Solvent-Directed Epoxide Opening with Primary Amines for the Synthesis of β-Amino Alcohols

Article abstract of DOI:10.1055/s-0036-1588356

An efficient synthesis of β-amino alcohols from a variety of epoxides and primary unbranched amines in the absence of any catalyst in high yields and regioselectivities is reported. A variety of polar mixed solvent systems allow for the selective formation of secondary amino alcohols over tertiary amino alcohols. The reaction scope extends to a wide variety of aromatic and aliphatic substituted epoxides and primary amines bearing complex functionality.

Full text of DOI:10.1055/s-0036-1588356

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2016, 48, A–L
paper
A
J. R. Lizza, G. Moura-Letts
Paper
Synthesis
Solvent-Directed Epoxide Opening with Primary Amines for the
Synthesis of β-Amino Alcohols
Joseph R. Lizza
R2
N
OH
Gustavo Moura-Letts*
R2
DMF/H2O
60 °C
R1
R2
39 examples
43–98% yield
OH
+
R1
NH2
+
NH
O
R1
Chemistry and Biochemistry Department, Rowan University,
Glassboro, NJ 08028, USA
R1
OH
OH
moura-letts@rowan.edu
OH
O
H
N
H
N
O
O
metoprolol
95%
atenolol
82.5%
MeO
H2N
scalable + atom economical
β1-blocker synthesis
20 g scale
Received: 02.10.2016
Accepted after revision: 27.10.2016
Published online: 29.11.2016
the least substituted side of the epoxide decreases signifi-
cantly in the presence of promoters.9 Thus, there is a clear
void for an efficient method for the chemo- and regio-
selective epoxide opening with unhindered primary
amines.
The search for such methods has led us to focus on the
development of novel and efficient synthetic methods for
the selective introduction of N-nucleophiles for the synthe-
sis of pharmacologically relevant molecular scaffolds.10 β-
Amino alcohols are a highly recurrent scaffold among most
β-blockers;11 however, their production has proven to re-
quire longer synthetic sequences due to low selectivities on
the key epoxide-opening step.
DOI: 10.1055/s-0036-1588356; Art ID: ss-2016-m0690-op
Abstract An efficient synthesis of β-amino alcohols from a variety of
epoxides and primary unbranched amines in the absence of any catalyst
in high yields and regioselectivities is reported. A variety of polar mixed
solvent systems allow for the selective formation of secondary amino
alcohols over tertiary amino alcohols. The reaction scope extends to a
wide variety of aromatic and aliphatic substituted epoxides and primary
amines bearing complex functionality.
Key words β-amino alcohols, primary amines, epoxide opening reac-
tions, solvent-directed reactions, β-blockers
Herein, we report a chemo- and regioselective approach
for the highly selective synthesis of β-amino alcohols with
unhindered primary amines.
β-Amino alcohols are an important class of compounds
in organic chemistry.1 Moreover, they can be used as chem-
ical synthons for the synthesis of more complex heterocy-
clic scaffolds.2 Their importance also extends to drug dis-
covery due to their high occurrence in commercially avail-
able drugs.3 A long list of methods to construct this scaffold
has been reported in the literature.4 Among these, ring
opening of epoxides with amine nucleophiles is one of the
most straightforward approaches due to the high availabili-
ty of either substrates and the comprehensive understand-
ing of nucleophilic substitutions.5 Most methods rely on
high temperatures and high excess of reagents to achieve
high conversions and chemoselectivity.6 Significant efforts
have also shown that epoxide aminolysis can be efficiently
promoted in the presence of lanthanide triflates, Lewis
acids, solid acid supports, or by using solvents such as wa-
ter.7 While these methods are effective, the epoxide open-
ing with unhindered primary amines introduces a large
number of issues with the chemo- and regioselectivity of
this reaction. Double alkylation for this approach is widely
reported to lower the productivity and ease of isolation for
unbranched primary amines.8 Moreover, regioselectivity for
This study started by assessing the reaction outcomes
between phenylglycidyl ether and phenethylamine (PEA) as
proof of principle substrates (Table 1). The results showed
that in aprotic solvents (heptanes, Et2O, CH2Cl2) at room
temperature and after 24 hours, a 2.5:1 mixture of 1a and
1b was obtained with very low conversion (Table 1, entries
1, 2, and 3). On the other hand, polar protic solvents (EtOH,
TFE, H2O) provided reaction products with much higher
conversions (>84%), but with lower selectivities for monoal-
kylation product 1a (entries 4, 5, and 6). The drastic in-
crease in conversion is derived from the protic solvent ep-
oxide activation.8d Moreover, under neat conditions the re-
action proceeded in >99% conversion and in a 2.5:1 ratio for
1a:1b (entry 7).
Further exploration of solvent effects provided complete
selectivity with DMF but low conversion (25%, Table 1, en-
try 8). Despite the high selectivity with DMF, reaction pro-
ductivity at 40 °C remained far from ideal (27%, entry 9).
The high selectivity could be explained by the reduced nuc-
leophilicity of secondary amine 1a through intramolecular
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–L

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J. R. Lizza, G. Moura-Letts
Paper
Synthesis
Table 1 Reaction Discovery and Optimization
Ph
OH
Ph
PEA, conditions
24 h
PhO
O
OH
PhO
N
+
PhO
NH
PhO
OH
1a
1b
Entrya
Solvent
Concn (M)
Temp (°C)
Conv. (%)b,c
Yield (%)d 1a
Yield (%)d 1b
1
2
heptane
Et2O
0.1
0.1
0.1
0.1
0.1
0.1
–
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
40
3 (7:3)
5 (7:3)
5 (7:3)
85
–
–
–
–
3
CH2Cl2
EtOH
–
–
4
70
48
40
71
95
91
90
75
79
72
95
94
94
95
83
98
30
50
59
28
0
5
TFE
95
6
H2O
>99
>99
25
7
neat
8
DMF
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.15
0.2 M
0.15 M
9
DMF
27
9
10
11
12
13
14
15
16
17
18
19
DMF
60
42
9
DMF
80
50
23
20
28
3
DMF
100
120
r.t.
40
53
DMF
68
DMF/H2Oe
DMF/H2Oe
DMF/H2Oe
DMF/H2Oe
DMF/H2Oe
DMF/H2Oe,f
25
69
5
60
92
5
60
99
3
60
>99
98
16
<2
60
a Epoxide/amine ratio = 1:1.5.
b Measured by 1H NMR spectroscopy.
c Ratio of 1a/1b.
d Isolated yields.
e H2O: 50 equiv.
f H2O added after 12 h.
hydrogen bonding. Nonetheless, the poor conversion arises
from poor activation of the epoxide. Higher temperatures
did provide a significant increase in conversion (42, 50, 53,
68% conversion, for 60, 80, 100 and 120 °C, entries 10–13,
respectively). However, the reaction selectivity decreased
proportionally to the increase in conversion. The reaction
displayed similar high selectivities when exposed to DMF
with 50 equivalents of H2O at room temperature (25% con-
version, 95% of 1a, entry 14). There was a concern with po-
tential erosion of selectivity at higher temperatures, but it
was discovered that at 40 °C the reaction conversion in-
creased to 69% with no erosion on the selectivity (94% 1a,
entry 15). Moreover, at 60 °C the conversion increased to
92% with 1a as the major isomer (94%, entry 16). Further
increasing the reaction temperature failed to improve the
reaction selectivity. Based on the SN2 nature of this reac-
tion, raising the concentration proved to slightly improve
the reaction productivity and selectivity (99%, 95% of 1a,
entry 17); however, at 0.2 M the selectivity had begun to
erode (83% of 1a, 16% of 1b, entry 18). Eventually it was dis-
covered that adding H2O after 12 hours in DMF provided the
ideal results (>99%, 98% of 1a, entry 19). These results are
supported by the decreased nucleophilicity of 1a relative to
the primary amine with H2O as a reagent rather than as sol-
vent.
The identification of a highly selective set of conditions
shifted the focus towards addressing other reaction charac-
teristics. β-Blockers, among other key pharmacophoric
scaffolds, share the β-amino alcohol moiety with a variety
of substitution pattern on the nitrogen atom. Thus, it is fun-
damental to fully address the reaction scope to further vali-
date this method as a successful route for this key scaffold.
Previous studies on the selective amine opening of epox-
ides are widely diverse in conversion and scope.5 Thus, the
scope study aimed to provide a comprehensive analysis of
steric and electronic factors among different primary
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–L

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J. R. Lizza, G. Moura-Letts
Paper
Synthesis
Table 2 (continued)
Entry RNH2
amine substrates (Table 2). Aliphatic primary amines dis-
played very high conversions and yields for the desired
monoalkylated product (entries 1–6). Interestingly, allyl
and propargyl amine provided the desired amino alcohol in
the highest yields. Sterically hindered α-branched primary
amines (cyclohexyl, cyclopentyl, and isopropyl) were also
successful at selectively providing the expected products in
very high yields (entries 7–9).
Product
Yield (%)b
76
OH
OH
H
N
H2N
PhO
13
H
N
H2N
PhO
14
71
94
Table 2 Reaction Scope for Aminesa
Ph
Ph
NH2
RNH2
OH
R
15
OH
OH
OH
Ph
PhO
O
PhO
NH
Ph
PhO
PhO
PhO
NH
DMF/H2O
60 °C
H
N
16
90
94
H2N
Entry RNH2
Product
PhO
Yield (%)b
94
O
NH2
O
OH
OH
Ph
H
N
1
H2N
17
NH
N
N
NH2
NH2
2
3
95
92
PhO
NH
NH2
18
93
90
92
OH
OH
PhO
PhO
NH
NH
OH
OH
OH
PhO
PhO
PhO
NH
O
N
O
19
C4H9
NH
NH2
4
5
6
93
91
92
NH2
C3H7
NH
N
NH2
NH2
NH2
NH2
20
OH
OH
OH
PhO
PhO
PhO
NH
C6H13
NH
OH
OH
NH2
PhO
PhO
F
F
F
F
21
22
92
86
H
N
H2N
H2N
NH
7
94
NH2
NH2
H
N
OH
H
N
a Reaction conditions: Epoxide (1 mmol) and amine (1.5 mmol) were dis-
solved in DMF and then heated to 60 °C for 12 h, then H2O (50 mmol) was
added and heated for an additional 12 h.
PhO
8
9
92
92
b Isolated yields.
OH
OH
NH2
PhO
PhO
NH
Due to the high recurrence of this scaffold among phar-
macophores, functional group tolerance would allow access
to a wider variety of more complex scaffolds. Thus, 2-ami-
nophenethyl alcohol and 4-amino-2,2,6,6-tetrameth-
ylpiperidine reacted with comparable high yields to provide
the expected regioisomer (Table 2, entries 10 and 11). De-
spite the conflicting reports, α-quaternary amines have
been shown to react with lower conversions and selectivi-
ties.12 The reaction of tert-butylamine, dimethylpropargyl-
amine, and 1-acetylynecyclohexylamine displayed slightly
lower yields for the desired product, but with complete re-
gioselectivity (entries 12–14). Moreover, diphenylpropan-
1-amine, isobutylamine, 2-aminopyrrolidinylethanone, and
Ph
NH2
OH
H
N
10
87
HO
OH
OH
H
N
H2N
PhO
PhO
11
86
94
NH
NH
NH2
NH
12
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–L

