Regio- And Diastereoselective Synthesis of 2-Arylazetidines: Quantum Chemical Explanation of Baldwin's Rules for the Ring-Formation Reactions of Oxiranes ?

Article abstract of DOI:10.1021/acs.joc.0c01310

A general, scalable two-step regio- and diastereoselective method has been described for the synthesis of versatile alkaloid-type azetidines from simple building blocks with excellent overall yields. In the kinetically controlled reaction, only the format

Full text of DOI:10.1021/acs.joc.0c01310

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Article
Regio- and Diastereoselective Synthesis of 2-
Arylazetidines. Quantum Chemical Explanation of Baldwin’s
Rules for the Ring-formation Reactions of Oxiranes.
Ervin Kovács, Ferenc Faigl, and Zoltán Mucsi
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c01310 • Publication Date (Web): 10 Aug 2020
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The Journal of Organic Chemistry
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Regio- and Diastereoselective Synthesis of 2-Arylazetidines. Quantum
Chemical Explanation of Baldwin’s Rules for the Ring-formation Reac-
tions of Oxiranes.
Ervin Kovács,†,‡, §,* Ferenc Faigl‡ and Zoltán Mucsi§,*
†
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Institute of Materials and Environmental Chemistry, Research Centre for Natural Sciences, Hungarian Academy of
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Sciences, Budapest, H-1117 Hungary
‡MTA-BME Organic Chemical Technology Research Group, Budapest University of Technology and Economics, Bu-
dafoki út 8, H-1111 Budapest, Hungary
§Femtonics Ltd., Budapest, H-1094 Hungary
Supporting Information Placeholder
This research paper is dedicated to the memory of Professor Sir Jack Edward Baldwin who pioneered the selectivity of the ring
closure reactions of alicyclic compounds.
challenging synthetic topic for nowadays chemists. Com-
pared to their widespread uses, there are relatively few
synthetic methods available, although they cover a wide
range of structural variability.3,36–38 In conclusion, there are
no general methods for the synthesis of azetidines, with
wide variety of functional groups.39 Only a few methods for
the preparation of drug-like azetidines have been report-
ed.40–46
ABSTRACT: A general, scaleable two-step regio- and dia-
stereoselective method has been described for the synthe-
sis of versatile alkaloid-type azetidines from simple build-
ing blocks with excellent overall yields. In the kinetically
controlled reaction, only the formation of the strained
four-membered ring can be achieved instead of the ther-
modynamically favorable five-membered rings under ap-
propriate conditions. Remarkable functional group toler-
ance has also been demonstrated. In this paper we give a
new scope of Baldwin’s rules by DFT calculations with
explicit solvent model, confirming the proposed reaction
mechanisms and the role of kinetic controls in the stereo-
chemical outcome of the reported transition metal-free
carbon-carbon bond formation reactions.
2-Arylazetidines have also a huge potential in synthetic
and medicinal chemistry47–51 (Scheme 1) even though
there is no general synthetic method is known. Only a few
approaches have been developed for the synthesis of 2-
phenylazetidines. N-protected 2-arylazetidines can be
synthetized by stereospecific cross-coupling reactions52, by
selective intermolecular sp3-C–H amination53 or by [2+2]
photocycloaddition1. A few efficient synthesis of diversely
substituted N-aryl-2-cyanoazetidines have also published,
based on an anionic ring closure reaction, that requires the
presence of electron withdrawing group in the starting
material.54 A similar reaction promoted by non-commonly
used base has been reported by our group few years ago.55
INTRODUCTION
Despite the irrefutable importance of azetidines as bio-
active compounds and pharmaceutical building blocks,
they have received moderate attention compared to larger
ring sized pyrrolidines and piperidines.1–3 The most im-
portant strategy for the synthesis of saturated N-
heterocycles relies on unimolecular cyclization reactions
by nucleophilic substitution. This approach results in the
efficient formation of three-, five-, and six-membered het-
erocycles, but often fails to result four-membered. In gen-
eral, azetidines are considered the most difficult of all to
form.4 Azetidines have excellent physicochemical proper-
ties, bioavailability and metabolic stability5–8. Wide variety
of antibiotics,9–13 numerous anti-cancer agents14,15 con-
tained azetidines as well as other drug molecules devel-
oped over the last decade13,16–21. They have a significant
role as synthetic building blocks of foldamers,22,23 N-
heterocycles24–28 and polymers29. It has also been demon-
strated, that the introduction of these strained rings im-
prove enormously the fluorescent properties of rhoda-
mines30–32 and coumarins33, the efficacy of homogenous
catalyst as ligands,34,35 which makes them an attractive and
Our goal was to enrich the available chemical library
with trans-3-(hydroxymethyl)-2-arylazetidines (1 in
Scheme 1) for a fragment-based drug discovery, by a novel
and versatile chemical synthesis from simple and readily
available oxiranylmethyl substituted benzylamines. This
method is inspired and designed according to Baldwin’s
rules.56 While some theoretical explanation were published
in the last decade,57–59 the quantum chemical background
has not been established up since now.
