A Single-Step Synthesis of Azetidine-3-amines

Article abstract of DOI:10.1021/acs.joc.0c01831

The azetidine group is frequently encountered within contemporary medicinal chemistry. However, the introduction of an azetidine can be synthetically challenging. Herein, a straightforward synthesis of azetidine-3-amines, starting from a bench stable, commercial material is presented. The reaction tolerates common functionality and proceeds in moderate-to-high yield with secondary amines, and moderate-to-low yield with primary amines. The methodology compares favorably to alternative procedures and can be utilized in "any-stage"functionalization, including late-stage azetidinylation of approved drugs and other compounds with pharmacological activity.

Full text of DOI:10.1021/acs.joc.0c01831

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Note
A Single-Step Synthesis of Azetidine-3-amines
Brian J Wang, and Matthew A. J. Duncton
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c01831 • Publication Date (Web): 15 Sep 2020
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The Journal of Organic Chemistry
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A Single-Step Synthesis of Azetidine-3-amines
Brian J. Wang† and Matthew A. J. Duncton*,‡
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†Ryss Laboratories Inc., 29540 Kohoutek Way, Union City, CA 94587, United States
‡Duncton, LLC, 851 Cherry Avenue, Suite 27/604, San Bruno, CA 94066, United States
KEYWORDS (Word Style “BG_Keywords”). If you are submitting your paper to a journal that requires keywords, provide
significant keywords to aid the reader in literature retrieval.
ABSTRACT: The azetidine group is frequently encountered within contemporary medicinal chemistry. However, the
introduction of an azetidine can be synthetically challenging. Herein, a straight-forward synthesis of azetidine-3-amines,
starting from a bench stable, commercial material is presented. The reaction tolerates common functionality, and proceeds
in moderate-to-high yield with secondary amines, and moderate-to-low yield with primary amines. The methodology
compares favorably to alternative procedures and can be utilized in “any-stage” functionalization, including late-stage
azetidinylation of approved drugs and other compounds with pharmacological activity.
The azetidine motif is one of the most important
substructures in pharmaceuticals and is present in a
number of approved drugs such as antibiotics,1 kinases2
(e.g. baricitinib, cobimetinib, itacitinib), and other
azetidine-3-amine products. We found a simple “mix-and-
heat” approach could be used at any stage of a synthesis,
including the late-stage functionalization of approved
drugs and other substances with pharmacological activity.
In addition, this simple displacement approach seems to
compare favorably to related strain-release methodology,
particularly in-terms of experimental setup, yield and
scope of substrate that can be employed.
compound
ximelagatran/melagatran;
classes3
(e.g.
thrombin
Ca-channel
inhibitor,
blocker,
azelnidipine). The azetidine group is also attractive since it
can restrict the conformation of an acyclic counterpart
(rigidification),4 and lead to compounds with an improved
pharmacokinetic or toxicity profile.5 Azetidine-3-amines
(3-aminoazetidines, or azaazetidines) are a less well
developed subset of azetidines, that nonetheless have
found important applications in medicinal chemistry, being
a substructure of JNJ-41443532 (a CCR2 antagonist),6
macrolide antibiotics,7 triple reuptake inhibitors8 and
kinase inhibitors,9 amongst others (Figure 1).10 Recently,
there has been a renewed interest in the synthesis of
azetidine-3-amines, by modifying ring-opening conditions
of azabicyclobutane (ABB) with amine nucleophiles in a
strain-release reaction.11,12 Other approaches to azetidine-
3-amines are based upon reductive amination.8,13 Yet
another synthesis of azetidine-3-amines, which has been
used sporadically, is the direct displacement of an
azetidine electrophile with an amine nucleophile.14 This
approach is more frequently encountered in the patent
A. Representative bioactive azetidine-3-amines.6-10
N
H
O
N
S
NH
N
N
NH
HO
HN
N
O
O
NH
kinase inhibitor9
O
R2
CF3
N
R1
JNJ-414435326
HN
Triple reuptake inhibitors8
B. Representative synthesis of azetidine-3-amines.11-15
I. Ring-openig of ABB11,12
R1
R2
N
Br
Br
NH2
literature,15 with
a
direct displacement of 1-
N
N
R
benzhydrylazetidin-3-yl methanesulfonate 1 being the
most frequently encountered azetidine electrophile.14,15
The resulting 1-benzhydrylazetidinazetidine-3-amine
products can be easily deprotected to the parent
azetidine.16,17 In other cases, it is also possible to transform
II. This work
R1
N
MsO
R2
Ph
N
N
Ph
the 1-benzyhydryl protecting group directly to
a
carbamoyl chloride.18 One of us has prior experience of the
amine displacement reaction with compound 1,19 and also
has an interest in the azetidine group within drug
discovery.20 In this paper we undertake a detailed study of
the reaction of compound 1 with amines to afford
1
Ph
Ph
Figure 1. (A) Representative bioactive azetidine-3-amines.
(B) Representative synthesis of azetidine-3-amines.
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We initiated our studies by examining the displacement of
The overall versatility and success of this straight-forward
displacement reaction deserves some comment, especially
in relation to complementary methodology such as the
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1-benzhydrylazetidin-3-yl methanesulfonate 1 with simple
amines. Compound 1 is a well-known,,21 commercially
available intermediate, although for our studies, we
prepared the material in a single batch starting from 1-
benzyhydryl-3-azetidinol. In our hands, 1 was stable at
ambient (room) temperature for at least nine (9) months.