D
J. R. Lizza, G. Moura-Letts
Paper
Synthesis
Table 3 (continued)
Entry Epoxide
benzylamine were also successful at providing the respec-
tive amino alcohols in very high yields and selectivities (en-
tries 15–18). Added complexity on the amine substrate
(furfurylamine, picolylamine, and 2,4-difluorobenzyl-
amine) did not affect the productivity of the reaction and
the respective products were obtained in similar high
yields (entries 19–21). Further evidence of the highly selec-
tive nature of this approach was obtained with 4-(amino-
methyl)aniline. This reaction provided the respective ami-
no alcohol with complete selectivity for the primary amine
over the aniline epoxide-opening pathway (entry 22).
The success realized among amines of different steric
and electronic properties prompted us to turn our focus on
the reaction scope for epoxides (Table 3). Aryl glycidyl
ethers are widely commercially available and can be easily
constructed through the reaction of phenols and epichloro-
hydrin. Thus, we were interested in assessing the effect of
substituents with different electronic properties. Activated
phenyl glycidyl ethers proved to undergo epoxide opening
with allylamine in excellent yields and regioselectivities
(entries 1–3). It has also been established that fluorinated
phenyl ethers are good pharmacophores for many biologi-
cal targets.3d The reactions with 4-fluorophenyl and 3,4-di-
fluorophenyl glycidyl ethers also demonstrated to provide
the respective amino alcohols in excellent yields and selec-
tivities (entries 4 and 5) providing quick and efficient ac-
cess to highly relevant pharmacophoric scaffolds.
Product
Yield
(%)b
OH
OH
O
6
7
8
9
95
91
94
88
O
O
NH
NH
O
O
O
O
O
OH
O
NH
Ph
N
H
OH
O
F
F
10
11
12
86
85
85
N
H
O
OH
OH
Cl
Br
Cl
Br
N
H
O
N
H
O
O
OH
OH
H
O
O
13
14
15
91
43
93
O
N
Table 3 Reaction Scope for Epoxidea
OH
DMF/H2O
60 °C
R
OH
+
H2N
O
NH
N
H
R
OH
Entry Epoxide
Product
Yield
(%)b
H
N
O
a Reaction conditions: Epoxide (1 mmol) and amine (1.5 mmol) were dis-
solved in DMF with H2O (25 mmol) and then heated to 60 °C for 24 h.
b Isolated yields.
MeO
MeO
OH
1
95
94
O
O
NH
O
Moreover, potential success with the epoxide opening of
benzyl and furfuryl glycidyl ethers would provide further
access to complex substituted amino alcohols (Table 3, en-
tries 6 and 7). Alkenyl oxides are another family of relevant
electrophiles that can be easily accessed. More importantly,
they tend to react with poorer conversion and regioselec-
tivities. The reaction conditions showed that oxides of allyl-
benzene and allylstyrene provide the desired amino alco-
hols as the expected regioisomer in very high yields (en-
tries 8 and 9).
Moreover, 4-fluoro-, 4-chloro-, and 4-bromostyrene ox-
ides were also successful at providing the proposed prod-
ucts (Table 3, entries 10–12). Aliphatic oxides also dis-
played high conversions and selectivities. However, we
found that cyclic alkenyl oxides provide complete selectivi-
OH
2
3
O
NH
O
O
OH
92
93
O
O
NH
O
F
F
F
OH
OH
4
O
O
O
O
NH
O
F
F
F
5
91
NH
O
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–L

E
J. R. Lizza, G. Moura-Letts
Paper
Synthesis
Synthesis of selective β1-blockers atenolol and metoprolol
isopropylamine (24.3 equiv)
48.2% yield
OH
MeOH, 12 h, 110 °C
O
H
O
N
US 3663607
O
O
O
atenolol
H2N
H2N
isopropylamine (1.5 equiv)
82.5% yield
DMF, H2O, 24 h, 60 °C
this work
isopropylamine (20 equiv)
42.3% yield
OH
i-PrOH, overnight, 100 °C
H
O
O
N
US 3873600
O
metoprolol
MeO
MeO
isopropylamine (1.5 equiv)
95% yield
DMF, H2O, 24 h, 60 °C
this work
Scheme 1 Synthesis of commercial β-blockers
ty for the monoalkylated product albeit with poor conver-
sion to the desired amino alcohol (entries 13–15).
excellent yields. The reaction has also proven to be highly
scalable in comparison to some commercial methods; the
respective β-amino alcohols can be obtained in much high-
er yields. The scaffolds made in this study will be further
evaluated for their pharmacological profile as potential β-
blockers.
The high productivity found for this reaction proposes
an important advancement in the search for better methods
for the synthesis of highly coveted β-amino alcohols. The
commercial synthesis of β-blockers has often relied on
harsh conditions to achieve the key epoxide-opening reac-
tion. Thus, the synthesis of known β-blockers (metoprolol
and atenolol) would serve as proof of principle to further
validate the strength of this method. Moreover, to further
assess the scalability of this reaction, we designed the syn-
thesis of these drugs in 20 gram scale (Scheme 1).
Reagents were obtained from Sigma-Aldrich, Acros Organics, or Alfa
Aesar and used without further purification. Solvents were obtained
from EMD Miliphore DrySol and degassed with N2. Solution-phase re-
actions were performed in glass vials or round bottom flasks without
inert atmosphere and magnetic stirring.
This study also intended to compare our results with
the industrial standard for obtaining these drugs. We fol-
lowed patents (US 3663607 and US 3873600)13 for the syn-
thesis of atenolol and metoprolol as reference approaches.
This comparison showed that our method was more ef-
ficient at providing the respective β-blockers (48.2/82.5%
for atenolol and 42.3/95% for metoprolol) than the available
industrial methods. Moreover, this work is highly atom eco-
nomical and provides the desired β-amino alcohols. The
scale-up for the synthesis of these two molecules provided
to be similarly efficient: atenolol was obtained in 82.5%
(21.5 g) and metoprolol in 95% (23.3 g).
In summary, we have discovered a more efficient and
atom economic approach for the synthesis of β-amino alco-
hols as potential β-blockers. This reaction allows for the
synthesis of such scaffolds with complete regioselectivity
and with minimal purification. The scope study demon-
strated that a variety of amines with different substitution
patterns and orthogonal functional groups could tolerate
the reaction conditions and provide the desired product in
TLC was performed on 0.25 mm E. Merck silica gel 60 F254 plates and
visualized under UV light (254 nm) or by staining with KMnO4. Silica
gel flash chromatography was performed on E. Merck 230–400 mesh
silica gel 60. Automated chromatography was performed on an
ISOLERA Prime instrument with 10 g. SNAP silica gel normal phase
cartridges. Analytical LC/MS was carried out on an Agilent 1100 UPLC
System with Ion Trap MS Detector with a Phenomenex 5 cm, 4.6 mm,
3 μm, 120 Å, C18 reverse phase column. IR spectra were recorded on a
Perkin Elmer Spectrum 100 FTIR spectrophotometer. NMR spectra
were recorded on Varian Mercury II 400 MHz Spectrometer at 24 °C
in CDCl3 unless otherwise indicated. Chemical shifts are expressed in
ppm relative to TMS (1H, 0 ppm) or solvent signals: CDCl3 (1H, 7.23
ppm; 13C, 77.0 ppm) coupling constants are expressed in hertz. High-
resolution mass spectroscopy was performed on a Agilent 6220 Accu-
rate-Mass Time-of-Flight LC/MS at the Mass Spectrometry facility at
Princeton University.
Amino Alcohols from Epoxides and Amines; General Procedure
A 20 mL pressure vessel (for volatile amines) was charged with the
appropriate epoxide (1.0 mmol, 1.0 equiv) and the respective amine
(1.5 mmol, 1.5 equiv) in reagent grade DMF (6.7 mL). The reaction
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–L