Scheme 1. Chemical skeleton of 2-arylazetidine-3-
ylmethanol derivatives (1) and selected examples for bio-
active 2-arylazetidines. (LG: leaving group.)
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RESULTS AND DISCUSSION
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Our synthetic method to prepare 2-arylazetidines 1,
consists of only two or four simple synthetic steps form
commercially available starting materials (substituted
oxiranes and N-alkyl-benzylamines), providing large range
for functionalization. The key intermediates 2 were syn-
thesized from N-substituted benzylamines (3) and epichlo-
rohydrin (4) or readily prepared 2-substituted-(oxiran-2-
yl)methyl 4-toluenesulfonates (5–7) (Scheme 2). As it was
demonstrated earlier, this versatile epoxide intermediates
could be synthetized easily in a two-step procedure from
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commercially available allyl alcohol derivatives (8) 60,61
.
Scheme 2. Synthesis and isolated yields of the key inter-
mediate oxiranylmethyl-benzylamine derivatives (2) from
epichlorohydrine (4) or tosylates (5-7).
The key intermediates 2 (0.5 mmol) were treated with
the mixture of lithium diisopropylamide and potassium
tert-butoxyde (LiDA-KOR superbase) in tetrahydrofuran at
–78 °C. The four membered ring was formed regio- and
diastereoselectively55. Noteworthy, that compound 2 re-
acted exclusively on its benzylic position (Scheme 3), ex-
cluding the formation of alternative cyclic products. Spec-
troscopic investigations (J in 1H NMR, ROESY, NOESY) of
products confirmed that the substituents were situated in
a trans-geometry around the azetidine ring in position 2
and 3.The application of other bases did not yield product
1. To test the feasibility of the reaction, the metalation of
2d (in structure 2 R1 = Pr, R2 = H, R3 = Me, R4 = H) were
investigated by different types of organometallic bases
used in analogue cases under similar conditions62. Using 3
equivalents of LDA (lithium diisopropyl amide) or LiTMP
(lithium 2,2,6,6-tetramethyl pyperidide) or KHMDS (po-
tassium hexamethyldisilazide), only unreacted 2d oxirane
was isolated. When the reaction was performed by BuLi or
LiC-KOR (mixture of butyl lithium and potassium tert-
butoxyde), a complex mixture was obtained with low con-
version and azetidine 1d was detected only in traces.
Scheme 3. Scope of the LiDA-KOR induced azetidine for-
a
mation. Isolated yields of the products are also given. See
b
Scheme 4. Other products also formed see Experimental
Section.
In contrast to them, the expected yields were slightly
reduced for R2 = CH2OTrt products, as some unidentified
side-products were formed in small amounts.
Various R3 alkyl groups typically do not influence the
good yields of the reactions. However, benzyl substitution
allows the formation of certain by-products trough alter-
native deprotonation, lowering the overall yields. In the
case of the product 1g, two diastereomers formed in 5/1
ratio (LC-MS), which were separated by common column
chromatography. The N-Boc protection at the N atom al-
lows the parallel deprotonation at the C atom in cca. 1/1
ratio and the formation of an allylic-type byproduct (9,
Scheme 4), which competes with the main ring opening
mechanism.
This reaction was proved to be a scalable process as 1k
were prepared in 20 mmol scale with similar yields of the
0.5 mmol reaction.
In general, the isolated yields varied between moderate
to good values with rather good substituent tolerance,
except few examples. Comparing this two-step synthetic
procedure with alternate literature alternative protocols,
this furnishes significantly higher overall production and
efficacy. In the cases when the R1/R2 group is H, Pr or Ph,
the yields of the azetidine products resulted moderate to
good yields without significant appearance of any side-
product.
The EDG substituents (tBu, OMe) and F at the Ph ring
(R4) had beneficial effect on the yields of the reaction. In
contrast to that, the strong EWG CF3 group at para and
ortho positions (see SI) could stabilize the benzyl anion
and decreased its nucleophilic character to inhibit the ring
opening. Benzylamine moiety containing bicyclic com-
pounds were also tested. The N-oxiranylmethyl isoindole
did not afford the desired fused heterocyclic product under
the conditions applied. However, it should be emphasized
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that the reaction of the very similar tetrahydroisoquinoline
data allowed us to conclude that the reaction was con-
trolled kinetically.