Compound 1 was reacted with 1 equiv piperidine and 1
equiv of Hunig’s base (iPr2NEt) in acetonitrile (MeCN) at 80
°C to give a 33% yield of the desired displacement product
2. A large improvement to the yield could be realized by
using 2 equiv of piperidine and omitting Hunig’s base
altogether. This afforded the desired product 2 in 72%
isolated yield after purification by column chromatography
(Scheme 1). The yield compares favorably to that reported
when using strain-release methodology (56% yield,
reported in brackets in Scheme 1).11 Except for examples
giving compounds 3 and 4, we employed 2 equiv of amine
for all subsequent reactions. As can be seen in Scheme 1,
simple cyclic amines afforded fine isolated yields of
products 2 to 8. A more complex spirocyclic amine gave a
lower 21% yield of product 9. Significantly, we could also
utilize anilines in the displacement reaction, something
that was not reported for the recently-reported strain-
release technique.11,22 Thus, compound 10 was produced
in 34% isolated yield when 1,2,3,4-tetrahydroquinoline
was used as a nucleophile. We also used acyclic secondary
amines in the displacement. Again, good yields were
obtained. For example, N-methylbenzylamine gave 11 in
69% isolated yield (cf. 46% using strain-release). Even the
use of diisopropylamine, a very hindered secondary amine
most commonly encountered in non-nucleophilic bases
(e.g. diisopropylamide, LDA), but also a substructure of the
herbicides diallate and triallate, afforded a 49% isolated
yield of product 12. Late-stage azetidinylation of
pharmacologically-active drug substances could also be
undertaken in high-to-moderate yield. Thus, the 5-HT2C
agonist, 1-(3-trifluoromethylphenyl) piperazine (TFMPP),
and the selective serotonin reuptake inhibitors, fluoxetine
and sertraline, gave products 13 (87%), 14 (79%) and 15
(59% cf. 45% using strain-release).
recently-reported
strain-release
approach
to
azetidinylation.11 The direct displacement described in this
paper uses mild and very simple reaction conditions
(mixing of two substances in reagent grade MeCN and
heating to 80 °C), with equipment that does not have to be
flame-dried prior to use. In comparison, azetidinylation
using strain-release methodology requires the use of PhLi,
added dropwise and slowly,23 at -78 °C to form
azabicyclobutane (ABB), in preparation for a “spring-
loaded” ring-opening. In a separate flame-dried flask, an
amine nucleophile also needs to be activated with a turbo-
Grignard (iPrMgCl.LiCl), with evolution of gas.23 After 2h,
the “turbo-amide” is added dropwise to the pre-formed
solution of ABB at -78 °C. It should be noted that the
reaction is sensitive to the time used to form ABB, with 2 h
reaction time being optimal for maximal yield,23 so timings
have to be quite well-controlled. The strain-release
reaction seems to occur uneventfully overnight from -78 °C
to room temperature. However, quenching to give a Boc-
azetidine product occurs at 0 °C and requires the slow
addition of di-tert-butyl dicarbonate (Boc2O) in dry THF.23
Unfortunately, carbamates and free alcohols are
incompatible with the strain-release technique,23 whereas
free alcohols, carbamates and an unprotected heterocyclic
nitrogen (e.g. indole of 5-MT) are all tolerated in the direct
displacement reaction described in this paper. We did not
evaluate the use of amines containing a ketone group,
sulfide, or amide functionality, which are also incompatible
with strain-release methodology.23 Future work can
ascertain whether such functionality is unaffected with the
direct displacement reaction. The isolated yields obtained
with a direct displacement appear to be slightly higher
than an analogous reaction using strain-release
methodology (e.g. isolated yields for 2, 3, 4, 7, 11 and 15;
the yield for compound 6 was slightly lower than the
strain-release approach). The higher yields may be
reflective of the multi-operational nature of experiments
using strain-release methodology, as compared to a simple
“mix-and-heat” approach for displacement methodology.
Perhaps, the biggest difference between the displacement
and strain-release techniques, concerns the participation
of primary amines. The use of primary amines in the
displacement reaction was successful, giving moderate-to-
low yields of product, whereas primary amines are
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Next, we sought to extend the methodology to the use of
primary amines, since these could not be utilized in
analogous strain-release methodology.23 The use of simple
chain
amines
such
as
benzylamine,
alpha-
methylbenzylamine, or octylamine gave good yields of
products 16 (48%), 17 (60%) and 18 (47%). We then
extended the methodology to the use of functionalized
amines. Significantly, the reaction tolerated common
functionality found in medicinal chemistry, such as
difluoromethyl (19; 42%), trifluoromethyl (20; 44%),
methoxy (21; 33%) and even a free hydroxyl group (22;
27%). The use of primary amines appended to a cyclic
system were also successful giving products 23 (54%), 24
(28%) and 25 (27%) in moderate-to-low yield. In the case
of products 23 and 24 a Boc-protected amine was
unaffected in the reaction. Finally, we undertook a late-
stage azetidinylation of 5-methoxytryptamine (5-MT; aka,
mexamine), which contains an unprotected indole
nitrogen, to give 26 in 17% isolated yield.
incompatible
with
the
strain-release
method.23
Considering the above, we conclude that the direct
displacement may offer advantages over strain-release
methodology, especially in-terms of operational simplicity,
scope of substrate and isolated yield. The facile nature of
the displacement reaction, even for late-stage
functionalization of unprotected starting materials, may
appeal to those working in an industrial environment,
where complexity (time) considerations are important.
In summary, this paper describes a simple one-step
synthesis of azetidine-3-amines from
a bench-stable
commercial starting material. Both secondary and primary
amines can successfully participate in the reaction, and the
procedure tolerates common functionality such as ether,
halide, difluoromethyl, trifluoromethyl, carbamate,
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The Journal of Organic Chemistry
unprotected heterocyle and even free hydroxyl groups.
The methodology can be used for the late-stage
functionalization of substances with pharmacological
activity and compares favorably to complementary
techniques such as strain-release azetidinylation. It is
anticipated that the methodology described in this paper
will find application in medicinal, biochemical, materials,
polymer and agrochemical disciplines, where the azetidine
group has shown to be a very useful and desirable motif.
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Scheme 1. Scope of azetidinylation upon reaction of 1-benzhydrylazetidin-3-yl methanesulfonate 1 with amines.
