl3): δ = 1.27ꢀ1.31 (m, 12H); 2.25 (s, 6H);
2.44ꢀ2.62 (m, 2H); 4.54ꢀ4.61 (m, 1H); 6.75ꢀ6.83 (m, 2H); 7.05ꢀ7.09 (m, 1H); 7.20ꢀ7.22 (m, 1H)
ppm. 13CꢀNMR (100 MHz, CDCl3): δ = 17.5, 28.9, 33.8, 45.3, 63.9, 69.9, 111.2, 118.8, 125.8,
125.8, 137.4, 154.9 ppm.
1-(2-(tert-butyl)phenoxy)-N,N-dimethylpropan-2-amine 8. 39 % yield (172 mg) as a brown oil by
column chromatography on silica gel using diethyl ether as elution mixture. GCꢀMS Calcd for
C15H25NO 235.37 g.molꢀ1; Found 235.2 g.molꢀ1. HRMS (EI) m/z: [M]+ Calcd for C15H25NO
1
235.1936; Found 235.1927. HꢀNMR (400 MHz, CDCl3): δ = 1.17 (d, 3H); 1.32 (s, 9H); 2.31 (s,
6H); 2.93ꢀ3.01 (m, 1H); 3.77ꢀ4.06 (m, 2H); 6.80ꢀ6.84 (m, 2H); 7.08ꢀ7.13 (m, 1H); 7.21ꢀ7.23 (m,
13
1H) ppm. CꢀNMR (100 MHz, CDCl3): δ = 13.2, 29.9, 34.8, 41.6, 58.8, 70.2, 112.0, 120.4, 126.7,
127.0, 138.1, 157.6 ppm.
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2-(2,6-di-tert-butylphenoxy)-N,N-dimethylpropan-1-amine 9. The pure compound was obtained in
18 % yield (98 mg) as a brown oil by column chromatography on silica gel using hexane : diethyl
ether (1 : 1) as elution mixture. GCꢀMS Calcd for C19H33NO 291.5 g.molꢀ1; Found 291.3 g.molꢀ1.
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HRMS (EI) m/z: [M]+ Calcd for C19H33NO 291.2562; Found 291.2566. H NMR (400 MHz,
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CDCl3): δ = 0.90 (d, 3H), 1.33 (s, 18H), 2.22 (s, 6H), 2.47 (d, 2H), 4.40 (sext, 1H), 6.80ꢀ6.85 (m,
13
1H), 7.08ꢀ7.12 (m, 2H) ppm. C NMR (100 MHz, CDCl3): δ = 17.7, 32.2, 35.7, 46.6, 65.0, 76.8,
121.6, 126.0, 143.2, 154.8 ppm.
1-(2,6-di-tert-butylphenoxy)-N,N-dimethylpropan-2-amine 10. The pure compound was obtained in
38 % yield (205 mg) as a brown oil by column chromatography on silica gel using hexane : diethyl
ether (1:1) as elution mixture. GCꢀMS Calcd for C19H33NO 291.5 g.molꢀ1; Found 291.2 g.molꢀ1.
HRMS (EI) m/z: [M]+ Calcd for C19H33NO 291.2562; Found 291.2567. 1H NMR (400 MHz,
CDCl3): δ = 1.20 (d, 3H), 1.36 (s, 18H), 2.25 (s, 6H), 3.10 (sext, 1H), 3.64ꢀ3.69 (m, 1H) 3.73ꢀ3.79
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(m, 1H), 6.87ꢀ6.93 (m, 1H), 7.18ꢀ7.20 (m, 1H) ppm. C NMR (100 MHz, CDCl3): δ = 12.9, 32.1,
35.7, 41.6, 58.7, 77.4, 122.8, 126.7, 143.7, 158.1 ppm.