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J. R. Lizza, G. Moura-Letts
Paper
Synthesis
vessel fitted with a stir bar, sealed, and heated at 60°C for 12 h, after
which the vessel was allowed to cool to r.t. (only for reactions ran in
pressure vessels) before adding deionized H2O (50 equiv) in one por-
tion. The vessel was resealed and stirred at 60 °C for an additional 12
h. Solvent was removed on a rotary evaporator (35 °C/22.5 mbar) and
the crude residue loaded directly onto a silica gel column (Tables 2
and 3). Chromatographic purification gave the pure desired product.
1-(Butylamino)-3-phenoxypropan-2-ol (T1D)
Prepared from 2-(phenoxymethyl)oxirane (150 mg, 1.0 mmol) and
butan-1-amine (110 mg, 1.5 mmol). Purification by silica gel chroma-
tography (isocratic, 4% MeOH/CHCl3) afforded T1D (207 mg, 93%) as a
white solid; Rf = 0.28 (1:9 MeOH/CHCl3).
IR (thin film): 3291, 3062, 2957, 1599 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.27 (d, J = 7.1 Hz, 2 H), 6.91 (t, J = 7.1
Hz, 1 H), 6.88 (d, J = 7.1 Hz, 2 H), 4.11 (dddd, J = 7.5, 7.2, 7.1, 6.8 Hz, 1
H), 3.96 (dd, J = 7.2, 7.1 Hz, 2 H), 3.47 (br s, 1 H), 2.82 (dd, J = 7.1, 6.8
Hz, 1 H), 2.68 (dd, J = 7.5, 6.8 Hz, 1 H), 2.66–2.62 (m, 2 H), 1.49 (quint,
J = 7.1 Hz, 2 H), 1.34 (sext, J = 7.1 Hz, 2 H), 0.91 (t, J = 7.1 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 158.5, 129.3, 120.7, 114.3, 70.5, 67.9,
52.0, 49.5, 31.8, 20.3, 13.9.
ESI-MS: m/z (%) = (pos) 224.1 ([M + H]+, 100); (neg) 222.1 ([M – H]–,
100).
HRMS (ESI): m/z calcd for C13H22NO2+: 224.16451; found: 224.16488.
Absolute difference (ppm): 1.65.
1-(Phenethylamino)-3-phenoxypropan-2-ol (T1A)
Prepared from 2-(phenoxymethyl)oxirane (150 mg, 1.0 mmol) and 2-
phenylethan-1-amine (182 mg, 1.5 mmol). Purification by silica gel
chromatography (isocratic, 4% MeOH/CHCl3) afforded T1A (255 mg,
94%) as a white solid; Rf = 0.33 (1:9 MeOH/CHCl3).
IR (thin film): 3306, 3062, 2927, 1600 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.31–7.12 (m, 7 H), 6.93 (t, J = 7.1 Hz, 1
H), 6.88 (d, J = 7.1 Hz, 2 H), 4.04 (ddt, J = 7.5, 7.1, 6.8 Hz, 1 H), 3.94 (d,
J = 7.5 Hz, 2 H), 2.93–2.73 (m, 6 H).
13C NMR (100 MHz, CDCl3): δ = 158.5, 139.6, 129.4, 128.6, 128.4,
126.1, 120.9, 114.4, 70.3, 68.1, 51.7, 51.0, 36.2.
ESI-MS: m/z (%) = (pos) 272.2 ([M + H]+, 100); (neg) 270.2 ([M – H]–,
100).
HRMS (ESI): m/z calcd for C17H22NO2+: 272.16451; found: 272.16438.
Absolute difference (ppm): 0.48.
1-Phenoxy-3-(propylamino)propan-2-ol (T1E)
Prepared from 2-(phenoxymethyl)oxirane (150 mg, 1.0 mmol) and
propan-1-amine (89 mg, 1.5 mmol). Purification by silica gel chroma-
tography (isocratic, 4% MeOH/CHCl3) afforded T1E (190 mg, 91%) as a
white solid; Rf = 0.34 (1:9 MeOH/CHCl3).
IR (thin film): 3277, 3079, 2930, 1598 cm–1
.
1-(Allylamino)-3-phenoxypropan-2-ol (T1B)
1H NMR (400 MHz, CDCl3): δ = 7.23 (d, J = 7.1 Hz, 2 H), 6.93–6.86 (m, 3
H), 4.11 (ddt, J = 7.5, 7.1, 6.8 Hz, 1 H), 3.92 (d, J = 7.5 Hz, 2 H), 3.45 (br
s, 1 H), 2.82 (dd, J = 6.8, 6.4 Hz, 1 H), 2.71 (dd, J = 7.1, 6.4 Hz, 1 H),
2.59–2.53 (m, 2 H), 1.52 (sext, J = 7.1 Hz, 2 H), 0.91 (t, J = 7.1 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 158.5, 129.3, 120.7, 114.3, 70.5, 67.9,
51.9, 51.6, 22.8, 11.6.
Prepared from 2-(phenoxymethyl)oxirane (150 mg, 1.0 mmol) and
prop-2-en-1-amine (86 mg, 1.5 mmol). Purification by silica gel chro-
matography (isocratic, 4% MeOH/CHCl3) afforded T1B (197 mg, 95%)
as a white solid; Rf = 0.34 (1:9 MeOH/CHCl3).
IR (thin film): 3306, 3074, 2978, 1599 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.25 (d, J = 7.1 Hz, 2 H), 6.91 (t, J = 7.1
Hz, 1 H), 6.88 (d, J = 7.1 Hz, 2 H), 5.89 (dddd, J = 16.1, 9.9, 7.1, 6.8 Hz, 1
H), 5.18 (d, J = 16.1 Hz, 1 H), 5.08 (d, J = 9.9 Hz, 1 H), 4.08 (ddt, J = 7.5,
7.3, 7.1 Hz, 1 H), 3.94–3.90 (m, 2 H), 3.25 (d, J = 7.1 Hz, 2 H), 2.80 (dd,
J = 7.3, 7.1 Hz, 1 H), 2.68 (dd, J = 7.3, 6.8 Hz, 1 H).
ESI-MS: m/z (%) = (pos) 210.1 ([M + H]+, 100); (neg) 208.1 ([M – H]–,
100).
1-(Hexylamino)-3-phenoxypropan-2-ol (T1F)
Prepared from 2-(phenoxymethyl)oxirane (150 mg, 1.0 mmol) and
hexan-1-amine (152 mg, 1.5 mmol). Purification by silica gel chroma-
tography (isocratic, 4% MeOH/CHCl3) afforded T1F (231 mg, 92%) as a
white solid; Rf = 0.27 (1:9 MeOH/CHCl3).
13C NMR (100 MHz, CDCl3): δ = 158.4, 136.1, 129.3, 120.7, 116.3,
114.3, 70.5, 68.1, 52.1, 51.3.
ESI-MS: m/z (%) = (pos) 208.1 ([M + H]+, 100); (neg) 206.1 ([M – H]–,
100).
IR (thin film): 3290, 3062, 2957, 1599 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.25 (d, J = 7.1 Hz, 2 H), 6.93 (t, J = 7.1
Hz, 1 H), 6.89 (d, J = 7.1 Hz, 2 H), 4.11 (ddt, J = 7.5, 7.1, 6.6 Hz, 1 H),
3.92 (dd, J = 7.2, 7.1 Hz, 2 H), 3.43 (br s, 1 H), 2.84 (dd, J = 7.1, 6.6 Hz, 1
H), 2.68 (dd, J = 7.5, 7.1 Hz, 1 H), 2.64–2.60 (m, 2 H), 1.49 (quint, J = 7.1
Hz, 2 H), 1.29–1.23 (m, 6 H), 0.88 (t, J = 7.1 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 158.5, 129.3, 120.8, 114.3, 70.5, 67.8,
52.0, 49.8, 31.6, 29.7, 26.8, 22.5, 13.9.
1-Phenoxy-3-(prop-2-yn-1-ylamino)propan-2-ol (T1C)
Prepared from 2-(phenoxymethyl)oxirane (150 mg, 1.0 mmol) and
prop-2-yn-1-amine (83 mg, 1.5 mmol). Purification by silica gel chro-
matography (isocratic, 4% MeOH/CHCl3) afforded T1C (189 mg, 92%)
as a yellow oil; Rf = 0.31 (1:9 MeOH/CHCl3).
IR (thin film): 3682, 3294, 2924, 1599 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.29–7.25 (m, 2 H), 6.93 (t, J = 7.1 Hz, 1
H), 6.89 (d, J = 7.1 Hz, 2 H), 4.11 (tt, J = 7.5, 7.1 Hz, 1 H), 3.98 (d, J = 7.5
Hz, 2 H), 3.47 (d, J = 7.1 Hz, 2 H), 2.95 (dd, J = 7.1, 4.8 Hz, 1 H), 2.84
(dd, J = 7.1, 4.8 Hz, 1 H), 2.24 (t, J = 4.8 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 158.4, 129.4, 120.9, 114.4, 81.6, 71.8,
70.3, 68.3, 50.7, 38.1.
ESI-MS: m/z (%) = (pos) 252.1 ([M + H]+, 100); (neg) 250.1 ([M – H]–,
100).
1-(Cyclohexylamino)-3-phenoxypropan-2-ol (T1G)
Prepared from 2-(phenoxymethyl)oxirane (150 mg, 1.0 mmol) and
cyclohexylamine (149 mg, 1.5 mmol). Purification by silica gel chro-
matography (isocratic, 4% MeOH/CHCl3) afforded T1G (234 mg, 94%)
as a white solid; Rf = 0.17 (1:9 MeOH/CHCl3).
ESI-MS: m/z (%) = (pos) 206.1 ([M + H]+, 100); (neg) 204.1 ([M – H]–,
100).
IR (thin film): 3305, 3013, 2926, 1600 cm–1
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–L