R1
MsO
N
R2
N
N
Ph
Ph
1
Ph
Ph
Cl
Boc
Ph
Ph
N
O
N
N
N
Ph
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
Ph
Ph
Ph
Ph
Ph
4: 77%b 5: 59%a (26%b) 6: 48%a
(58%c) (60%c)
Ph
Ph
Ph Ph
Ph
Ph
Ph Ph
Ph
Ph
Ph Ph
Ph
Ph
Ph Ph
Ph
2: 72%a (33%b)
3: 64%b
7: 75%a
8: 69%a
9: 21%a
10: 34%a
11: 69%a 12: 49%a
(56%c)
(52%c)
(65%c) "azetidinylated"
cetirizine impurity
(46%c)
CF3
Cl
Cl
F
N
N
F3C
F
F
F
F
Ph
Ph
O
N
N
HN
N
HN
HN
HN
HN
N
N
N
N
N
N
N
Ph
13: 87%a
"azetidinylated" TFMPP "azetidinylated" fluoxetine
OMe OH
Ph
Ph
14: 79%a
Ph
Ph
15: 59%a
"azetidinylated" sertraline (45%c)
Ph
Ph
16: 48%a
Ph
Ph
17: 60%a
Ph
Ph
Ph
Ph
Ph Ph
Ph
18: 47%a
19: 42%a
20: 44%a
Boc
N
NH
N
Boc
HN
HN
HN
HN
HN
HN
N
OMe
N
N
N
N
N
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
21: 33%a
22: 27%a
23: 54%a
24: 28%a
25: 27%a
26: 17%a "azetidinylated" 5-MT
aIsolated yield from reaction of 1 with 2.0 equiv R1R2NH,or R1NH2, MeCN, 80 °C; bIsolated yield from reaction of 1 with 1.0 equiv of R1R2NH, 1.0 equiv
of iPr2NEt, MeCN, 80 °C; cYield of an analogous reaction using "strain-release" methodology to give an N-Boc azetidine
dip, or phosphomolybdic acid in ethanol dip. Flash
EXPERIMENTAL SECTION
chromatography was carried out using an automated
system with pre-packed silica columns.. Yields refer to
General. All reagents were purchased from commercial
sources and used without further purification. All solvents
were reagent, or HPLC grade. Heating was undertaken
using a heating block. EtOAc refers to ethyl acetate, MeOH
refers to methanol, and Et3N refers to triethylamine.
Analytical TLC was performed on silica gel 60 F254 plates
and visualized by UV if possible, or by staining with KMnO4
1
isolated yields of pure compounds. H NMR and 13C NMR
spectra were recorded on a 300 MHz spectrometer at
ambient temperature. Chemical shifts are reported in parts
per million (ppm) relative to deuterated solvent, or a TMS
internal standard. Multiplicities are reported as follows: s
= singlet; d = doublet, t = triplet; dd = doublet of doublets;
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dt = doublet of triplets; m = multiplet; br = broad; f = fine.
High-resolution mass spectrometry was obtained on a
Waters Xevo G2-XS QToF.
NMR (75 MHz, CDCl3): δ 142.3, 128.4, 127.6, 127.1, 78.1,
58.7, 55.4, 51.1, 25.4, 24.2; HRMS (ESI): [M+H]+ calcd for
C21H27N2 m/z 307.2174; found 307.2177.
1
2
1-benzhydrylazetidin-3-yl methanesulfonate (1).21,24 MsCl
(3.9 mL, 50 mmol) was added dropwise to a solution of 1-
benzyhydryl-3-azetidinol (10 g, 42 mmol) and Et3N (8.2
mL, 59 mmol) in DCM (125 mL) at 0 °C (ice-water bath),
and the mixture was stirred at 0 °C (ice-water bath), for 1
h. Saturated aqueous NaHCO3 was added. The phases were
separated, and the aqueous layer was extracted with DCM
(3 x 125 mL). The combined organic layers were dried
over Na2SO4, filtered, and concentrated to give the product
1-(1-Benzhydrylazetidin-3-yl)pyrrolidine (5). Purified using
0:1 to 5:95 MeOH / DCM as eluent to give an oil (174 mg,
59% yield). LC-MS: m/z = 293.27 [M+H]+; 1H NMR (300
MHz, CDCl3): δ 7.43-7.41 (m, 4H), 7.34-7.24 (m, 4H), 7.20-
7.15 (m, 2H), 4.43 (s, 1H), 3.42-3.37 (m, 2H), 3.11-2.95 (m,
3H), 2.40-2.38 (m, 4H), 1.83-1.73 (m, 4H); 13C{1H} NMR
(75 MHz, CDCl3): δ 142.3, 128.5, 127.6, 127.1, 78.3, 59.0,
53.9, 51.5, 23.5; HRMS (ESI): [M+H]+ calcd for C20H25N2 m/z
293.2018; found 293.2023.
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6
7
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1
as a solid (14.2 g, 100%). LC-MS: 317.88 [M+H]+; H NMR
2-(1-benzhydrylazetidin-3-yl)decahydroisoquinoline
(6).
(300 MHz, CDCl3): δ 7.41-7.38 (m, 4H), 7.30-7.25 (m, 4H),
7.22-7.17 (m, 2H), 5.10 (m, 1H), 4.41 (s, 1H), 3.67-3.62 (m,
2H), 3.23-3.18 (m, 2H), 2.98 (s, 3H).
After stirring at 80 °C overnight, the mixture was placed in
a -20 °C freezer for 16 h, giving crystals. These were
collected by filtration and rinsed with cold MeCN to give a
crude solid, which was recrystallized from MeCN (x 2) to
give a solid (173 mg, 48% yield). LC-MS: m/z = 361.14
[M+H]+; 1H NMR (300 MHz, CDCl3): δ 7.42-7.40 (m, 4H),
7.29-7.24 (m, 4H), 7.21-7.15 (m, 2H), 4.43 (s, 1H), 3.44-
3.38 (m, 2H), 2.88-2.84 (m, 3H), 2.22-2.05 (m, 4H), 1.67-
1.34 (m, 10H); 13C{1H} NMR (75 MHz, CDCl3): δ 142.4,
128.5, 127.6, 127.1, 78.3, 59.0, 58.8, 55.3, 33.9; HRMS
(ESI): [M+H]+ calcd for C25H33N2 m/z 361.2644; found
361.2643.