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derivatives have different routes, yielded completely dif-
ferent bridged heterocyclic systems.63
In the next section, we sought to answer the question of
why the formation of the thermodynamically unfavorable
four-member azetidines is more advantageous, in agree-
ment with the Baldwin’s rules. The two lowest TSs un-
doubtedly belong to the formation of the two azetidines
1d-H+-t and 1d-H+-c, preferring the formation of trans
product, in contrast to the formation of pyrrolidines
(10d-H+-c, 10d-H+-t). The enthalpy (H‡) and Gibbs free
energy (G‡) difference between of the two lowest gaps is
only about 10 kJ mol–1. Due to the low reaction tempera-
ture applied, this difference provides the sufficient dia-
stereo selectivity under kinetic control, being in good
agreement with the experiments.
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Scheme 4. The formation of the allylic side-product (9) in the
case of N-Boc protection of the amine.
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Reaction mechanism study
It is well known for ring closure reactions that general-
ly five-member heterocycles form more commonly than
four-member products. In general, the relative reaction
rate of cyclisation steps can be two order of magnitude
larger for five membered rings.4
Table 1. Conversion of the epoxides (2d-H+) to the four
possible products (1d and 10d, t = trans, c = cis) and their
reaction enthalpy (H), Gibbs free energy (G) in kJ mol–1
and entropy (S) in J mol–1 K–1. The thermodynamic values
of the (11+12)→TS-13→13 process are also given. For
details see Figure 1.
Theoretical
calculations
were
performed
at
M06-2X/6-31G(d,p) level of theory64 with the implementa-
tion of implicit-explicit solvatation model65 ( = 12.2), by
G1666. The explicit model67 includes one Li+-ion and one
K+-ion, bounded to the O– and the Ph ring, respectively, as
shown in Figure 1. Moreover, both cations were solvated
by two-two explicit THF molecules, in order to mimic the
surrounding media in the best way. Calculated values are
given in the SI.
TS
Product-H+
2d-H+→
1d-H+-t
H
G
S
‡
‡
‡
H
G
S
50.5 58.0 -25.2 -160.2 -152.4 -26.1
1d-H+-c 65.6 67.7 -6.8 -128.8 -120.8 -27.1
10d-H+-t 70.8 79.4 -28.7 -267.1 -245.1 -73.6
10d-H+-c 77.1 80.8 -12.4 -215.3 -205.9 -31.8
TS-13
13
60.2 70.8 -72.1
11→13
-197.0 -167.4 -99.3
From thermodynamic point of view, there are five
deprotonation sites at compound 2. However, the enthal-
pically and kinetically more favorable deprotonation was
found at the benzylic position (C1), in agreement with the
experiment. During this reaction mechanism studies, we
focused only on the ring closure steps from the metalation,
leading to products for one selected molecule as example
(2d→1d), including all the possible routes (Ia, Ib, IIa and
IIb, see Table 1 and Figure 1). The ring closure (Figure 1)
of the metalated benzylaminomethyloxirane 2d-H+ may
theoretically result in both pyrrolidine (10d-H+-c, 10d-H+-
t) and azetidine products (1d-c, 1d-t), but in our experi-
ments the trans four-membered heterocycle formed regi
(up to 90%) and diastereoselectively.
Although, the computed TS values confirm the experi-
mental findings, those did not give a deep explanation for
the exclusive formation of the azetidine derivatives. More-
over, the Baldwin’s rules provide also only a superficial
and phenomenological interpretation. To reveal more
details about the mechanism, a bimolecular model reaction
(11+12)→TS-13→13, Route III in Figure 1) was also
computed under the same condition as a concerted SN2-
type reaction, which mimics an non-restricted alternative
of the previous reaction (Figure 1). Here the deprotonated
dimethyl benzylamide anion (12) reacts with trans
oxiranes (11). Surprisingly, the computed activation pa-
rameters (H‡ and G‡) are significantly higher compared
to the formation of the stretched four-member product
and somewhat lower than in the case of the five-member
product. On that basis, we suppose that the azetidine for-
mation is super-beneficial.
The resulting negatively charged nucleophilic carbon
atom (C1) can react with both electrophilic carbon atoms
in the oxirane (C2 and C3) from two faces (Route Ia, Ib, IIa
and IIb), as showed in Figure 1 leading to the two cis-trans
product pairs (1d-c/1d-t and 10d-c/10d-t), allowed by
the Baldwin’s rules. In terms of the calculated thermody-
namic stability of the resulting products, the two five-
membered pyrrolidine derivatives are more stable than
the more stressed four-membered azetidine derivatives,
regardless of their cis (10d-c→1d-c: 80.2 kJ mol–1) or trans
(10d-t→1d-t: 63.0 kJ mol–1) arrangements. In general, the
trans geometries are always more stable than cis (1d-
c→1d-t: 25.3 kJ mol–1; 10d-c→10d-t: 8.1 kJ mol–1), which
is due to larger steric hindrance of the neighboring sub-
stituents (Table 1). Since the isolated products were azet-
idine derivatives in all the cases, these thermodynamic
In the ideal transition state for SN2 reactions, the direc-
tion of the electrophile attack should be around 180 with
the central atom and the leaving group, which provides the
highest overlap between the nucleophilic HOMO and the
electrophilic LUMO molecular orbitals. In this ring closure
reaction, the central atom (C2 or C3), the attacking carban-
ion (C1), and the leaving oxygen atom (O) cannot be in this
optimal linear arrangement in either case, due to the bent
bond angles in the oxirane-ring.