2-(4-methoxyphenoxy)-N,N-dimethylpropan-1-amine 11. The pure compound was obtained in 27%
(107 mg) yield as a brown oil by column chromatography on silica gel using diethyl ether :
methanol (9 : 1) as elution mixture. GCꢀMS Calcd for C12H19NO2 209.3 g.molꢀ1; Found 209.2
1
g.molꢀ1. HRMS (EI) m/z: [M]+ Calcd for C12H19NO2 209.1426; Found 209.1416. H NMR (400
MHz, CDCl3): δ = 1.18 (d, 3H), 2.26 (s, 6H) 2.32ꢀ2.39 (m, 1H), 2.54ꢀ2.60 (m, 1H), 3.69 (s, 3H),
13
4.34 (sext, 1H), 6.71ꢀ6.83 (m, 4H) ppm. C NMR (100 MHz, CDCl3): δ = 18.5, 46.2, 55.7, 64.8,
73.1, 114.6, 117.6, 151.8, 154.0
1-(4-methoxyphenoxy)-N,N-dimethylpropan-2-amine 12. The pure compound was obtained in 44%
(107 mg) yield as a brown oil by column chromatography on silica gel using diethyl ether :
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methanol (9 : 1) as elution mixture. GCꢀMS Calcd for C12H19NO2 209.3 g.molꢀ1; Found 209.2
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g.molꢀ1. HRMS (EI) m/z: [M]+ Calcd for C12H19NO2 209.1414; Found 209.1416. H NMR (400
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(m, 1H), 6.72ꢀ6.82 (m, 4H) ppm. 13C NMR (100 MHz, CDCl3): δ = 12.3, 41.5, 55.7, 58.5, 70.6,
114.6, 115.6, 153.1, 153.9 ppm.
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2-(4-bromophenoxy)-N,N-dimethylpropan-1-amine 13. The pure compound was obtained in 35%
(178 mg) yield as a brown oil by column chromatography on silica gel using Et2O : CH3OH (9 : 1)
as elution mixture. GCꢀMS Calcd for C11H16BrNO 258.15 g.molꢀ1; Found 258.1 g.molꢀ1. HRMS (EI)
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m/z: [M]+ Calcd for C11H16BrNO 257.0415; Found 257.0417. H NMR (400 MHz, CDCl3): 1.20
(d,3H), 2.27 (s, 6H), 2.37ꢀ2.44 (m, 1H), 2.57ꢀ2.64 (m, 1H), 4.45 (sext, 1H), 3.90ꢀ3.96 (m, 1H),
6.71ꢀ6.76 (m, 2H), 7.27ꢀ7.31 (m,2H) ppm. 13C NMR (100 MHz, CDCl3): δ = 18.2, 46.2, 64.7, 72.5,
112.8, 117.8, 132.3, 156.9 ppm.
1-(4-bromophenoxy)-N,N-dimethylpropan-2-amine 14. The pure compound was obtained in 29%
(145 mg) yield as a brown oil by column chromatography on silica gel using Et2O : CH3OH (9 : 1)
as elution mixture. GCꢀMS Calcd for C11H16BrNO 258.15 g.molꢀ1; Found 257.9 g.molꢀ1. HRMS (EI)
m/z: [M]+ Calcd for C11H16BrNO; Found 257.0413. 1H NMR (400 MHz, CDCl3): 1.05 (d,3H), 2.28
(s, 6H), 2.88 (sext, 1H), 3.70ꢀ3.76 (s, 1H), 3.89ꢀ3.95 (m, 1H), 6.70ꢀ6.75 (m, 2H), 7.27ꢀ7.31 (m, 2H)
ppm. 13C NMR (100 MHz, CDCl3): δ = 11.2, 40.5, 57.3, 69.2, 111.9, 115.4, 131.2, 157.0 ppm.