General procedure for the synthesis of azetidine-3-
amines using 1 equiv of amine. A solution of 1 (630 mg,
i
2 mmol) in MeCN (9.5 mL) was treated with Pr2NEt (0.35
mL, 2 mmol) and amine (2 mmol). The reaction mixture
was sealed and stirred at 80 °C overnight. The mixture was
concentrated, and the residue was dissolved in 1:1 EtOAc /
hexanes (30 mL). The organic layer was washed with 1:1
H2O / brine (30 mL), brine (30 mL), dried over MgSO4,
filtered, concentrated and purified by silica gel column
chromatography to give the product.
1-(1-benzhydrylazetidin-3-yl)-4-phenylpiperidine (7). After
stirring at 80 °C overnight, the mixture was placed in a -20
°C freezer for 16 h, giving crystals. The solid was purified
by silica gel column chromatography using 0:1 to 1:4
EtOAc / hexanes to give a solid (288 mg, 75% yield). LC-
MS: m/z = 383.14 [M+H]+; 1H NMR (300 MHz, CDCl3): δ
7.46-7.43 (m, 4H), 7.34-7.17 (m, 11H), 4.48 (s, 1H), 3.49-
3.45 (m, 2H), 3.05-2.85 (m, 5H), 2.55-2.44 (m, 1H), 1.93-
1.71 (m, 6H); 13C{1H} NMR (75 MHz, CDCl3): δ 146.3, 142.3,
128.5, 127.6, 127.2, 126.9, 126.3, 78.1, 58.8, 55.3, 51.1,
42.6, 32.9; HRMS (ESI): [M+H]+ calcd for C27H31N2 m/z
383.2487; found 383.2475.
N,N-diallyl-1-benzhydrylazetidin-3-amine (3). Purified
using 0:1 to 3:7 EtOAc / hexanes as eluent to give a solid
(408 mg, 64% yield). LC-MS: m/z = 319.34 [M+H]+; 1HNMR
(300 MHz, CDCl3): δ 7.42-7.38 (m, 4H), 7.29-7.24 (m, 4H),
7.20-7.15 (m, 2H), 5.88-5.74 (m, 2H), 5.15-5.08 (m, 4H),
4.38 (s, 1H), 3.43-3.27 (m, 3H), 3.01 (d, J = 6.4 Hz, 4H),
2.88-2.83 (m, 2H); 13C{1H} NMR (75 MHz, CDCl3): δ 142.3,
134.7, 128.5, 127.6, 127.2, 118.2, 78.5, 59.8, 54.3, 52.9;
HRMS (ESI): [M+H]+ calcd for C22H27N2 m/z 319.2174;
found, 319.2171.
4-(1-Benzhydrylazetidin-3-yl)morpholine (4). Purified using
0:1 to 1:1 EtOAc / hexanes as eluent to give an oil (239 mg,
77% yield). LC-MS: m/z = 309.29 [M+H]+; 1H NMR (300
MHz, CDCl3): δ 7.42-7.40 (m, 4H), 7.28-7.24 (m, 4H), 7.20-
7.15 (m, 2H), 4.51 (s, 1H), 3.42-3.39 (m, 2H), 3.17 (m, 3H),
2.63 (m, 4H), 1.88 (m, 4H); 13C{1H} NMR (75 MHz, CDCl3):
δ 142.2, 128.5, 127.6, 127.2, 78.3, 66.7, 58.0, 55.0, 50.3;
HRMS (ESI): [M+H]+ calcd for C20H25N2O m/z 309.1967;
found 309.1968.
1-(1-Benzhydrylazetidin-3-yl)-4-((4-
chlorophenyl)(phenyl)methyl)piperazine (8). Purified using
5:95 to 45:55 EtOAc / hexanes as eluent to give a solid
(355 mg, 69% yield). LC-MS: m/z = 508.07 [M+H]+; 1H NMR
(300 MHz, CDCl3): δ 7.40-7.31 (m, 8H), 7.28-7.15 (m, 11H),
4.40 (s, 1H), 4.21 (s, 1H), 3.41-3.37 (m, 2H), 3.01-2.95 (m,
1H), 2.89-2.85 (m, 2H), 2.32 (m, 8H); 13C{1H} NMR (75
MHz, CDCl3): δ 142.2, 142.1, 141.3, 132.6, 129.3, 128.7,
128.69, 128.5, 127.9, 127.6, 127.3, 127.2, 78.2, 75.4, 58.3,
55.0, 51.3, 50.2; HRMS (ESI): [M+H]+ calcd for C33H35ClN3
m/z 508.2519; found 508.2522.
General procedure for the synthesis of azetidine-3-
amines using 2 equiv of amine. A solution of 1 (317 mg,
1 mmol) in MeCN (5 mL) was treated with amine (2
mmol). The reaction mixture was sealed and stirred at 80
°C overnight. The mixture was concentrated, and the
residue was dissolved in 1:1 EtOAc / hexanes (30 mL). The
organic layer was washed with 1:1 H2O / brine (30 mL),
brine (30 mL), dried over MgSO4, filtered, concentrated
and purified by silica gel column chromatography.
Tert-butyl
2-(1-benzhydrylazetidin-3-yl)-2,6-
diazaspiro[3.4]octane-6-carboxylate (9). Purified using 1:1
to 1:0 EtOAc / hexanes as eluent to give an oil (94 mg, 21%
yield). LC-MS: m/z = 434.10 [M+H]+; 1H NMR (300 MHz,
CDCl3): δ 7.41-7.38 (m, 4H), 7.28-7.24 (m, 4H), 7.19-7.15
(m, 2H), 4.35 (s, 1H), 3.41 (s, 2H), 3.37-3.22 (m, 5H), 3.16-
3.12 (m, 4H), 2.93-2.89 (m, 2H), 2.06-1.95 (m, 2H), 1.45 (s,
9H); 13C{1H} NMR (75 MHz, CDCl3): δ 154.6, 142.3, 128.5,
127.5, 127.2, 79.4, 78.2, 60.4, 60.2, 56.7, 55.9, 55.2, 54.6,
44.9, 44.4, 40.6, 39.7, 36.3, 35.4, 28.6; HRMS (ESI): [M+H]+
calcd for C27H36N3O2 m/z 434.2808; found 434.2793.