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Figure 1. Conversion of the epoxide (2d-H+) to the four possible products (1d and 10d) via the four TSs (above), together
with the bimolecular reaction (below). For the corresponding thermodynamic values see Table 1.
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Analyzing the geometries of the transition states lead-
ing to the five- (TS-10d-H+-c and TS-10d-H+-t) and four-
membered rings (TS-1d-H+-c, TS-1d-H+-t; Figure 2), as
well as the TS-13, we found that the angle of the attack
enclosed by the C1-C2-O atoms is most favorable for the
formation of the four-membered trans and cis isomer
(trans: 166.2° and cis: 163.9°), than five member cases (C-
C3-O, trans: 133.2°, cis: 127.5°). Moreover, the non-
restricted model also exhibits lower angles, than TS-1d-H+
(150.6) The special preferred arrangement of the C1-C2-O
in the TS-1d-H+ is due to the stretched double bicyclic
transition structure, which provides the optimal arrange-
ment for the orbital overlap, can be illustrated by the 
value (= 180 – , blue angles in Figure 2 and Figure 3). In
the case of Route II, which leads to pyrrolidine is already
distorted in the opposite direction, thereby significantly
reducing the overlap.
Figure 2. Transition states (TS-1d-H+ and TS-10d-H+) of
the four ring closure reaction (without explicit ions and
This overlap between HOMO of 12 LUMO of 13 is sig-
nificantly less than that of the TS-1-H+, thanks to the dom-
ination of the steric hindrance in the absence of the sup-
porting ring stretch. Consequently, this may be the reason
for the lowest activation G‡ of the four-membered trans
azetidine derivative.
molecules), representing their HOMOs leading to the azet-
idine (1d) and pyrrolidine derivatives (10d) deriving from
the oxirane derivative 2d-H+. Black lines show the bond
angles between the C1-C2-O and C1-C3-O atoms, corre-
sponding to  (orange).  = 180 –  (blue). The carbon,
the hydrogen, the nitrogen, and the oxygen atoms are
marked in gray, white, blue and red.
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Excalibur). High resolution EI was obtained on an Au-
tospec (magnetic sector; analysed using MassLynx).
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Thin layer chromatography (TLC) was performed on
commercially available pre-coated TLC plates (Merck Silica
gel 60 F254 aluminium sheets or Merck Aluminium oxide 60
F254 plates). Visualisation was either achieved under UV
light at 254 nm or by exposing it with iodine or the aque-
ous solution of (NH4)6Mo7O24, Ce(SO4)2 and sulfuric acid.
8
9
Flash column chromatography was performed by a Com-
biFlash Rf 150 (Teledyne ISCO) apparatus using gradient
elution in normal (silica column; hexane−ethyl acetate as
eluent) phase mode. Gradient elution preparative HPLC was
applied (HPLC Gilson 333 instrument, UV detector 220 nm) on
a Phenomenex Gemini C18, 250×50.00 mm; 10 µm, 110A
column using 0.4 g NH4HCO3 in 1 L water and acetonitrile
(A/B) or 10 mL trifluoroacetic acid in 1 L water and acetoni-
trile (C/B) as the two solvents.
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Figure 3. The correlation between the  ( = 180 – .)
(blue) of TS-1d-H+, TS-10d-H+, TS-13 and the related G‡
values.
General Procedures
General procedure A for the preparation of trialkyl
amines from epichlorohydrin
CONCLUSIONS
To a solution of amine (30.0 mmol, 1.0 equiv.) in EtOH (4
mL) and water (2 mL) was added epichlorohydrin (30.0
mmol, 2.35 mL, 1.0 equiv.) at 0 °C using ice bath. Stirred for 5
hours at room temperature than cooled to 0 °C on an ice bath.
Toluene (3 mL) and NaOH (0.054 mmol, 2.16 g) was added
then stirred at 25 °C for 16 hours. The mixture was concen-
trated under reduced pressure then water (20.0 mL) was
added to it. The organic compounds were extracted with di-
chloromethane (4 × 30 mL). The combined organic layers
were washed with brine (10 mL), dried over sodium sulfate,
filtered and concentrated under reduced pressure. The crude
mixture was purified by column chromatography.