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J. R. Lizza, G. Moura-Letts
Paper
Synthesis
1H NMR (400 MHz, CDCl3): δ = 7.25 (d, J = 7.1 Hz, 2 H), 6.95–6.86 (m, 3
H), 4.11 (ddt, J = 7.5, 7.3, 6.8 Hz, 1 H), 3.96 (t, J = 7.3 Hz, 2 H), 3.05 (br
s, 1 H), 2.91 (dd, J = 7.5, 6.6 Hz, 1 H), 2.73 (dd, J = 6.8, 6.6 Hz, 1 H),
2.46–2.40 (m, 1 H), 1.92–1.90 (m, 2 H), 1.74–1.69 (m, 2 H), 1.61–1.58
(m, 1 H), 1.29–1.03 (m, 5 H).
ESI-MS: m/z (%) = (pos) 302.2 ([M + H]+, 100); (neg) 300.2 ([M – H]–,
100).
HRMS (ESI): calcd for C18H24NO3+: 302.17507; found: 302.17564. Ab-
solute difference (ppm): 1.89.
13C NMR (100 MHz, CDCl3): δ = 158.6, 129.3, 120.8, 114.4, 70.5, 68.2,
56.8, 49.0, 33.5, 33.4, 25.9, 24.9.
ESI-MS: m/z (%) = (pos) 250.2 ([M + H]+, 100); (neg) 248.2 ([M – H]–,
100).
HRMS (ESI): m/z calcd for C15H24NO2+: 250.18016; found: 250.18035.
Absolute difference (ppm): 0.76.
1-Phenoxy-3-[(2,2,6,6-tetramethylpiperidin-4-yl)amino]propan-
2-ol (T1K)
Prepared from 2-(phenoxymethyl)oxirane (150 mg, 1.0 mmol) and
2,2,6,6-tetramethylpiperidin-4-amine (234 mg, 1.5 mmol). Purifica-
tion by silica gel chromatography (isocratic, 4% MeOH/CHCl3) afforded
T1K (263 mg, 86%) as a clear oil; Rf = 0.31 (1:9 MeOH/CHCl3).
IR (thin film): 3295, 3066, 2956, 1600 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.29 (d, J = 7.1 Hz, 2 H), 6.95–6.88 (m, 3
H), 4.06–4.02 (m, 1 H), 3.98–3.96 (m, 2 H), 2.96–2.92 (m, 2 H), 2.78
(dd, J = 7.1, 6.8 Hz, 1 H), 1.89 (dd, J = 7.3, 3.5 Hz, 2 H), 1.18 (s, 6 H),
1.12 (s, 6 H), 0.86 (t, J = 6.2 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 158.5, 129.4, 120.9, 114.4, 70.4, 68.4,
50.9, 50.0, 48.7, 46.3, 46.1, 35.0, 28.7, 28.5.
1-(Cyclopentylamino)-3-phenoxypropan-2-ol (T1H)
Prepared from 2-(phenoxy methyl)oxirane (150 mg, 1.0 mmol) and
cyclopentylamine (128 mg, 1.5 mmol). Purification by silica gel chro-
matography (isocratic, 4% MeOH/CHCl3) afforded T1H (216 mg, 92%)
as a white solid; Rf = 0.26 (1:9 MeOH/CHCl3).
IR (thin film): 3299, 3063, 2950, 1600 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.25 (d, J = 7.1 Hz, 2 H), 6.97–6.88 (m, 3
H), 4.08 (ddt, J = 7.5, 7.1, 6.8 Hz, 1 H), 3.94–3.89 (m, 2 H), 3.32 (br s, 1
H), 3.05 (quint, J = 7.1 Hz, 1 H), 2.82 (dd, J = 7.5, 6.6 Hz, 1 H), 2.71 (dd,
J = 6.8, 6.6 Hz, 1 H), 1.87–1.81 (m, 2 H), 1.69–1.63 (m, 2 H), 1.54–1.47
(m, 2 H), 1.37–1.29 (m, 2 H).
13C NMR (100 MHz, CDCl3): δ = 158.5, 129.3, 120.7, 114.3, 70.5, 68.1,
59.8, 50.8, 32.9, 32.8, 23.8, 23.7.
ESI-MS: m/z (%) = (pos) 307.2 ([M + H]+, 100); (neg) 305.2 ([M – H]–,
100).
1-(tert-Butylamino)-3-phenoxypropan-2-ol (T1L)
Prepared from 2-(phenoxymethyl)oxirane (150 mg, 1.0 mmol) and 2-
methylpropan-2-amine (110 mg, 1.5 mmol). Purification by silica gel
chromatography (isocratic, 4% MeOH/CHCl3) afforded T1L (210 mg,
94%) as a white solid; Rf = 0.18 (1:9 MeOH/CHCl3).
ESI-MS: m/z (%) = (pos) 236.2 ([M + H]+, 100); (neg) 234.2 ([M – H]–,
100).
IR (thin film): 3309, 3063, 2965, 1599 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.27 (d, J = 7.3 Hz, 2 H), 6.93–6.86 (m, 3
H), 4.04–3.91 (m, 3 H), 3.07 (br s, 1 H), 2.82 (dd, J = 7.3, 6.4 Hz, 1 H),
2.68 (dd, J = 7.1, 6.6 Hz, 1 H), 1.16 (s, 9 H).
13C NMR (100 MHz, CDCl3): δ = 158.6, 129.3, 120.8, 114.4, 70.5, 68.4,
50.4, 44.8, 28.9.
1-(Isopropylamino)-3-phenoxypropan-2-ol (T1I)
Prepared from 2-(phenoxymethyl)oxirane (150 mg, 1.0 mmol) and
propan-2-amine (89 mg, 1.5 mmol). Purification by silica gel chroma-
tography (isocratic, 4% MeOH/CHCl3) afforded T1I (192 mg, 92%) as a
white solid; Rf = 0.26 (1:9 MeOH/CHCl3).
ESI-MS: m/z (%) = (pos) 224.2 ([M + H]+, 100); (neg) 222.2 ([M – H]–,
100).
IR (thin film): 3295, 3062, 2967, 1600 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.21 (d, J = 7.1 Hz, 2 H), 6.93–6.86 (m, 3
H), 4.08 (ddt, J = 7.3, 7.1, 6.6 Hz, 1 H), 3.38 (br s, 1 H), 2.88–2.82 (m, 2
H), 2.68 (dd, J = 6.8, 6.6 Hz, 1 H), 1.09 (d, J = 7.1 Hz, 6 H).
13C NMR (100 MHz, CDCl3): δ = 158.5, 129.3, 120.7, 114.3, 70.5, 68.1,
49.5, 48.8, 22.7, 22.6.
1-[(2-Methylbut-3-yn-2-yl)amino]-3-phenoxypropan-2-ol (T1M)
Prepared from 2-(phenoxymethyl)oxirane (150 mg, 1.0 mmol) and 2-
methylbut-3-yn-2-amine (125 mg, 1.5 mmol). Purification by silica
gel chromatography (isocratic, 4% MeOH/CHCl3) afforded T1M (177
mg, 76%) as a white solid; Rf = 0.40 (1:9 MeOH/CHCl3).
ESI-MS: m/z (%) = (pos) 210.1 ([M + H]+, 100); (neg) 208.1 ([M – H]–,
100).
IR (thin film): 3291, 3067, 2981, 1600 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.29 (d, J = 6.9 Hz, 2 H), 6.98–6.91 (m, 3
H), 4.08 (ddt, J = 7.5, 7.3, 6.8 Hz, 1 H), 3.98 (d, J = 7.3 Hz, 2 H), 2.97 (dd,
J = 7.5, 6.6 Hz, 1 H), 2.86 (dd, J = 6.8, 6.6 Hz, 1 H), 2.31 (s, 1 H), 1.38 (s,
3 H), 1.36 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 158.4, 129.3, 120.8, 114.4, 88.2, 70.4,
70.1, 68.8, 49.4, 46.5, 29.6, 29.1.
(2S)-2-[(2-Hydroxy-3-phenoxypropyl)amino]-3-phenylpropan-1-
ol (T1J)
Prepared from 2-(phenoxymethyl)oxirane (150 mg, 1.0 mmol) and
(S)-2-amino-3-phenylpropan-1-ol (227 mg, 1.5 mmol). Purification
by silica gel chromatography (isocratic, 4% MeOH/CHCl3) afforded T1J
(262 mg, 87%) as a white solid; Rf = 0.31 (1:9 MeOH/CHCl3).
ESI-MS: m/z (%) = (pos) 234.1 ([M + H]+, 100); (neg) 232.1 ([M – H]–,
100).
IR (thin film): 3357, 3062, 2924, 1600 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.29–7.13 (m, 7 H), 6.95 (t, J = 7.1 Hz, 1
H), 6.84 (d, J = 7.1 Hz, 2 H), 4.04 (dddd, J = 7.5, 7.3, 7.1, 6.8 Hz, 1 H),
3.89–2.83 (m, 2 H), 3.63–3.58 (m, 1 H), 3.38–3.34 (m, 1 H), 2.91–2.86
(m, 2 H), 2.80–2.75 (m, 2 H), 2.71–2.64 (m, 1 H).
13C NMR (100 MHz, CDCl3): δ = 158.4, 138.4, 129.4, 129.1, 128.4,
126.3, 120.9, 114.4, 77.2, 70.1, 68.9, 68.6, 62.7, 62.6, 60.8, 60.5, 49.4,
49.3, 37.7, 37.6.
HRMS (ESI): m/z calcd for C14H20NO2+: 234.14886; found: 234.14828.
Absolute difference (ppm): 2.48.
1-[(1-Ethynylcyclohexyl)amino]-3-phenoxypropan-2-ol (T1N)
Prepared from 2-(phenoxymethyl)oxirane (150 mg, 1.0 mmol) and 1-
ethynylcyclohexan-1-amine (185 mg, 1.5 mmol). Purification by silica
gel chromatography (isocratic, 4% MeOH/CHCl3) afforded T1N (194
mg, 71%) as a white solid; Rf = 0.43 (1:9 MeOH/CHCl3).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–L