4-(1-(dimethylamino)propan-2-yloxy)benzonitrile 15. Reaction time 7 h. The pure compound was
obtained in 85% (545 mg) yield as a brown oil by column chromatography on silica gel using
diethyl ether : methanol (9 : 1) as elution mixture. GCꢀMS Calcd for C12H16N2O 204.3 g.molꢀ1 ;
1
Found 204.1 g.molꢀ1. HRMS (EI) m/z: [M]+ Calcd for C12H16N2O 204.1267; Found 204.1262. H
NMR (400 MHz, CDCl3): δ = 1.25 (d, 3H), 2.24 (s, 6H), 2.35ꢀ2.42 (m, 1H), 2.56ꢀ2.63 (m, 1H), 4.51
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(sext, 1H), 6.86ꢀ6.92 (m, 2H), 7.46ꢀ7.52 (m, 2H) ppm. 13C NMR (100 MHz, CDCl3): δ = 18.1, 46.2,
64.5, 72.7, 103.7, 116.2, 119.3, 134.0, 161.3 ppm
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4-(2-(dimethylamino)propoxy)benzonitrile 16. The pure compound was obtained in 14% (88 mg)
yield as a brown oil by column chromatography on silica gel using diethyl ether : methanol (9 : 1)
as elution mixture. GCꢀMS Calcd for C12H16N2O 204.3 g.molꢀ1; Found 204.1 g.molꢀ1. HRMS (EI)
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m/z: [M]+ Calcd for C12H16N2O 204.1267; Found 204.1266. H NMR (400 MHz, CDCl3): δ = 1.05
(d, 3H), 2.28 (s, 6H), 2.92 (sext, 1H), 3.78ꢀ3.83 (m, 1H), 3.97ꢀ4.02 (m, 1H), 6.86ꢀ6.92 (m, 2H),
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7.47ꢀ7.53 (m, 2H) ppm. C NMR (100 MHz, CDCl3): δ = 12.0, 41.4, 58.1, 70.3, 104.0, 115.3,
119.2, 133.9, 162.2 ppm.
N,N-dimethyl-2-(4-nitrophenoxy)propan-1-amine 17. The pure compound was obtained in 74%
(312 mg) yield as a brown oil by column chromatography on silica gel using diethyl ether :
methanol (2 : 1) as elution mixture. GCꢀMS Calcd for C11H16N2O3 224.3 g.molꢀ1; Found 224.2
1
g.molꢀ1. HRMS (EI) m/z: [M]+ Calcd for C11H16N2O3 224.1161; Found 224.1163. H NMR (400
MHz, CDCl3): δ = 1.28 (d, 3H), 2.28 (s, 6H), 2.42ꢀ2.48 (m, 1H), 2.62ꢀ2.69 (m, 1H), 4.61 (sext, 1H),
6.88ꢀ6.93 (m, 2H), 8.10ꢀ8.14 (m, 2H) ppm. 13C NMR (100 MHz, CDCl3): δ = 18.1, 46.2, 64.5, 73.2,
115.4, 125.9, 141.2, 163.2 ppm.
Reaction of nitrogen half mustard carbonates 2 with different nucleophiles. In a typical
experiment, a solution of selected nucleophile (1.0 mol eq.) and HMC 2 (1.0 mol eq.) in 100.0 mL
of acetonitrile was placed into a steel autoclave and heated at 180 °C for 5ꢀ24 hours under pressure
while being stirred. The autoclave was then cooled and vented and the solvent was evaporated
under vacuum. The pure products were isolated as pure by column chromatography.
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(R)-1-methyl-3-phenoxypiperidine 19. The pure compound was obtained in 32% (114 mg) yield as a
brown oil by column chromatography on silica gel using methanol as elution mixture. GCꢀMS
Calcd for C12H17NO 191.3 g.molꢀ1; Found 191.1 g.molꢀ1. HRMS (EI) m/z: [M]+ Calcd for C12H17NO
191.1310; Found 191.1309. 1H NMR (400 MHz, CDCl3): δ = 1.35ꢀ1.48 (m, 1H), 1.50ꢀ1.64 (m,
1H), 1.72ꢀ1.82 (m, 1H), 1.89ꢀ1.99 (m, 1H), 2.02ꢀ2.18 (m, 2H), 2.25 (s, 3H), 2.51ꢀ2.60 (m, 1H),
2.84ꢀ2.93 (m, 1H), 2.28ꢀ4.37 (m, 1H),2.81ꢀ6.90 (m, 3H), 7.14ꢀ7.23 (m, 2H) ppm. 13C NMR (100
MHz, CDCl3): δ = 23.0, 29.2, 46.4, 55.5, 59.8, 72.6, 116.0, 120.9, 129.5, 157.6 ppm.