In summary, an efficient, scalable, stereo- and dia-
stereo-specific method has been developed for the prepa-
ration of 2-arylazetidines (1), by using strong alkali amide-
type bases. The results of quantum chemical investigation
of the mechanism are consistent with the experimental
findings and shed light on the details of the regio- and
stereoselectivity of the azetidine formation reaction. Thus
we were able to find the quantum mechanical and struc-
tural explanation of the Baldwin’s rules for the ring open-
ing of oxiranes, controlled by the balance between the ring
stretch and overlap.
General procedure B for the preparation of trialkyl
amines from tosylates
EXPERIMENTAL SECTION
Tosylate (10.0 mmol, 1.0 equiv.) was dissolved in dry DMF
(10 mL) under dry nitrogen atmosphere and potassium iodide
(5.00 mmol, 0.5 equiv.) was added into it. The solution was
cooled to 0 °C on an ice bath and the secondary amine (HNRR’,
21.00 mmol, 2.1 equiv.) was added into the solution. The
reaction mixture was stirred for 24 hours at 40 °C heated by
an oil bath then it was poured into a mixture of ice (100 g),
saturated sodium hydrogen carbonate solution (200 mL) and
diethyl ether (50 mL) than the phases were separated and the
aqueous mixture was extracted with diethyl ether (4 × 60
mL). The combined organic layers were washed with brine
(50 mL), dried over sodium sulfate, filtered and concentrated
under reduced pressure. The crude mixture was purified by
column chromatography.
General remarks
All commercial starting materials were purchased from
Sigma-Aldrich Kft. Hungary and were used without further
purification. All organometallic reactions were conducted
under nitrogen atmosphere using Schlenk-technique under
dry nitrogen atmosphere. Solvents were freshly distilled
and dried over molecular sieves.
1H NMR and 13C {1H} NMR were recorded at 500/300
MHz, 126/75 MHz on Bruker Avance 500 or 300 spec-
1
trometers. All H NMR and 13C chemical shifts were refer-
enced to the TMS. All chemical shifts are quoted in parts
per million (ppm), measured from the centre of the signal
except in the case of multiplets, which are quoted as a
range. Coupling constants are quoted to the nearest 0.1 Hz.
Splitting patterns are abbreviated as follows: singlet (s),
doublet (d), triplet (t), quartet (q), quintet (quin), sextet
(sxt), multiplet (m), broad singlet (br. s) and combinations
thereof. Assignment of spectra was aided by DEPT 135 and
1D (NOESY), 2D NMR spectroscopy (NOESY, ROESY,
HSQC). For assignment see SI NMR Spectra.
HRMS-EI+ data were obtained using either electrospray
ionization (ESI) or electron impact (EI) techniques. High-
resolution ESI analyses were performed on an Agilent
6230 TOF LC/MS spectrometer (ion trap; analysed using
General procedure C for the preparation of N-Boc ami-
nomethyloxiranes
Sodium hydride (55% in mineral oil, 1.8 mmol, 72.2 mg,
1.5 equiv.) was washed with dry hexane (3 × 3 mL) under dry
nitrogen atmosphere, then it was dried under vacuo followed
by the addition of dry DMF (2 mL) than it was cooled (0 °C on
an ice bath). A dimethylformamide solution (7 mL) of N-Boc-
benzylamine derivative68 (1.20 mmol, 1.0 equiv.) was added
dropwise to the cold (0 °C) suspension of sodium hydride and
DMF and the mixture was stirred for 2 hours at room temper-
ature. The obtained yellowish solution was slowly added into
a dry DMF solution (7 mL) of tosylate (1.2 mmol, 1.0 equiv.) at
5 °C cooled on an ice bath under nitrogen atmosphere. The
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The Journal of Organic Chemistry
reaction mixture was stirred for 24 hours then it was poured
mmol, 2.35 mL). Purification by column chromatography on
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into a mixture of ice (15 g) and saturated sodium hydrogen
carbonate solution (10 mL). The aqueous mixture was ex-
tracted with diethyl ether (5 × 10 mL). The combined organic
layers were washed with brine (10 mL), dried over sodium
sulfate, filtered and concentrated under reduced pressure.