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J. R. Lizza, G. Moura-Letts
Paper
Synthesis
IR (thin film): 3294, 3063, 2932, 1601 cm–1
.
ESI-MS: m/z (%) = (pos) 279.2 ([M + H]+, 100); (neg) 277.2 ([M – H]–,
100).
1H NMR (400 MHz, CDCl3): δ = 7.25 (d, J = 7.3 Hz, 2 H), 6.95–6.88 (m, 3
H), 4.08 (ddt, J = 7.3, 7.1, 6.9 Hz, 1 H), 3.96 (d, J = 7.1 Hz, 2 H), 2.99 (dd,
J = 7.3, 6.2 Hz, 1 H), 2.88 (dd, J = 6.9, 6.2 Hz, 1 H), 2.37 (s, 1 H), 1.89–
1.86 (m, 2 H), 1.67–1.54 (m, 4 H), 1.43–1.32 (m, 2 H), 1.23–1.16 (m, 1
H).
13C NMR (100 MHz, CDCl3): δ = 158.5, 129.3, 120.7, 114.3, 87.0, 72.2,
70.4, 68.8, 54.0, 45.4, 37.9, 37.6, 25.5, 22.7, 22.5.
1-(Benzylamino)-3-phenoxypropan-2-ol (T1R)
Prepared from 2-(phenoxymethyl)oxirane (150 mg, 1.0 mmol) and
benzylamine (161 mg, 1.5 mmol). Purification by silica gel chroma-
tography (isocratic, 4% MeOH/CHCl3) afforded T1R (229 mg, 93%) as a
white solid; Rf = 0.33 (1:9 MeOH/CHCl3).
IR (thin film): 3305, 3063, 2924, 1599 cm–1
.
ESI-MS: m/z (%) = (pos) 274.2 ([M + H]+, 100); (neg) 272.2 ([M – H]–,
1H NMR (400 MHz, CDCl3): δ = 7.32–7.21 (m, 7 H), 6.93 (t, J = 7.1 Hz, 1
H), 6.88 (d, J = 7.1 Hz, 2 H), 4.08 (ddt, J = 7.5, 7.1, 6.8 Hz, 1 H), 3.92 (d,
J = 7.1 Hz, 2 H), 3.78 (d, J = 6.4 Hz, 2 H), 2.84 (dd, J = 7.5, 6.6 Hz, 1 H),
2.68 (dd, J = 6.8, 6.6 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 158.5, 139.6, 129.3, 128.4, 128.1,
127.0, 120.8, 114.4, 70.3, 68.2, 53.7, 51.2.
100).
1-[(3,3-Diphenylpropyl)amino]-3-phenoxypropan-2-ol (T1O)
Prepared from 2-(phenoxymethyl)oxirane (150 mg, 1.0 mmol) and
3,3-diphenylpropan-1-amine (317 mg, 1.5 mmol). Purification by sili-
ca gel chromatography (isocratic, 4% MeOH/CHCl3) afforded T1O (339
mg, 94%) as a white solid; Rf = 0.39 (1:9 MeOH/CHCl3).
ESI-MS: m/z (%) = (pos) 258.1 ([M + H]+, 100); (neg) 256.1 ([M – H]–,
100).
IR (thin film): 3305, 3061, 2925, 1599 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.29–7.12 (m, 13 H), 6.95 (t, J = 7.1 Hz,
1 H), 6.84 (d, J = 7.1 Hz, 2 H), 4.02–3.96 (m, 2 H), 3.89–3.83 (m, 2 H),
2.73 (dd, J = 7.5, 6.8 Hz, 1 H), 2.68 (dd, J = 7.1, 6.8 Hz, 1 H), 2.57–2.53
(m, 2 H), 2.24–2.17 (m, 2 H).
13C NMR (100 MHz, CDCl3): δ = 158.5, 144.5, 129.4, 128.4, 127.6,
126.1, 120.8, 114.4, 70.3, 68.0, 51.8, 48.9, 48.2, 35.7.
1-[(Furan-2-ylmethyl)amino]-3-phenoxypropan-2-ol (T1S)
Prepared from 2-(phenoxymethyl)oxirane (150 mg, 1.0 mmol) and
furan-2-ylmethanamine (146 mg, 1.5 mmol). Purification by silica gel
chromatography (isocratic, 4% MeOH/CHCl3) afforded T1S (222 mg,
90%) as a white solid; Rf = 0.31 (1:9 MeOH/CHCl3).
IR (thin film): 3311, 3115, 3066, 2924 cm–1
.
ESI-MS: m/z (%): (pos) 348.2 ([M + H]+, 100); (neg) 346.2 ([M – H]–,
1H NMR (400 MHz, CDCl3): δ = 7.36 (d, J = 2.6 Hz, 1 H), 7.27 (d, J = 7.1
Hz, 2 H), 6.93 (t, J = 7.1 Hz, 1 H), 6.89 (d, J = 7.1 Hz, 2 H), 6.31 (d, J = 2.6
Hz, 1 H), 6.19 (d, J = 2.6 Hz, 1 H), 4.06 (ddt, J = 7.7, 7.3, 6.9 Hz, 1 H),
3.94 (d, J = 7.3 Hz, 2 H), 3.81 (s, 2 H), 2.84 (dd, J = 7.7, 6.6 Hz, 1 H), 2.75
(dd, J = 6.9, 6.6 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 158.5, 153.4, 141.9, 129.4, 120.9,
114.4, 110.1, 107.1, 70.2, 68.3, 51.0, 45.9.
100).
1-(Isobutylamino)-3-phenoxypropan-2-ol (T1P)
Prepared from 2-(phenoxymethyl)oxirane (150 mg, 1.0 mmol) and 2-
methylpropan-1-amine (210 mg, 1.5 mmol). Purification by silica gel
chromatography (isocratic, 4% MeOH/CHCl3) afforded T1P (210 mg,
90%) as a white solid; Rf = 0.24 (1:9 MeOH/CHCl3).
IR (thin film): 3319, 3032, 2954, 1600 cm–1
.
ESI-MS: m/z (%) = (pos) 248.1 ([M + H]+, 100); (neg) 246.1 ([M – H]–,
100).
1H NMR (400 MHz, CDCl3): δ = 7.27–7.24 (m, 2 H), 6.95–6.89 (m, 3 H),
4.08 (dddd, J = 7.5, 7.3, 7.1, 6.9 Hz, 1 H), 3.94 (dd, J = 7.3, 7.1 Hz, 2 H),
3.05 (s, 1 H), 2.82 (dd, J = 7.5, 6.6 Hz, 1 H), 2.73 (dd, J = 6.8, 6.6 Hz, 1
H), 2.48–2.42 (m, 2 H), 1.76 (nonet, J = 7.1 Hz, 1 H), 0.91 (d, J = 7.1 Hz,
6 H).
13C NMR (100 MHz, CDCl3): δ = 158.5, 129.3, 120.7, 114.3, 70.4, 67.9,
57.6, 51.9, 28.0, 20.4.
ESI-MS: m/z (%) = (pos) 224.2 ([M + H]+, 100); (neg) 222.2 ([M – H]–,
100).
HRMS (ESI): m/z calcd for C13H22NO2+: 224.16451; found: 224.16471.
HRMS (ESI): m/z calcd for C14H18NO3+: 248.12812; found: 248.12864.
Absolute difference (ppm): 2.09.
1-Phenoxy-3-[(pyridin-2-ylmethyl)amino]propan-2-ol (T1T)
Prepared from 2-(phenoxymethyl)oxirane (150 mg, 1.0 mmol) and
pyridin-2-ylmethanamine (162 mg, 1.5 mmol). Purification by silica
gel chromatography (isocratic, 4% MeOH/CHCl3) afforded T1T (237
mg, 92%) as a white semi-solid; Rf = 0.32 (1:9 MeOH/CHCl3).
IR (thin film): 3371, 3308, 2983, 1678 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 8.55 (d, J = 6.2 Hz, 1 H), 7.63 (t, J = 6.6
Hz, 1 H), 7.29–7.25 (m, 3 H), 7.16 (dd, J = 6.6, 6.2 Hz, 1 H), 6.95 (t, J =
7.1 Hz, 2 H), 6.88 (d, J = 7.1 Hz, 1 H), 4.13 (ddt, J = 7.5, 7.1, 6.8 Hz, 1 H),
3.98–3.94 (m, 4 H), 2.93 (dd, J = 7.5, 6.6 Hz, 1 H), 2.84 (dd, J = 6.8, 6.6
Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 159.3, 158.5, 149.1, 136.6, 129.3,
122.2, 122.0, 120.8, 114.4, 70.2, 68.3, 54.7, 51.8.
Absolute difference (ppm): 0.89.
2-[(2-Hydroxy-3-phenoxypropyl)amino]-1-(pyrrolidin-1-
yl)ethan-1-one (T1Q)
Prepared from 2-(phenoxymethyl)oxirane (150 mg, 1.0 mmol) and 2-
amino-1-(pyrrolidin-1-yl)ethan-1-one (192 mg, 1.5 mmol). Purifica-
tion by silica gel chromatography (isocratic, 4% MeOH/CHCl3) afforded
T1Q (261 mg, 94%) as a white solid; Rf = 0.29 (1:9 MeOH/CHCl3).
ESI-MS: m/z (%) = (pos) 259.1 ([M + H]+, 100); (neg) 257.1 ([M – H]–,
100).
IR (thin film): 3370, 3066, 2952, 1628 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.27 (d, J = 7.1 Hz, 2 H), 6.93–6.88 (m, 3
H), 4.06–3.96 (m, 3 H), 3.49 (t, J = 7.3 Hz, 2 H), 3.41 (s, 2 H), 3.32 (t, J =
7.3 Hz, 2 H), 2.93 (dd, J = 7.5, 6.6 Hz, 1 H), 2.82 (dd, J = 6.8, 6.6 Hz, 2 H),
1.96 (quint, J = 7.3 Hz, 2 H), 1.89 (quint, J = 7.3 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 169.7, 158.6, 129.3, 120.7, 114.3, 70.0,
68.2, 52.5, 51.2, 45.7, 45.3, 25.9, 23.9.
1-[(2,4-Difluorobenzyl)amino]-3-phenoxypropan-2-ol (T1U)
Prepared from 2-(phenoxymethyl)oxirane (150 mg, 1.0 mmol) and
(2,4-difluorophenyl)methanamine (110 mg, 1.5 mmol). Purification
by silica gel chromatography (isocratic, 4% MeOH/CHCl3) afforded
T1U (270 mg, 92%) as a white solid; Rf = 0.18 (1:9 MeOH/CHCl3).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–L