1-(1-Benzhydrylazetidin-3-yl)piperidine (2). Purified using
0:1 to 1:4 EtOAc / hexanes as eluent to give a solid (221
mg, 72% yield). LC-MS: m/z = 307.36 [M+H]+; 1H NMR (300
MHz, CDCl3): δ 7.41-7.38 (m, 4H), 7.27-7.22 (m, 4H), 7.17-
7.13 (m, 2H), 4.42 (s, 1H), 3.39 (m, 2H), 2.88 (m, 3H), 2.17
(m, 4H), 1.55-1.52 (m, 4H), 1.41-1.40 (m, 2H). 13C{1H}
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1-(1-benzhydrylazetidin-3-yl)-1,2,3,4-tetrahydroquinoline
1H), 2.32-2.24 (m, 1H), 2.15-2.03 (m, 4H), 1.99-1.90 (m,
1H); 13C{1H} NMR (75 MHz, CDCl3): δ 160.8, 142.2, 142.2,
141.2, 128.9, 128.5, 128.5, 127.9, 127.6, 127.2, 126.9 (q, J =
4 Hz, 2C), 125.9, 124.5 (q, J = 271 Hz, 1C), 122.8 (q, J = 33
Hz, 1C), 115.9, 78.6, 78.3, 59.22, 59.16, 55.2, 50.7, 38.5,
36.3; 19F NMR (282 MHz, CDCl3): δ -61.5; HRMS (ESI):
[M+H]+ calcd for C33H34F3N2O m/z 531.2623; found
531.2625.
1
2
3
4
5
6
7
8
(10). After stirring at 80 °C overnight, the mixture was
placed in a 0-5 °C fridge for 16 h, giving crystals. The solid
was purified by silica gel column chromatography using
0:1 to 1:9 EtOAc +1% Et3N / hexanes +1% Et3N as eluent to
give a solid (121 mg, 34% yield). LC-MS: m/z = 355.05
[M+H]+; 1H NMR (300 MHz, CDCl3): δ 7.45-7.42 (m, 4H),
7.31-7.26 (m, 4H), 7.22-7.16 (m, 2H), 7.00-6.95 (m, 2H),
6.64 (t, J = 7.3 Hz, 1H), 6.34 (d, J = 8.2 Hz, 1H), 4.36 (s, 1H),
4.05 (m, 1H), 3.67 (t, J = 7.3 Hz, 2H), 3.03 (m, 4H), 2.74 (t, J
= 6.4 Hz, 2H), 1.94 (m, 2H); 13C{1H} NMR (75 MHz, CDCl3):
δ 145.9, 142.1, 128.9, 128.6, 127.6, 127.3, 126.9, 124.7,
117.4, 112.0, 78.6, 59.7, 49.7, 44.5, 27.7, 22.9; HRMS (ESI):
[M+H]+ calcd for C25H27N2 m/z 355.2174; found 355.2176.
1-Benzhydryl-N-((1S,4S)-4-(3,4-dichlorophenyl)-1,2,3,4-
tetrahydronaphthalen-1-yl)-N-methylazetidin-3-amine (15).
Purified using 0:1 to 1:4 EtOAc / hexanes as eluent to give
a solid (313 mg, 59% yield). LC-MS: m/z = 527.17 [M+H]+;
1H NMR (300 MHz, CDCl3): δ 7.80 (d, J = 7.6 H, 1H), 7.45-
7.42 (m, 4H), 7.31-7.25 (m, 6H), 7.22-7.11 (m, 3H), 7.07 (s,
1H), 6.87 (d, J = 7.6 Hz, 1H), 6.79 (d, J = 6.4 Hz, 1H), 4.38 (s,
1H), 4.12-4.08 (m, 1H), 3.76 (t, J = 7.9 Hz, 1H), 3.57-3.51
(m, 1H), 3.43-3.41 (m, 2H), 2.89-2.88 (m, 2H), 2.12-1.90
(m, 5H), 1.59-1.52 (m, 2H); 13C{1H} NMR (75 MHz, CDCl3):
δ 147.5, 142.3, 139.0, 138.2, 132.2, 130.8, 130.3, 130.0,
130.0, 128.5, 128.3, 127.6, 127.2, 127.1, 126.9, 78.7, 59.6,
59.0, 58.3, 51.6, 43.6, 32.5, 30.2, 15.8; HRMS (ESI): [M+H]+
calcd for C33H33Cl2N2 m/z 527.2021; found 527.2021.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1-Benzhydryl-N-benzyl-N-methylazetidin-3-amine
(11).
After stirring at 80 °C overnight, the mixture was placed in
a -20 °C freezer for 16 h, giving crystals. These were
collected by filtration and carefully rinsed with a small
amount of cold MeCN to give a solid (239 mg, 69% yield).
1
LC-MS: m/z = 343.02 [M+H]+; H NMR (300 MHz, CDCl3): δ
7.44-7.41 (m, 4H), 7.33-7.16 (m, 11H), 4.42 (s, 1H), 3.45 (t,
J = 6.7 Hz, 2H), 3.33 (s, 2H), 3.11 (m, 1H), 2.91 (t, J = 7.0 Hz,
2H), 1.97 (s, 3H); 13C{1H} NMR (75 MHz, CDCl3): δ 142.3,
137.7, 129.5, 128.5, 128.3, 127.6, 127.24, 127.21, 78.5,
59.2, 59.0, 54.7, 38.3; HRMS (ESI): [M+H]+ calcd for
C24H27N2 m/z 343.2174; found 343.2172.