The crude mixture was purified by column chromatography.
silica gel (0–15% EtOAc in hexane) 2c as a yellowish oil (1.98
g, 7.80 mmol, 26%). 1H-NMR (CDCl3, 300 MHz) δH: 7.38 (4H, d,
J= 7.2 Hz, 4 × C[6]-H), 7.30 (4H, t, J= 7.2 Hz, 4 × C[7]-H), 7.26 –
7.20 (2H, m, Hz, 2 × C[8]-H), 3.80 (2H, AB d, J= 13.7, Hz, 2 ×
C[4]-H), 3.56 (1H, AB d, J= 13.7, Hz, 2 × C[4]-H), 3.06 (1H, td, J=
6.2 Hz, 3.4 Hz, C[2]-H), 2.76 (1H, dd, J= 13.8 Hz, 3.4 Hz, C[3]-H)
2.65 (1H, t, J= 4.5 Hz, C[1]-H), 2.46 – 2.37 (2H, m, C[1]-H, C[3]-
H). 13C{1H} NMR (CDCl3, 75 MHz), C: 139.3 (C[5]), 128.8
(C[6]), 128.2 (C[7]), 126.9 (C[8]), 58.9 (C[4]), 55.8 (C[3]), 51.0
(C[2]), 45.0 (C[1]). HRMS (ESI) m/z: [M+H]+ Calcd for
C17H20NO 254.1539; Found 254.1539.
General procedure D for the preparation of azetidines
via superbase induced reactions
Potassium tert-butoxide in THF (1.0 mmol, 1 mL in 1M
THF solution) was cooled to -78 °C on an cold bath, using dry
ice in acetone, in a Schlenk tube under nitrogen atmosphere
and diluted with 1 mL of abs THF. Diisopropylamine (1.0
mmol, 0.10 g, 0.14 mL, 2.0 equiv.) followed by a 1.59 M hexane
solution of butyllithium (1.5 mmol, 0.94 mL, 3.0 equiv.) were
added dropwise into the solution. The reaction mixture was
stirred for 20 minutes at -78 °C. Oxirane (2, 0.5 mmol, 1.0
equiv.) in abs. THF (2 mL) was added dropwise, the mixture
was stirred at -78 °C for 2 hours. Water (10.0 mL) and diethyl
ether (5 mL) were added to the cold mixture then it was al-
lowed to warm up to room temperature. The phases were
separated, the aqueous phase was extracted with diethyl ether
(3 × 5 mL). The combined organic layers were washed with
brine (1×10 mL), dried over sodium sulfate, filtered and con-
centrated under reduced pressure. The crude mixture was
purified by column chromatography or in some cases by pre-
parative HPLC.
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N-Benzyl-N-methyl-1-(3-propyloxiran-2-
yl)methanamine (2d): Prepared according to General Proce-
dure B using N-methylbenzylamine (16.6 mmol, 2.01 g, 2.15
mL),
and
(3-propyloxiran-2-yl)methyl
4-
methylbenzenesulfonate (6.67 mmol, 1.80 g). Purification by
column chromatography on silica gel (0–25% EtOAc in hex-
ane) afforded the title compound (2d) as a yellowish oil (1.26
g, 5.75 mmol, 86%). 1H-NMR (CDCl3, 300 MHz) δH: 7.34 – 7.24
(5H, m, C[7,8,9]-H), 3.63 (1H, AB d, J= 13.0 Hz, C[5]-H), 3.50
(1H, d, J= 13.0 Hz, C[5]-H), 2.91 – 2.85 (1H, m, C[2]-H), 2.71 –
2.64 (2H, m C[1]-H, C[3]-H), 2.40 (1H, AB dd, J= 13.2 Hz, 6.2
Hz, C[3]-H) 2.30 (3H, s, 3 × C[4]-H), 1.53 – 1.44 (4H, m, 2 ×
C[10]-H, 2 × C[11]-H), 0.95 (3H, t, J= 6.9 Hz, 3 × C[12]-H).
13C{1H} NMR (CDCl3, 75 MHz), C: 138.7 (C[6]), 129.0 (C[7]),
128.3 (C[8]), 127.1 (C[9]), 62.6 (C[5]), 59.3 (C[3]), 57.0
(C[1/2]), 56.8 (C[1/2]), 42.9 (C[4]), 33.9 (C[10]), 19.3 (C[11]),
13.9 (C[12]). HRMS (ESI) m/z: [M+H]+ Calcd for C14H22NO
220.1701; Found 220.1703.