I
J. R. Lizza, G. Moura-Letts
Paper
Synthesis
IR (thin film): 3269, 3044, 2927, 1600 cm–1
.
13C NMR (100 MHz, CDCl3): δ = 154.2, 136.2, 134.4, 127.4, 126.4,
125.8, 125.5, 125.2, 121.8, 120.5, 116.4, 104.9, 70.6, 68.4, 52.2, 51.4.
ESI-MS: m/z (%) = (pos) 258.1 ([M + H]+, 100); (neg) 256.1 ([M – H]–,
100).
HRMS (ESI): m/z calcd for C16H20NO2+: 258.14886; found: 258.14926.
Absolute difference (ppm): 1.54.
1H NMR (400 MHz, CDCl3): δ = 7.29–7.25 (m, 3 H), 6.93 (t, J = 7.1 Hz, 1
H), 6.88 (d, J = 7.1 Hz, 2 H), 6.80–6.73 (m, 2 H), 4.08 (ddt, J = 7.5, 7.1,
6.8 Hz, 1 H), 3.92 (d, J = 7.1 Hz, 2 H), 3.81 (s, 2 H), 2.80 (dd, J = 7.5, 6.6
Hz, 1 H), 2.71 (dd, J = 6.8, 6.6 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 162.8 (d, J = 216 Hz, 1 C), 160.2 (d, J =
224 Hz, 1 C), 158.4, 130.9, 129.4, 122.5, 120.9, 114.4, 110.9, 103.7 (t,
J = 25 Hz, 1 C), 70.3, 68.3, 51.0, 46.5.
1-(Allylamino)-3-(o-tolyloxy)propan-2-ol (T2C)
ESI-MS: m/z (%) = (pos) 294.1 ([M + H]+, 100); (neg) 292.1 ([M – H]–,
100).
Prepared from 2-[(o-tolyloxy)methyl]oxirane (150 mg, 0.91 mmol)
and prop-2-en-1-amine (78 mg, 1.37 mmol). Purification by silica gel
chromatography (isocratic, 4% MeOH/CHCl3) afforded T2C (186 mg,
92%) as a white solid; Rf = 0.23 (1:9 MeOH/CHCl3).
+
HRMS (ESI): m/z calcd for
C
16H18F2NO2
:
294.13001; found:
294.13044. Absolute difference (ppm): 1.46.
IR (thin film): 3311, 3077, 2923, 1603 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.12–7.08 (m, 2 H), 6.88 (t, J = 6.8 Hz, 1
H), 6.79 (d, J = 6.8 Hz, 1 H), 5.89 (dddd, J = 16.2, 10.4, 7.5, 7.1 Hz, 1 H),
5.14 (d, J = 16.2 Hz, 1 H), 5.09 (d, J = 10.4 Hz, 1 H), 4.08 (ddt, J = 7.3,
7.1, 6.6 Hz, 1 H), 3.98–3.89 (m, 2 H), 3.29–3.27 (m, 2 H), 2.91–2.86 (m,
2 H), 2.79 (dd, J = 6.8, 6.6 Hz, 1 H), 2.2 (s, 3 H).
1-[(4-Aminobenzyl)amino]-3-phenoxypropan-2-ol (T1V)
Prepared from 2-(phenoxymethyl)oxirane (150 mg, 1.0 mmol) and 4-
aminobenzylamine (183 mg, 1.50 mmol). Purification by silica gel
chromatography (isocratic, 4% MeOH/CHCl3) afforded amino alcohol
T1V (237 mg, 86%) as a clear oil; Rf = 0.20 (1:9 MeOH/CHCl3).
IR (thin film): 3345, 3225, 3101, 1615 cm–1
.
13C NMR (100 MHz, CDCl3): δ = 156.6, 136.2, 130.6, 126.8, 126.6,
120.6, 116.3, 111.0, 70.4, 68.3, 52.2, 51.4, 16.2.
ESI-MS: m/z (%) = (pos) 222.1 ([M+ H]+, 100); (neg) 220.1 ([M – H]–,
100).
1H NMR (400 MHz, CDCl3): δ = 7.23 (t, J = 7.1 Hz, 2 H), 7.01 (d, J = 6.9
Hz, 2 H), 6.93 (t, J = 7.1 Hz, 1 H), 6.77 (d, J = 6.9 Hz, 2 H), 6.53 (d, J = 7.1
Hz, 2 H), 4.02 (ddt, J = 7.5, 7.1, 6.8 Hz, 1 H), 3.81–3.78 (m, 2 H), 3.54
(dd, J = 7.3, 7.1 Hz, 2 H), 3.49 (br s, 1 H), 2.75 (dd, J = 7.5, 6.6 Hz, 1 H),
2.64 (dd, J = 6.8, 6.6 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 158.4, 145.3, 129.2, 129.1, 120.6,
114.9, 114.3, 70.3, 67.9, 53.0, 51.1.
1-(Allylamino)-3-(4-fluorophenoxy)propan-2-ol (T2D)
Prepared from 2-[(4-fluorophenoxy)methyl]oxirane (150 mg, 0.89
mmol) and prop-2-en-1-amine (76 mg, 1.34 mmol). Purification by
silica gel chromatography (isocratic, 4% MeOH/CHCl3) afforded T2D
(187 mg, 93%) as a white solid; Rf = 0.41 (1:9 MeOH/CHCl3).
ESI-MS m/z (%) = (pos) 273.2 ([M + H]+, 100); (neg) 271.2 ([M – H]–,
100).
IR (thin film): 3315, 3077, 2923, 1602 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 6.91–6.88 (m, 2 H), 6.79–6.73 (m, 2 H),
5.83 (dddd, J = 16.0, 10.8, 7.1, 6.9 Hz, 1 H), 5.12 (d, J = 16.0 Hz, 1 H),
5.05 (d, J = 10.8 Hz, 1 H), 4.04–3.98 (m, 1 H), 3.87 (d, J = 7.1 Hz, 2 H),
3.23 (d, J = 6.9 Hz, 2 H), 2.97 (br s, 1 H), 2.78 (dd, J = 7.5, 6.8 Hz, 1 H),
2.68 (dd, J = 6.9, 6.8 Hz, 1 H).
1-(Allylamino)-3-(4-methoxyphenoxy)propan-2-ol (T2A)
Prepared from 2-[(4-methoxyphenoxy)methyl)oxirane (150 mg, 0.83
mmol) and prop-2-en-1-amine (71 mg, 1.25 mmol). Purification by
silica gel chromatography (isocratic, 4% MeOH/CHCl3) afforded T2A
(188 mg, 95%) as a white semi-solid; Rf = 0.29 (1:9 MeOH/CHCl3).
IR (thin film): 3308, 3077, 2924, 1645 cm–1
.
13C NMR (100 MHz, CDCl3): δ = 158.4, 155.3 (d, J = 240 Hz, 1 C), 136.2,
116.3, 115.8, 115.4, 71.2, 68.2, 52.1, 51.2.
ESI-MS: m/z (%) = (pos) 226.1 ([M + H]+, 100); (neg) 224.1 ([M – H]–,
100).
1H NMR (400 MHz, CDCl3): δ = 6.79 (d, J = 6.8 Hz, 4 H), 5.85 (dddd, J =
16.0, 10.6, 7.3, 7.1 Hz, 1 H), 5.12 (d, J = 16.2 Hz, 1 H), 5.07 (d, J = 10.6
Hz, 1 H), 4.02 (ddt, J = 7.5, 7.1, 6.8 Hz, 1 H), 3.87 (d, J = 7.1 Hz, 2 H),
3.69 (s, 3 H), 3.23 (d, J = 7.1 Hz, 2 H), 2.82 (br s, 1 H), 2.77 (dd, J = 7.5,
6.6 Hz, 1 H), 2.68 (dd, J = 6.8, 6.6 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 153.9, 152.7, 136.2, 116.2, 115.4,
114.5, 71.2, 68.3, 55.6, 52.1, 51.2.
1-(Allylamino)-3-(3,4-difluorophenoxy)propan-2-ol (T2E)
Prepared from 2-[(3,4-difluorophenoxy)methyl]oxirane (150 mg,
0.81 mmol) and prop-2-en-1-amine (69 mg, 1.21 mmol). Purification
by silica gel chromatography (isocratic, 4% MeOH/CHCl3) afforded T2E
(178 mg, 91%) as a white solid; Rf = 0.42 (1:9 MeOH/CHCl3).
ESI-MS: m/z (%) = (pos) 238.1 ([M + H]+, 100); (neg) 236.1 ([M – H]–,
100).
IR (thin film): 3309, 3086, 2927, 1608 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 6.98 (dd, J = 12.5, 4.8 Hz, 1 H), 6.73
(ddd, J = 11.6, 7.1, 4.8 Hz, 1 H), 6.55 (d, J = 7.1 Hz, 1 H), 5.78 (dddd, J =
15.2, 10.1, 7.5, 7.3 Hz, 1 H), 5.14 (d, J = 15.2 Hz, 1 H), 5.10 (d, J = 10.1
Hz, 1 H), 4.00 (ddt, J = 7.3, 7.1, 6.8 Hz, 1 H), 3.81 (d, J = 7.1 Hz, 2 H),
3.23 (d, J = 6.9 Hz, 2 H), 3.05 (br s, 1 H), 2.75 (dd, J = 7.3, 6.4 Hz, 1 H),
2.64 (dd, J = 6.8, 6.4 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 154.9 (d, J = 8 Hz, 1 C), 150.3 (dd, J =
247, 14 Hz, 1 C), 145.1 (dd, J = 245, 13 Hz, 1 C), 136.1, 117.1 (d, J = 19
Hz, 1 C), 116.4, 109.7, 104.1 (d, J = 20 Hz, 1 C), 71.4, 68.0, 52.1, 51.1.
1-(Allylamino)-3-(naphthalen-1-yloxy)propan-2-ol (T2B)
Prepared from 2-[(naphthalen-1-yloxy)methyl]oxirane (150 mg, 0.75
mmol) and prop-2-en-1-amine (64 mg, 1.12 mmol). Purification by
silica gel chromatography (isocratic, 4% MeOH/CHCl3) afforded T2B
(181 mg, 94%) as an orange oil; Rf = 0.33 (1:9 MeOH/CHCl3).
IR (thin film): 3310, 3054, 2924, 1581 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 8.24 (d, J = 6.8 Hz, 1 H), 7.78 (d, J = 6.8
Hz, 1 H), 7.47–7.39 (m, 3 H), 7.32 (t, J = 7.1 Hz, 1 H), 6.79 (d, J = 7.1 Hz,
1 H), 5.89 (dddd, J = 15.8, 10.2, 7.5, 7.1 Hz, 1 H), 5.16 (d, J = 15.8 Hz, 1
H), 5.09 (d, J = 10.2 Hz, 1 H), 4.02 (ddd, J = 7.5, 7.3, 7.1, 6.8 Hz, 1 H),
4.13–4.06 (m, 2 H), 3.32–3.27 (m, 2 H), 2.94–2.82 (m, 3 H).
ESI-MS: m/z (%) = (pos) 244.1 ([M + H]+, 100); (neg) 242.1 ([M – H]–,
100).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–L