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(S)-1-methyl-2-(phenoxymethyl)pyrrolidine 20. The pure compound was obtained in 46% (164 mg)
yield as a brown oil by column chromatography on silica gel using methanol as elution mixture.
GCꢀMS Calcd for C12H17NO 191.3 g.molꢀ1; Found 191.1 g.molꢀ1. HRMS (EI) m/z: [M]+ Calcd for
1
C12H17NO 191.1310; Found 191.1313. H NMR (400 MHz, CDCl3): δ = 1.70ꢀ1.93 (m, 3H), 2.00ꢀ
2.10 (m, 1H), 2.28ꢀ2.37 (m, 1H), 2.51 (s, 3H), 2.64ꢀ2.72 (m, 1H), 3.10ꢀ3.18 (m, 1H), 3.88ꢀ3.93 (m,
1H), 4.00ꢀ4.05 (m, 1H), 6.91ꢀ7.00 (m, 3H), 7.26ꢀ7.34 (m, 2H) ppm. 13C NMR (100 MHz, CDCl3): δ
= 23.0, 28.8, 41.6, 57.7, 64.4, 70.7, 114.5, 120.7, 129.4, 159.0 ppm.
(R)-1-methyl-3-(naphthalen-2-yloxy)piperidine 21. The pure compound was obtained in 23% (141
mg) yield as a brown oil by column chromatography on silica gel using Et2O: CH3OH 8:2 as elution
mixture. GCꢀMS Calcd for C15H19NO 241.3 g.molꢀ1; Found 241.2 g.molꢀ1. HRMS (EI) m/z: [M]+
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Calcd for C15H19NO 241.1466; Found 241.1461. HꢀNMR (400 MHz, CDCl3): δ = 1.60ꢀ2.33 (m,
7H); 2.41 (s, 3H); 2.72ꢀ2.76 (m, 1H); 3.10ꢀ3.13 (m, 1H); 4.61ꢀ4.66 (m, 1H); 7.17ꢀ7.28 (m, 2H);
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7.33ꢀ7.37 (m, 1H); 7.43ꢀ7.47 (m, 1H); 7.72ꢀ7.80 (m, 3H) ppm. CꢀNMR (100 MHz, CDCl3): δ =
22.7, 29.0, 46.2, 55.4, 59.4, 72.2, 108.6, 119.5, 123.7, 126.3, 126.3, 126.8, 127.6, 129.0, 129.5,
134.5, 155.2 ppm.
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(S)-1-methyl-2-((naphthalen-2-yloxy)methyl)pyrrolidine 22. The pure compound was obtained in
35% (219 mg) yield as a brown oil by column chromatography on silica gel using Et2O : CH3OH
8:2 as elution mixture. GCꢀMS Calcd for C15H19NO 241.3 g.molꢀ1; Found 241.2 g.molꢀ1. HRMS
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=1.65ꢀ2.05 (m, 4H); 2.26ꢀ2.32 (m, 1H); 2.48 (s, 3H); 2.67ꢀ2.70 (m, 1H); 3.09ꢀ3.13 (m, 1H); 3.94ꢀ
3.98 (m, 1H); 4.06ꢀ4.10 (m, 1H); 7.07ꢀ7.11 (m, 2H); 7.23ꢀ7.27 (m, 1H); 7.33ꢀ7.37 (m, 1H); 7.63ꢀ
7.67 (m, 3H) ppm. 13CꢀNMR (100 MHz, CDCl3): δ = 22.9, 28.6, 41.5, 57.7, 64.6, 70.4, 106.7,
118.9, 123.6, 126.4, 126.8, 127.6, 134.5, 156.8 ppm.