Synthesis of benzylaminomethyl-oxiranes
N-Benzyl-N-methyl-1-(oxiran-2-yl)methanamine (2a):
N-Benzyl-N-ethyl-1-(3-propyloxiran-2-
yl)methanamine (2e): Prepared according to General Proce-
dure B using N-ethylbenzylamine (3.88 mmol, 0.525 g, 0.57
Prepared according to General Procedure
A using N-
methylbenzylamine (30.0 mmol, 3.64 g, 3.87 mL), and
epichlorohydrin (30.0 mmol, 2.35 mL). Purification by column
chromatography on silica gel (10–40% EtOAc in hexane)
afforded the title compound as a yellowish oil (2a, 3.16 g, 18.0
mmol, 60%). 1H-NMR (CDCl3, 300 MHz) δH: 7.37 – 7.21 (5H,
m, C[7,8,9]-H), 3.64 (1H, AB d, J= 13.1, Hz, C[5]-H), 3.50 (1H,
AB d, J= 13.1, Hz, C[5]-H), 3.15 – 3.07 (1H, m, C[2]-H), 2.81 –
2.68 (2H, m, 2 × C[1]-H), 2.49 – 2.41 (1H, m, C[3]-H), 2.38-2.32
(4H, m, C[3]-H, 3 × C[4]-H). 13C{1H} NMR (CDCl3, 75 MHz), C:
138.7 (C[6]), 129.0 (C[7]), 128.3 (C[8], 127.1 (C[9]), 62.6
(C[5]), 59.7 (C[3]), 50.8 (C[2]), 45.0 (C[1]), 42.9 (C[4]). HRMS
(ESI) m/z: [M+H]+ Calcd for C11H16NO 178.1226; Found
178.1219.
mL),
and
(3-propyloxiran-2-yl)methyl
4-
methylbenzenesulfonate (1.85 mmol, 0.500 g). Purification by
column chromatography on silica gel (0–30% EtOAc in hex-
ane) afforded the title compound as a yellowish oil (2e, 0.363
g, 1.55 mmol, 84%). 1H-NMR (CDCl3, 300 MHz) δH: 7.36 – 7.22
(5H, m, C[8,9,10]-H), 3.73 (1H, AB d, J=13.6 Hz, C[6]-H), 3.73
(1H, AB d, J=13.6 Hz, C[6]-H), 2.86 – 2.80 (1H, m, C[2]-H), 2.72
– 2.46 (5H, m, C[1]-H, 2 × C[4]-H, 2 × C[6]-H) 1.52 – 1.39 (4H,
m, 2 × C[11]-H, 2 × C[12]-H) 1.07 (3H, t, J=7.2 Hz, 3 × C[5]-H),
0.94 (3H, t, J= 6.8 Hz, 2 × C[13]-H). 13C{1H} NMR (CDCl3, 75
MHz), C: 139.6 (C[7]), 128.9 (C[8]), 128.2 (C[9]), 126.9
(C[10]), 58.5 (C[6]), 57.3 (C[1/2]), 57.0 (C[1/2]), 55.4 (C[3]),
48.1 (C[4]), 33.9 (C[12]), 19.3 (C[13]), 13.9 (C[14]), 11.8
(C[5]). HRMS (ESI) m/z: [M+H]+ Calcd for C15H24NO 234.1852;
Found 234.1861.
N-Benzyl-N-ethyl-1-(oxiran-2-yl)methanamine (2b):
Prepared according to General Procedure
A using N-
ethylbenzylamine (30.0 mmol, 4.06 g, 4.46 mL), and epichlo-
rohydrin (30.0 mmol, 2.35 mL). Purification by column chro-
matography on silica gel (0–30% EtOAc in hexane) afforded
2b as a yellowish oil (3.10 g, 16.2 mmol, 54%). 1H-NMR
(CDCl3, 300 MHz) δH: 7.37 – 7.21 (5H, m, C[8,9,10]-H), 3.76
(1H, AB d, J= 13.7, Hz, C[6]-H), 3.57 (1H, AB d, J= 13.7, Hz,
C[6]-H), 3.09 – 3.00 (1H, m, C[2]-H), 2.81 – 2.52 (4H, m, 2 ×
C[1]-H, 2 × C[4]-H), 2.52 – 2.37 (2H, m, C[3]-H), 1.08 (3H, t, J =
7.1 Hz, 3 × C[5]-H). 13C{1H} NMR (CDCl3, 75 MHz), C: 139.5
(C[7]), 128.9 (C[8]), 128.2 (C[9]), 126.9 (C[10]), 58.5 (C[6]),
55.8 (C[3]), 51.1 (C[2]), 48.2 (C[4]), 45.2 (C[1]), 11.9 (C[5]).
HRMS (ESI) m/z: [M+H]+ Calcd for C12H18NO 192.1383; Found
192.1382.