1-Benzhydryl-N-benzylazetidin-3-amine (16). Purified using
1:9 to 1:0 EtOAc +1% Et3N / hexanes +1% Et3N as eluent to
give a solid (159 mg, 48% yield). LC-MS: m/z = 329.21
1
[M+H]+; H NMR (300 MHz, CDCl3): δ 7.43-7.17 (m, 15H),
1-Benzhydryl-N,N-diisopropylazetidin-3-amine (12). After
stirring at 80 °C overnight, the mixture was placed in a 0-5
°C fridge for 16 h, giving crystals, which were washed with
cold MeCN to give a solid (158 mg, 49% yield). LC-MS: m/z
4.34 (s, 1H), 3.71 (s, 2H), 3.57-3.49 (m, 3H), 2.78-2.75 (m,
2H); 13C{1H} NMR (75 MHz, CDCl3): δ 142.3, 140.0, 128.6,
128.5, 128.3, 127.5, 127.2, 78.6, 61.9, 51.7, 48.4; HRMS
(ESI): [M+H]+ calcd for C23H25N2 m/z 329.2018; found
329.2015.
1
= 323.09 [M+H]+; H NMR (300 MHz, CDCl3): δ 7.43-7.40
(m, 4H), 7.29-7.24 (m, 4H), 7.21-7.16 (m, 2H), 4.37 (s, 1H),
3.71 (m, 1H), 3.42-3.37 (m, 2H), 2.94 (m, 2H), 2.83 (t, J =
7.6 Hz, 2H), 0.96 (d, J = 6.5 Hz, 12H); 13C{1H} NMR (75
MHz, CDCl3): δ 142.4, 128.5, 127.6, 127.1, 78.4, 61.3, 47.0,
46.5, 21.3; HRMS (ESI): [M+H]+ calcd for C22H31N2 m/z
323.2487; found 323.2488.
(S)-1-benzhydryl-N-(1-phenylethyl)azetidin-3-amine (17).
Purified using 0:1 to 3:7 EtOAc / hexanes as eluent to give
an oil (208 mg, 60% yield). LC-MS: m/z = 343.06 [M+H]+;
1H NMR (300 MHz, CDCl3): δ 7.40-7.36 (m, 4H), 7.33-7.15
(m, 11H), 4.29 (s, 1H), 3.73 (q, J = 6.4 Hz, 1H), 3.50-3.31 (m,
3H), 2.72 (t, J = 6.4 Hz, 1H), 2.62 (t, J = 6.4 Hz, 1H), 1.34 (d, J
= 7.0 Hz, 3H); 13C{1H} NMR (75 MHz, CDCl3): δ 145.2,
142.3, 128.6, 128.5, 127.5, 127.5, 127.2, 127.1, 127.1,
126.7, 78.6, 62.3, 62.3, 56.5, 47.0, 24.0; HRMS (ESI):
[M+H]+ calcd for C24H27N2 m/z 343.2174; found 343.2173.
1-(1-Benzhydrylazetidin-3-yl)-4-(3-
(trifluoromethyl)phenyl)piperazine (13). After stirring at 80
°C overnight, the mixture was cooled and treated with
EtOAc (10 mL), giving a solid, which was collected by
filtration. The filtrate was concentrated, and the residue
was purified by silica gel column chromatography using
5:95 to 3:7 EtOAc / hexanes as eluent to give a solid (397
mg, 87% yield). LC-MS: m/z = 452.10 [M+H]+; 1H NMR (300
MHz, CDCl3): δ 7.44-7.41 (m, 4H), 7.36-7.26 (m, 5H), 7.22-
7.17 (m, 2H), 7.08-7.02 (m, 3H), 4.44 (s, 1H), 3.45 (m, 2H),
3.25-3.22 (t, J = 5.0 Hz, 4H), 3.04-2.95 (m, 3H), 2.47-2.44 (t,
J = 5.0 Hz, 4H); 13C{1H} NMR (75 MHz, CDCl3): δ 151.4,
142.1, 131.5 (q, J = 32 Hz, 1C), 129.7, 128.6, 127.6, 127.3,
124.4 (q, J = 272 Hz, 1C), 118.8, 116.0 (q, J = 3 Hz, 1C),
112.3 (q, J = 4 Hz, 1C), 78.3, 58.2, 54.8, 49.8, 48.4; 19F NMR
(282 MHz, CDCl3): δ -62.7; HRMS (ESI): [M+H]+ calcd for
C27H29F3N3 m/z 452.2314; found 452.2302.
1-Benzhydryl-N-octylazetidin-3-amine (18). After stirring at
80 °C overnight, the mixture was placed in a 0-5 °C fridge
for 16 h, giving crystals. The filtrate was purified by silica
gel column chromatography using 1:4 to 3:7 EtOAc
/
hexanes as eluent to give a solid (165 mg, 47% yield). LC-
MS: m/z = 351.14 [M+H]+; 1H NMR (300 MHz, CDCl3): δ
7.42-7.38 (m, 4H), 7.29-7.24 (m, 4H), 7.21-7.15 (m, 2H),
4.32 (s, 1H), 3.54-3.42 (m, 3H), 2.74-2.70 (m, 2H), 2.50 (t, J
= 7.3 Hz, 2H), 1.45-1.41 (m, 3H), 1.32-1.20 (m, 10H), 0.88
(t, J = 6.7 Hz, 3H); 13C{1H} NMR (75 MHz, CDCl3): δ 142.3,
128.5, 127.6, 127.2, 78.7, 62.1, 48.9, 47.7, 31.9, 30.4, 29.6,
29.4, 27.5, 22.8, 14.2; HRMS (ESI): [M+H]+ calcd for
C24H35N2 m/z 351.2800; found 351.2794.