(R)-3-(4-bromophenoxy)-1-methylpiperidine 23. The pure compound was obtained in 37% (262
mg) yield as a brown oil by column chromatography on silica gel using methanol as elution
mixture. GCꢀMS Calcd for C12H16BrNO 270.2 g.molꢀ1; Found 270.0 g.molꢀ1. HRMS (EI) m/z: [M]+
Calcd for C12H16BrNO 271.0394; Found 271.0395. 1H NMR (400 MHz, CDCl3): δ = 1.36ꢀ1.47
(m, 1H), 1.52ꢀ1.64 (m, 1H), 1.72ꢀ1.82 (m, 1H), 1.86ꢀ1.95 (m, 1H), 2.05ꢀ2.19 (m, 2H), 2.25 (s, 3H),
2.50ꢀ2.60 (m, 1H), 2.80ꢀ2.89 (m, 1H), 4.24ꢀ4.32 (m, 1H), 6.73ꢀ6.77 (m, 2H), 7.26ꢀ7.30 (m, 2H)
ppm. 13C NMR (100 MHz, CDCl3): δ = 22.8, 29.0, 46.3, 55.4, 59.5, 72.9, 113.0, 117.7, 132.3, 156.6
ppm.
(S)-2-((4-bromophenoxy)methyl)-1-methylpyrrolidine 24. The pure compound was obtained in 54%
(374 mg) yield as a brown oil by column chromatography on silica gel using methanol as elution
mixture. GCꢀMS Calcd for C12H16BrNO 270.2 g.molꢀ1; Found 270.0 g.molꢀ1. HRMS (EI) m/z: [M]+
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Calcd for C12H16BrNO 271.0400; Found 271.0394. H NMR (400 MHz, CDCl3): δ = 1.59ꢀ1.85 (m,
3H), 1.89ꢀ2.00 (m, 1H), 2.19ꢀ2.28 (m, 1H), 2.41 (s, 3H), 2.55ꢀ2.62 (m, 1H), 3.02ꢀ3.08 (m, 1H),
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3.75ꢀ3.81 (m, 1H), 3.86ꢀ3.91 (m, 1H), 6.70ꢀ6.74 (m, 2H), 7.26ꢀ7.32 (m, 2H) ppm. C NMR (100
MHz, CDCl3): δ = 23.0, 28.6, 41.7, 57.7, 64.3, 71.0, 112.9, 116.3, 132.2, 158.1 ppm.
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(R)-N-methyl-3-(4-cyanophenoxy)piperidine 25. The pure compound was obtained in 56% (318 mg)
yield as a brown oil by column chromatography on silica gel using methanol as elution mixture.
GCꢀMS Calcd for C13H16N2O 216.3 g.molꢀ1; Found 216.0 g.molꢀ1. HRMS (EI) m/z: [M]+ Calcd for
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C13H16N2O 216.1262; Found 216.1265. H NMR (400 MHz, CDCl3): δ = 1.49ꢀ1.63 (m, 1H), 1.63ꢀ
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1.77 (m, 1H), 1.85ꢀ1.93 (m, 1H), 1.95ꢀ2.06 (m, 1H), 2.18ꢀ2.36 (m, 2H), 2.36 (s, 3H), 2.60ꢀ2.69 (m,
2H), 2.88ꢀ2.96 (s, 1H), 4.46ꢀ4.56 (m, 1H), 6.97ꢀ7.03 (m, 2H), 7.56ꢀ7.62 (m, 2H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 22.6, 28.8, 46.3, 55.3, 59.2, 72.8, 103.9, 116.1, 119.2, 134.1, 161.0 ppm.