J
J. R. Lizza, G. Moura-Letts
Paper
Synthesis
+
HRMS (ESI): m/z calcd for C12H16F2NO2
:
244.11436; found:
IR (thin film): 3310, 3065, 2982, 1645 cm–1
.
244.11453. Absolute difference (ppm): 0.71.
1H NMR (400 MHz, CDCl3): δ = 7.32–7.23 (m, 5 H), 5.81 (dddd, J =
18.4, 12.6, 7.5, 7.3 Hz, 1 H), 5.09 (d, J = 18.4 Hz, 1 H), 5.05 (d, J = 12.6
Hz, 1 H), 4.75 (dd, J = 7.5, 7.1 Hz, 1 H), 3.41 (br s, 1 H), 3.17 (d, J = 7.4
Hz, 2 H), 2.73–2.64 (m, 2 H), 2.28 (s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 143.0, 136.0, 128.2, 127.3, 125.7,
116.3, 71.7, 56.3, 51.7.
1-(Allylamino)-3-(benzyloxy)propan-2-ol (T2F)
Prepared from 2-[(benzyloxy)methyl]oxirane (150 mg, 0.91 mmol)
and prop-2-en-1-amine (78 mg, 1.37 mmol). Purification by silica gel
chromatography (isocratic, 4% MeOH/CHCl3) afforded T2F (192 mg,
95%) as a clear oil; Rf = 0.31 (1:9 MeOH/CHCl3).
ESI-MS: m/z (%) = (pos) 178.1 ([M+H]+, 100); (neg) 176.1 ([M–H]–,
100).
IR (thin film): 3310, 3066, 2907, 1644 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.32–7.27 (m, 5 H), 5.83 (dddd, J =
16.0, 10.6, 7.3, 6.9 Hz, 1 H), 5.12 (d, J = 16.0 Hz, 1 H), 5.07 (d, J = 10.6
Hz, 1 H), 4.53 (s, 2 H), 3.89 (ddt, J = 7.5, 7.3, 6.8 Hz, 1 H), 3.47–3.43 (m,
2 H), 3.21 (d, J = 7.1 Hz, 2 H), 3.09 (br s, 1 H), 2.68 (dd, J = 7.5, 6.9 Hz, 1
H), 2.62 (dd, J = 6.9, 6.6 Hz, 1 H).
2-(Allylamino)-1-(4-fluorophenyl)ethan-1-ol (T2J)
Prepared from 2-(4-fluorophenyl)oxirane (150 mg, 1.09 mmol) and
prop-2-en-1-amine (93 mg, 1.63 mmol). Purification by silica gel
chromatography (isocratic, 4% MeOH/CHCl3) afforded T2J (182 mg,
86%) as a white solid; Rf = 0.37 (1:9 MeOH/CHCl3).
13C NMR (100 MHz, CDCl3): δ = 137.8, 136.2, 128.1, 127.4, 116.0, 73.1,
72.9, 68.5, 51.9, 51.3.
ESI-MS: m/z (%) = (pos) 222.2 ([M + H]+, 100); (neg) 220.2 ([M – H]–,
100).
IR (thin film): 3309, 3077, 2982, 1645 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.29 (dd, J = 8.4, 7.3 Hz, 2 H), 6.99 (t, J =
7.1 Hz, 2 H), 5.81 (dddd, J = 18.2, 12.8, 7.5, 7.3 Hz, 1 H), 5.12 (d, J = 18.2
Hz, 1 H), 5.10 (d, J = 12.8 Hz, 1 H), 4.71 (dd, J = 7.7, 7.1 Hz, 1 H), 3.27
(br s, 1 H), 3.23–3.18 (m, 2 H), 2.75 (dd, J = 7.7, 6.9 Hz, 1 H), 2.66 (dd,
J = 7.1, 6.9 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 162.1 (d, J = 244 Hz, 1 C), 138.6, 136.0,
127.3, 116.4, 115.1 (d, J = 22 Hz, 1 C), 71.1, 56.4, 51.8.
1-(Allylamino)-3-(furan-2-ylmethoxy)propan-2-ol (T2G)
Prepared from 2-[(oxiran-2-ylmethoxy)methyl)]furan (150 mg, 0.97
mmol) and prop-2-en-1-amine (83 mg, 1.46 mmol). Purification by
silica gel chromatography (isocratic, 4% MeOH/CHCl3) afforded T2G
(187 mg, 91%) as a clear oil; Rf = 0.26 (1:9 MeOH/CHCl3).
ESI-MS: m/z (%) = (pos) 196.1 ([M + H]+, 100); (neg) 194.1 ([M – H]–,
100).
IR (thin film): 3316, 3116, 2910, 1644 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.32 (s, 1 H), 6.24 (d, J = 6.8 Hz, 2 H),
5.81 (dddd, J = 18.0, 11.6, 7.5, 6.8 Hz, 1 H), 5.09 (d, J = 18.0 Hz, 1 H),
5.03 (d, J = 11.6 Hz, 1 H), 4.42 (s, 2 H), 3.81 (ddt, J = 7.3, 7.1, 6.8 Hz, 1
H), 3.41–3.32 (m, 2 H), 3.18 (d, J = 7.1 Hz, 2 H), 2.77 (br s, 1 H), 2.60
(dd, J = 7.3, 6.9 Hz, 1 H), 2.53 (dd, J = 6.9, 6.8 Hz, 1 H).
2-(Allylamino)-1-(4-chlorophenyl)ethan-1-ol (T2K)
Prepared from 2-(4-chlorophenyl)oxirane (150 mg, 0.97 mmol) and
prop-2-en-1-amine (83 mg, 1.46 mmol). Purification by silica gel
chromatography (isocratic, 4% MeOH/CHCl3) afforded amino alcohol
T2K (175 mg, 85%) as a white semi-solid; Rf = 0.27 (1:9 MeOH/CHCl3).
13C NMR (100 MHz, CDCl3): δ = 151.4, 142.6, 136.3, 116.1, 110.1,
109.3, 72.7, 68.6, 65.0, 52.0, 51.2.
ESI-MS m/z (%) = (pos) 212.1 ([M + H]+, 100); (neg) 210.1 ([M – H]–,
100).
IR (thin film): 3310, 3082, 2923, 1645 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.32–7.25 (m, 4 H), 5.85 (dddd, J =
17.8, 11.8, 7.3, 7.1 Hz, 1 H), 5.16 (d, J = 17.8 Hz, 1 H), 5.12 (d, J = 11.8
Hz, 1 H), 4.71 (dd, J = 7.9, 6.9 Hz, 1 H), 3.27–3.21 (m, 2 H), 3.18 (br s, 1
H), 2.82 (dd, J = 7.9, 6.8 Hz, 1 H), 2.66 (dd, J = 7.9, 6.8 Hz, 1 H).
1-(Allylamino)-4-phenylbutan-2-ol (T2H)
13C NMR (100 MHz, CDCl3): δ = 141.2, 135.9, 133.1, 128.4, 127.1,
116.6, 71.0, 56.2, 51.7.
ESI-MS: m/z (%) = (pos) 212.1 ([M + H]+, 100); (neg) 210.1 ([M – H]–,
100).
HRMS (ESI): m/z calcd for C11H15ClNO+: 212.08367; found: 212.08397.
Absolute difference (ppm): 1.41.
Prepared from 2-benzyloxirane (150 mg, 1.12 mmol) and prop-2-en-
1-amine (96 mg, 1.68 mmol). Purification by silica gel chromatogra-
phy (isocratic, 4% MeOH/CHCl3) afforded T2H (201 mg, 94%) as a clear
oil; Rf = 0.37 (1:9 MeOH/CHCl3).
IR (thin film): 3310, 3065, 2919, 1644 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.32–7.18 (m, 5 H), 5.81 (dddd, J =
18.1, 12.1, 7.5, 7.1 Hz, 1 H), 5.12 (d, J = 18.1 Hz, 1 H), 5.09 (d, J = 12.1
Hz, 1 H), 3.85 (ddt, J = 7.5, 7.3, 6.8 Hz, 1 H), 3.21–3.16 (m, 2 H), 2.73–
2.64 (m, 5 H), 3.21 (dd, J = 6.9, 6.8 Hz, 1 H), 2.22 (s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 138.3, 136.4, 129.3, 128.3, 126.2,
116.1, 70.6, 54.0, 52.0, 45.4, 41.7.
2-(Allylamino)-1-(4-bromophenyl)ethan-1-ol (T2L)
Prepared from 2-(4-bromophenyl)oxirane (150 mg, 0.75 mmol) and
prop-2-en-1-amine (65 mg, 1.13 mmol). Purification by silica gel
chromatography (isocratic, 4% MeOH/CHCl3) afforded T2L (164 mg,
85%) as a clear oil; Rf = 0.28 (1:9 MeOH/CHCl3).
ESI-MS: m/z (%) = (pos) 192.1 ([M + H]+, 100); (neg) 190.1 ([M – H]–,
100).
IR (thin film): 3311, 3077, 2998, 1645 cm–1
.
HRMS (ESI): m/z calcd for C12H18NO+: 192.13829; found: 192.13864.
Absolute difference (ppm): 1.82.
1H NMR (400 MHz, CDCl3): δ = 7.49 (d, J = 7.3 Hz, 2 H), 6.97 (d, J = 7.3
Hz, 2 H), 5.85 (dddd, J = 18.8, 10.8, 7.1, 6.9 Hz, 1 H), 5.16 (d, J = 18.8
Hz, 1 H), 5.12 (d, J = 10.8 Hz, 1 H), 4.68 (dd, J = 7.5, 6.9 Hz, 1 H), 3.29–
3.23 (m, 2 H), 3.05 (br s, 1 H), 2.82 (dd, J = 7.5, 6.6 Hz, 1 H), 2.66 (dd, J =
6.9, 6.6 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 141.7, 136.1, 131.4, 127.5, 121.2,
116.4, 71.1, 56.2, 51.8.
2-(Allylamino)-1-phenylethan-1-ol (T2I)
Prepared from 2-phenyloxirane (150 mg, 1.25 mmol) and prop-2-en-
1-amine (107 mg, 1.87 mmol). Purification by silica gel chromatogra-
phy (isocratic, 4% MeOH/CHCl3) afforded T2I (195 mg, 88%) as a white
semi-solid; Rf = 0.33 (1:9 MeOH/CHCl3).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–L