1-Benzhydryl-N-methyl-N-(3-phenyl-3-(4-
(trifluoromethyl)phenoxy)propyl)azetidin-3-amine
Purified using 5:95 to 3:7 EtOAc / hexanes as eluent to give
an oil (423 mg, 79% yield). LC-MS: m/z = 531.10 [M+H]+;
1H NMR (300 MHz, CDCl3): δ 7.44-7.16 (m, 17H), 6.88 (d, J
= 8.8 Hz, 2H), 5.29-5.25 (m, 1H), 4.22 (s, 1H), 3.38-3.36 (m,
2H), 3.03-2.99 (m, 1H), 2.79-2.71 (m, 2H), 2.47-2.38 (m,
1-Benzhydryl-N-(2,2-difluoroethyl)azetidin-3-amine (19).
After stirring at 80 °C overnight, the mixture was placed in
a 0-5 °C fridge for 16 h, giving crystals. The filtrate was
purified by silica gel column chromatography using 0:1 to
1:9 MeOH/ DCM as eluent to give an oil (128 mg, 42%
yield). LC-MS: m/z = 302.99 [M+H]+; 1H NMR (300 MHz,
CDCl3): δ 7.41-7.37 (m, 4H), 7.29-7.25 (m, 4H), 7.21-7.16
(14).
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(m, 2H), 5.98-5.57 (m, 1H), 4.31 (s, 1H), 3.51-3.46 (m, 3H),
Page 6 of 8
MHz, CDCl3): δ 7.40-7.37 (m, 4H), 7.29-7.24 (m, 4H), 7.20-
7.15 (m, 2H), 4.30 (s, 1H), 3.98 (m, 2H), 3.57-3.51 (m, 3H),
2.75-2.66 (m, 4H), 2.62-2.52 (m, 1H), 1.73-1.70 (m, 2H),
1.43 (s, 9H), 1.28-1.14 (m, 2H); 13C{1H} NMR (75 MHz,
CDCl3): δ 154.8, 142.2, 128.5, 127.5, 127.2, 79.5, 78.6, 63.0,
54.1, 46.8, 33.0, 28.5; HRMS (ESI): [M+H]+ calcd for
C26H36N3O2 m/z 422.2808; found 422.2791.
2.97-2.85 (m, 2H), 2.77-2.70 (m, 2H); 13C{1H} NMR (75
MHz, CDCl3): δ 142.1, 128.6, 127.5, 127.2, 115.7 (t, J = 241
Hz, 1C), 78.5, 61.7, 49.7 (t, J = 24 Hz, 1C), 49.0; 19F NMR
(282 MHz, CDCl3): δ -122.1 (dt, J = 56, 15 Hz, 2F); HRMS
(ESI): [M+H]+ calcd for C18H21F2N2 m/z 303.1673; found
303.1673.
1
2
3
4
5
6
1-Benzhydryl-N-(2,2,2-trifluoroethyl)azetidin-3-amine (20).
Purified using 0:1 to 5:95 MeOH / DCM as eluent to afford
a crude solid, which was purified again using 0:1 to 3:7
EtOAc +1% Et3N / hexanes +1% Et3N as eluent to give a
solid (141 mg, 44% yield); LC-MS: m/z = 320.95 [M+H]+; 1H
NMR (300 MHz, CDCl3): δ 7.40-7.38 (m, 4H), 7.30-7.25 (m,
4H), 7.21-7.16 (m, 2H), 4.30 (s, 1H), 3.52-3.51 (m, 3H), 3.14
(q, J = 9.4 Hz, 2H), 2.74 (m, 2H); 13C{1H} NMR (75 MHz,
CDCl3): δ 142.1, 128.6, 127.5, 127.3, 125.3 (q, J = 279 Hz,
1C), 78.5, 62.0, 49.1 (q, J = 31 Hz, 1C), 49.0; 19F NMR (282
MHz, CDCl3): δ -72.2 (t, J = 9 Hz, 3F); HRMS (ESI): [M+H]+
calcd for C18H20F3N2 m/z 321.1579; found 321.1578.
1-Benzhydryl-N-cyclobutylazetidin-3-amine (25). After
stirring at 80 °C overnight, the mixture was placed in a 0-5
°C fridge for 16 h, giving crystals. The filtrate was
concentrated, and the residue was purified by silica gel
column chromatography using 0:1 to 1:9 MeOH / DCM,
then again using 1:4 to 1:1 EtOAc +1% Et3N / hexanes +1%
Et3N as eluent to give an oil (80 mg, 27% yield). LC-MS:
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
m/z = 293.00 [M+H]+; H NMR (300 MHz, CDCl3): δ 7.41-
7.39 (m, 4H), 7.29-7.24 (m, 4H), 7.20-7.16 (m, 2H), 4.30 (s,
1H), 3.52-3.42 (m, 3H), 3.23-3.16 (m, 1H), 2.75-2.67 (m,
2H), 2.16-2.07 (m, 2H), 1.74-1.54 (m, 5H); 13C{1H} NMR
(75 MHz, CDCl3): δ 142.3, 128.5, 127.5, 127.2, 78.7, 62.5,
52.9, 47.1, 31.7, 15.1; HRMS (ESI): [M+H]+ calcd for
C20H25N2 m/z 293.2018; found 293.2018.
1-Benzhydryl-N-(2-methoxyethyl)azetidin-3-amine
(21).
Purified using 0:1 to 5:95 MeOH / DCM +1% Et3N as eluent
to give an oil, which after cooling at -20 °C solidified to a
1-Benzhydryl-N-(2-(5-methoxy-1H-indol-3-yl)ethyl)azetidin-
3-amine (26). After stirring at 80 °C overnight, the mixture
was placed in a -20 °C freezer for 16 h, giving crystals. The
filtrate was concentrated, and the residue was purified by
silica gel column chromatography using 5:95 to 1:0 EtOAc
+1% Et3N/ hexanes +1% Et3N as eluent, then 1:99 to 5:95
MeOH / DCM as eluent to give a solid (71 mg, 17% yield).