(S)-4-((1-methylpyrrolidin-2-yl)methoxy)benzonitrile 26. The pure compound was obtained in 23%
(132 mg) yield as a brown oil by column chromatography on silica gel using methanol as elution
mixture. GCꢀMS Calcd for C13H16N2O 216.3 g.molꢀ1; Found 216.2 g.molꢀ1. HRMS (EI) m/z: [M]+
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Calcd for C13H16N2O 216.1262; Found 216.1267. H NMR (400 MHz, CDCl3): δ = 1.58ꢀ1.82 (m,
3H), 1.89ꢀ2.03 (m, 1H), 2.20ꢀ2.29 (m, 1H), 2.40 (s, 3H), 2.57ꢀ2.63 (m, 1H), 3.00ꢀ3.09 (m, 1H),
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3.82ꢀ3.88 (m, 1H), 3.90ꢀ3.97 (m, 1H), 6.85ꢀ6.92 (m, 2H), 7.47ꢀ7.53 (m, 2H) ppm. C NMR (100
MHz, CDCl3): δ = 23.1, 28.6, 41.7, 57.7, 64.1, 71.1, 104.0, 115.2, 119.3, 134.0, 162.3 ppm.
(R)-1-methyl-3-(4-nitrophenoxy)piperidine 27. The pure compound was obtained in 89% (558 mg)
yield as a brown oil by column chromatography on silica gel using methanol as elution mixture.
GCꢀMS Calcd for C12H16N2O3 236.3 g.molꢀ1; Found 236.0 g.molꢀ1. HRMS (EI) m/z: [M]+ Calcd for
1
C12H16N2O3 236.1160; Found 236.1158. H NMR (400 MHz, CDCl3): δ = 1.51ꢀ1.66 (m, 1H), 1.66ꢀ
1.78 (m, 1H), 1.85ꢀ1.94 (m, 1H), 1.98ꢀ2.08 (m, 1H), 2.20ꢀ2.37 (m, 2H), 2.37 (s, 3H), 2.59ꢀ2.69 (m,
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1H), 2.89ꢀ2.99 (m, 1H), 4.51ꢀ4.61 (m, 1H), 6.97ꢀ7.04 (m, 2H), 8.17ꢀ8.23 (m, 2H) ppm. C NMR
(100 MHz, CDCl3): δ = 22.6, 28.8, 46.2, 55.2, 59.1, 73.1, 115.3, 126.0, 141.4, 162.8 ppm.
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(S)-1-methyl-2-((4-nitrophenoxy)methyl)pyrrolidine 28. The pure compound was obtained in 3%
(17 mg) yield as a brown oil by column chromatography on silica gel using methanol as elution
mixture. GCꢀMS Calcd for C12H16N2O3 236.3 g.molꢀ1; Found 236.0 g.molꢀ1. HRMS (EI) m/z: [M]+
Calcd for C12H16N2O3 236.1160; Found 236.1154. 1H NMR (400 MHz, CDCl3): δ = 1.60ꢀ1.85 (m,
3H), 1.93ꢀ2.04 (m, 1H), 2.23ꢀ2.32 (m, 1H), 2.43 (s, 3H), 2.60ꢀ2.70 (m, 1H), 3.03ꢀ3.11 (m, 1H),
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3.89ꢀ3.94 (m, 1H), 3.96ꢀ4.03 (m, 1H), 6.87ꢀ6.94 (m, 2H), 8.09ꢀ8.16 (m, 2H) ppm. C NMR (100
MHz, CDCl3): δ = 23.1, 28.6, 41.7, 57.7, 64.0, 71.5, 114.5, 125.9, 141.5, 164.0 ppm.
Supporting Information†
The Supporting Information is available free of charge on the ACS Publications website and it
includes experimental details, compound characterization, and NMR spectra (PDF); Xꢀray data for
compound 25 (CIF).
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N
N
N
Ar OH
OAr
OCO2CH3
+
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ArO
Regioselective and Stereoselective (> 95%)
with Nu that are good leaving group
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