K
J. R. Lizza, G. Moura-Letts
Paper
Synthesis
ESI-MS: m/z (%) = (pos) 256.0 ([M + H]+, 100); (neg) 254.0 ([M – H]–,
IR (thin film): 3399, 3028, 2928, 1599 cm–1
.
100).
1H NMR (400 MHz, CDCl3): δ = 7.38–7.29 (m, 6 H), 7.25–7.18 (m, 4 H),
7.01 (t, J = 7.1 Hz, 2 H), 6.93 (d, J = 7.3 Hz, 3 H), 4.13–4.06 (m, 2 H),
3.97–3.92 (m, 4 H), 2.93–2.88 (m, 2 H), 2.84–2.79 (m, 6 H).
1-(Allylamino)-3-(allyloxy)propan-2-ol (T2M)
13C NMR (100 MHz, CDCl3): δ = 158.6, 140.0, 129.6, 128.8, 128.6,
126.3, 121.1, 114.6, 70.0, 68.1, 67.5, 58.0, 57.5, 57.4, 33.6, 33.5.
ESI-MS: m/z (%) = (pos) 422.2 ([M + H]+, 100); (neg) 420.2 ([M – H]–,
100).
Prepared from 2-[(allyloxy)methyl]oxirane (150 mg, 1.31 mmol) and
prop-2-en-1-amine (113 mg, 1.97 mmol). Purification by silica gel
chromatography (isocratic, 4% MeOH/CHCl3) afforded T2M (205 mg,
91%) as a clear oil, Rf = 0.28 (1:9 MeOH/CHCl3).
IR (thin film): 3311, 3080, 2981, 1645 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 5.85–5.72 (m, 2 H), 5.18–4.95 (m, 4 H),
3.89 (d, J = 7.5 Hz, 2 H), 3.78 (ddt, J = 7.5, 7.3, 6.9 Hz, 1 H), 3.34–3.29
(m, 2 H), 3.14 (d, J = 7.3 Hz, 2H ), 2.88 (br s, 1 H), 2.60 (dd, J = 7.5, 6.6
Hz, 1 H), 2.51 (dd, J = 6.9, 6.8 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 136.2, 134.4, 116.9, 116.0, 72.9, 72.1,
68.6, 52.0, 51.4.
2-{4-[2-Hydroxy-3-(isopropylamino)propoxy]phenyl}acetamide
(Atenolol)
4-Hydroxyphenylacetamide (20 g, 95.55 mmol) and propan-2-amine
(8.56 g, 143.30 mmol) were combined in DMF and heated to 60 °C in a
pressure vessel for 12 h, after which the vessel was allowed to cool to
r.t. before adding deionized H2O (32.28 mL, 50 equiv) in one portion.
The flask was resealed and allowed to react for an additional 12 h at
60 °C. Solvent and excess amine were removed on a rotary evaporator
(35 °C/22.5 mbar) and purification was accomplished in accordance
with the procedure described in the US patent 3 663 60713a to furnish
the atenolol freebase (21.2 g, 82.5%) as a white solid.; Rf = 0.28 (1:9
MeOH/CHCl3).
ESI-MS: m/z (%) = (pos) 172.1 ([M + H]+, 100); (neg) 170.1 ([M – H]–,
100).
2-(Allylamino)cyclohexan-1-ol (T2N)
Prepared from cyclohexene oxide (150 mg, 1.53 mmol) and prop-2-
en-1-amine (131 mg, 2.29 mmol). Purification by silica gel chroma-
tography (isocratic, 4% MeOH/CHCl3) afforded T2N (102 mg, 43%) as a
clear oil; Rf = 0.14 (1:9 MeOH/CHCl3).
IR (thin film): 3350, 3162, 2965, 1635 cm–1
.
1H NMR (400 MHz, DMSO-d6): δ = 7.43 (br s, 1 H), 7.18 (d, J = 7.1 Hz, 2
H), 7.18 (d, J = 7.1 Hz, 2 H), 3.89 (ddt, J = 7.5, 7.3, 6.9 Hz, 1 H), 3.83 (d,
J = 7.3 Hz, 2 H), 3.29 (s, 2 H), 2.71–2.66 (m, 2 H), 2.53 (sept, J = 7.1 Hz,
1 H), 0.99 (d, J = 6.8 Hz, 6 H).
13C NMR (100 MHz, DMSO-d6): δ = 172.7, 157.3, 130.0, 128.4, 114.2,
70.9, 68.4, 50.1, 48.3, 41.4, 23.0, 22.9.
IR (thin film): 3300, 3081, 2930, 1645 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 5.87 (dddd, J = 16.8, 12.5, 7.3, 7.1 Hz, 1
H), 5.12 (d, J = 16.8 Hz, 1 H), 5.07 (d, J = 12.5 Hz, 1 H), 3.38 (dd, J = 7.3,
6.6 Hz, 1 H), 3.21–3.01 (m, 2 H), 2.40 (br s, 1 H), 2.19 (ddd, J = 7.3, 7.1,
6.4 Hz, 1 H), 2.08–1.94 (m, 2 H), 1.69–1.65 (m, 2 H), 1.27–1.16 (m, 3
H), 1.01–0.91 (m, 1 H).
ESI-MS: m/z (%) = (pos) 267.2 ([M + H]+, 100); (neg) 265.2 ([M – H]–,
100).
13C NMR (100 MHz, CDCl3): δ = 136.7, 116.1, 73.6, 62.9, 49.2, 33.4,
30.3, 25.1, 24.3.
1-(Isopropylamino)-3-[4-(2-methoxyethyl)phenoxy]propan-2-ol
(Metoprolol)
ESI-MS: m/z (%) = (pos) 156.1 ([M + H]+, 100); (neg) 154.1 ([M – H]–,
100).
2-{[4-(2-Methoxyethyl)phenoxy]methyl}oxirane (20 g, 93.1 mmol)
and propan-2-amine (8.34 g, 139.7 mmol) were combined in DMF
and heated to 60 °C in a pressure vessel for 12 h, after which the ves-
sel was allowed to cool to r.t. before adding deionized H2O (32.28 mL,
50 equiv) in one portion. The flask was resealed and allowed to react
for an additional 12 h at 60 °C. Solvent and excess amine were re-
moved on a rotary evaporator (35 °C/22.5) to afford 24.5 g (95%) of
metoprolol freebase as a white semi-solid in >95% purity (1H NMR);
Rf = 0.28 (1:9 MeOH/CHCl3).
HRMS (ESI): m/z calcd for C9H18NO+: 156.13829; found: 156.13871.
Absolute difference (ppm): 2.68.
1-(Allylamino)octan-2-ol (T2O)
Prepared from 2-hexyloxirane (150 mg, 1.17 mmol) and prop-2-en-
1-amine (100 mg, 1.75 mmol). Purification by silica gel chromatogra-
phy (isocratic, 4% MeOH/CHCl3) afforded T2O (202 mg, 93%) as a pale
yellow oil; Rf = 0.28 (1:9 MeOH/CHCl3).
IR (thin film): 3310, 3078, 2957, 1645 cm–1
.
IR (thin film): 3299, 3034, 2966, 1613 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 5.81 (dddd, J = 18.3, 12.7, 7.5, 7.3 Hz, 1
H), 5.09 (d, J = 18.3 Hz, 1 H), 5.03 (d, J = 12.7 Hz, 1 H), 3.58–3.52 (m, 1
H), 3.23–3.14 (m, 2 H), 2.73 (br s, 1 H), 2.62 (dd, J = 7.5, 6.9 Hz, 1 H),
2.39 (dd, J = 7.3, 6.9 Hz, 1 H), 1.41–1.29 (m, 3 H), 1.25–1.16 (m, 7 H),
0.82 (t, J = 7.3 Hz, 3 H).
1H NMR (400 MHz, CDCl3): δ = 7.03 (d, J = 7.1 Hz, 2 H), 6.77 (d, J = 7.1
Hz, 2 H), 4.00 (ddt, J = 7.5, 7.3, 6.8 Hz, 1 H), 3.83–5.09 (m, 2 H), 3.49 (t,
J = 7.5 Hz, 2 H), 3.27 (s, 3 H), 3.23 (br s, 1 H), 3.78–3.72 (m, 4 H), 2.71
(dd, J = 6.8, 6.6 Hz, 1 H), 1.03 (d, J = 6.9 Hz, 6 H).
13C NMR (100 MHz, CDCl3): δ = 157.0, 131.0, 129.5, 114.2, 73.6, 70.6,
68.1, 58.4, 59.5, 48.7, 35.1, 22.7, 22.6.
13C NMR (100 MHz, CDCl3): δ = 136.3, 116.2, 69.5, 54.6, 52.0, 35.2,
31.7, 29.3, 25.6, 22.5, 14.0.
ESI-MS: m/z (%) = (pos) 186.2 ([M + H]+, 100); (neg) 184.2 ([M – H]–,
ESI-MS: m/z (%) = (pos) 268.2 ([M + H]+, 100); (neg) 266.2 ([M – H]–,
100).
100).
3,3′-(Phenethylazanediyl)bis(1-phenoxypropan-2-ol) (1b)
Acknowledgment
Prepared from 2-(phenoxymethyl)oxirane (150 mg, 1.0 mmol) and 2-
phenylethan-1-amine (182 mg, 1.50 mmol). Purification by silica gel
chromatography (isocratic, 4% MeOH/CHCl3) afforded 1b (211 mg,
50%) as a white solid; Rf = 0.45 (1:9 MeOH/CHCl3).
The donors of the American Chemical Society Petroleum Research
Fund financially supported these research efforts. We are also thank-
ful to Dr. John F. Eng at Princeton University for his help with HRMS
analysis.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–L

L
J. R. Lizza, G. Moura-Letts
Paper
Synthesis
Supporting Information
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NMR spectra are included.
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–L