1
solid (99 mg, 33% yield). LC-MS: m/z = 297.04 [M+H]+; H
NMR (300 MHz, CDCl3): δ 7.41-7.37 (m, 4H), 7.29-7.23 (m,
4H), 7.20-7.15 (m, 2H), 4.32 (s, 1H), 3.54-3.48 (m, 3H), 3.44
(t, J = 5.3 Hz, 2H), 3.34 (s, 3H), 2.76-2.68 (m, 4H); 13C{1H}
NMR (75 MHz, CDCl3): δ 142.3, 128.5, 127.5, 127.1, 78.6,
72.1, 61.9, 58.9, 48.8, 47.0; HRMS (ESI): [M+H]+ calcd for
C19H25N2O m/z 297.1967; found 297.1972.
1
LC-MS: m/z = 412.10 [M+H]+; H NMR (300 MHz, CDCl3): δ
7.93 (s, 1H), 7.39-7.36 (m, 4H), 7.32-7.23 (m, 5H), 7.19-
7.15 (m, 2H), 7.00 (dd, J = 8.8, 2.4 Hz, 2H), 6.86 (dd, J = 8.8,
2.3 Hz, 1H), 4.30 (s, 1H), 3.83 (s, 3H), 3.56-3.47 (m, 3H),
2.94-2.83 (m, 4H), 2.74-2.71 (m, 2H), 1.75 (s, 1H); 13C{1H}
NMR (75 MHz, CDCl3): δ 154.0, 142.2, 131.6, 128.5, 127.8,
127.5, 127.2, 122.9, 113.5, 112.4, 112.0, 100.7, 78.5, 61.7,
56.0, 48.8, 47.6, 26.1; HRMS (ESI): [M+H]+ calcd for
C27H30N3O m/z 412.2389; found 412.2379.
2-((1-Benzhydrylazetidin-3-yl)amino)ethanol (22). Purified
using 1:9 to 1:0 EtOAc +1% Et3N / hexanes +1% Et3N as
eluent to give a solid (78 mg, 27% yield); LC-MS: m/z =
1
282.96 [M+H]+; H NMR (300 MHz, CDCl3): δ 7.41-7.38 (m,
4H), 7.30-7.24 (m, 4H), 7.21-7.18 (m, 2H), 4.33 (s, 1H), 3.62
(t, J = 5.0 Hz, 2H), 3.50-3.49 (m, 3H), 2.80-2.79 (m, 2H),
2.70 (t, J = 5.0 Hz, 2H); 13C{1H} NMR (75 MHz, CDCl3): δ
142.0, 128.5, 127.5, 127.2, 78.5, 61.3, 60.9, 48.8, 48.4;
HRMS (ESI): [M+H]+ calcd for C18H23N2O m/z 283.1811;
found 283.1811.
ASSOCIATED CONTENT
Supporting Information. FAIR Data is available as
Supporting Information for Publication and includes the
primary NMR FID files for compounds 2-26. Graphical
representation of a 1 mmol scale reaction. Analytical data (1H,
13C, 19F NMR, HPLC) for all new compounds (PDF). The
Supporting Information is available free of charge on the
Internet at http://pubs.acs.org.
(R)-tert-butyl
3-((1-benzhydrylazetidin-3-
yl)amino)pyrrolidine-1-carboxylate (23). After stirring at
80 °C overnight, the mixture was placed in a -20 °C freezer
for 16 h, giving crystals. The filtrate was purified by silica
gel column chromatography using 0:1 to 9:1 EtOAc /
hexanes as eluent to give a solid (221 mg, 54% yield). LC-
MS: m/z = 408.10 [M+H]+; 1H NMR (300 MHz, CDCl3): δ
7.40-7.38 (m, 4H), 7.31-7.24 (m, 4H), 7.20-7.15 (m, 2H),
4.30 (s, 1H), 3.53-3.34 (m, 5H), 3.31-3.25 (m, 2H), 3.02-
2.96 (m, 1H), 2.69 (m, 2H), 2.02-1.93 (m, 1H), 1.66-1.55 (m,
2H), 1.43-1.42 (m, 9H); 13C{1H} NMR (75 MHz, CDCl3): δ
154.6, 142.1, 128.6, 127.5, 127.2, 79.3, 78.6, 62.7, 62.4,
56.5, 55.7, 52.0, 51.7, 47.8, 44.4, 44.0, 32.4, 31.7, 28.6;
HRMS (ESI): [M+H]+ calcd for C25H34N3O2 m/z 408.2651;
found 408.2638.
AUTHOR INFORMATION
Corresponding Author
*matt@dunctonllc.com
Author Contributions
All authors have given approval to the final version of the
manuscript.
Tert-butyl 4-((1-benzhydrylazetidin-3-yl)amino)piperidine-
1-carboxylate (24). After stirring at 80 °C overnight, the
mixture was placed in a 0-5 °C fridge for 16 h, giving
crystals. The filtrate was concentrated, and the residue
was purified by silica gel column chromatography using
1:9 to 1:0 EtOAc / hexanes as eluent to give a solid (122
mg, 28% yield). LC-MS: m/z = 422.13 [M+H]+; 1H NMR (300
Notes
The authors declare no competing conflicts.
ACKNOWLEDGMENT
We thank Vanessa Portman of Sygnature Discovery, BioCity,
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The Journal of Organic Chemistry
Antibiotics and Their Use as Antibacterial and
Antiprotozoal Agents. US20060135447 (2006); Chem.
Abstr. 145, 83616.
Pennyfoot Street, Nottingham, NG1 1GR, United Kingdom for
high-resolution mass spectrometry.
1
2
3
4
5
6
7
8
9
(8) Han, M.; Song, C.; Jeong, N.; Hahn, H. Exploration of 3-
Aminoazetidines as Triple Reuptake Inhibitors by
Bioisosteric Modification of 3-α-Oxyazetidine. ACS Med.
Chem. Lett. 2014, 5, 999−1004.
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(24) Available from from ca. $200 for 100g (ca. $2 per 1g).
R1
MsO
N
R2
N
N
Ph
Ph
Ph
Ph
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