N,N-Dibenzyl-1-(3-propyloxiran-2-yl)methanamine
(2f): Prepared according to General Procedure B using diben-
zylamine (3.88 mmol, 0.765 g, 0.745 mL), and (3-
propyloxiran-2-yl)methyl 4-methylbenzenesulfonate (1.85
mmol, 0.500 g). Purification by column chromatography on
silica gel (0–12% EtOAc in hexane) afforded the title com-
pound as a yellowish oil (0.535 g, 1.81 mmol, 93%). 1H-NMR
(CDCl3, 300 MHz) δH: 7.38 (4H, d, J= 7.2 Hz, 4 × C[6]-H), 7.31
(4H, t, J= 7.2 Hz, 4 × C[7]-H), 7.26 – 7.19 (2H, m, Hz, 2 × C[8]-
H), 3.76 (2H, AB d, J=13.5 Hz, 2 × C[4]-H), 3.56 (2H, AB d,
J=13.5 Hz, 2 × C[4]-H), 2.86 – 2.84 (1H, m, C[1]-H), 2.68 (1H,
dd, J= 13.5 Hz, 4.1 Hz, C[3]-H), 2.62 (1H, m, C[2]-H), 2.49 (1H,
dd, J= 13.5 Hz, 5.7 Hz, C[3]-H), 1.44 – 1.42 (4H, m, 2 × C[9]-H, 2
× C[10]-H) 0.92 (3H, t, J=7.2 Hz, 3 × C[11]-H). 13C{1H} NMR
(CDCl3, 75 MHz), C: 139.4 C[5], 128.8 (C[6]), 128.2 (C[7]),
N,N-Dibenzyl-1-(oxiran-2-yl)methanamine (2c): Pre-
pared according to General Procedure A using dibenzylamine
(30.0 mmol, 5.92 g, 5.77 mL), and epichlorohydrin (30.0
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126.9 (C[8]), 58.9 (C[4]), 57.2 (C[1/2]), 56.8 (C[1/2]), 55.5
(C[3]), 33.8 (C[9]), 19.3 (C[10]), 13.9 (C[11]). HRMS (ESI)
m/z: [M+H]+ Calcd for C20H26NO 296.2009; Found 296.2021.
(1.85 mmol, 490 mg), and (3-propyloxiran-2-yl)methyl 4-
1
2
3
4
5
6
7
8
methylbenzenesulfonate (1.85 mmol, 500 mg). Purification by
column chromatography on Florisil (0–20% EtOAc in hexane)
afforded the title compound as a yellowish oil (540 mg, 1.49
mmol, 81%). 1H-NMR (CDCl3, 300 MHz) δH: 1H-NMR (CDCl3,
300 MHz) δH: 7.33 (2H, d, J= 7.8 Hz, 2 × C[10]-H), 7.17 (2H, d,
J= 7.5 Hz, 2 × C[9]-H), 4.59 (1H, AB d, J= 15.3 Hz, C[7]-H), 4.38
(1H, AB d, J= 15.3 Hz, C[7]-H), 3.56-2.63 (4H, m, C[1]-H, C[2]-
H, 2 × C[3]-H), 1.53-1.38 (13H, m, 9 × C[13]-H, 2 × C[14]-H, 2 ×
C[15]-H), 1.31 (9H, s, 9 × C[6]-H), 0.93 (3H, t, J= 6.3 Hz, C[16]-
H). 13C{1H} NMR (CDCl3, 75 MHz), C: 155.7 (C[4]), 150.2
(C[11]), 135.2 (C[8]), 127.6 (C[9]), 127.3 (C[9]), 125.4 (C[10]),
80.1 (C[5]), 57.6 (C[2]), 56.8 (C[1]), 57.0 (C[2]), 51.0 (C[7]),
50.6 (C[7]), 48.0 (C[3]), 34.5 (C[12]), 33.7 (C[14]), 31.4 (C[6]),
28.5 (C[13]), 19.2 (C[15]), 13.9 (C[16]). HRMS (ESI) m/z:
[M+H-tBu]+ Calcd for C18H28NO3 306.2064; Found 306.2077.
(1R)-N-Benzyl-1-phenyl-N-((3-propyloxiran-2-
yl)methyl)ethan-1-amine (2g): Prepared according to Gen-
eral Procedure B using (R)-N-benzyl-1-phenylethan-1-amine
(3.89 mmol, 0.822 g), and (3-propyloxiran-2-yl)methyl 4-
methylbenzenesulfonate (1.85 mmol, 500 mg). Purification by
column chromatography on silica gel (0–10% EtOAc in hex-
ane) afforded 2g as a yellowish oil (0.430 g, 1.39 mmol, 75%).
1H-NMR (CDCl3, 300 MHz) δH: 7.45 – 7.18 (10H, m, C[6-8, 12-
14]-H), 4.00 (1H, td, J= 17.9 Hz, 67 Hz, C[9]-H NHCH3), 3.79 –
3.71 (1H, m, C[4]-H), 3.60 – 3.46 (1H, m, C[4]-H), 2.77 – 2.49
(4H, m, C[1]-H, C[2]-H, 2 × C[3]-H), 1.43 – 1.31 (7H, m, 3 ×
C[9]-H, 2 × C[15]-H, 2 × C[16]-H), 0.90 (3H, m, 3 × C[17]-H).
13C{1H} NMR (CDCl3, 75 MHz), C: 143.7, 142.9, 140.5, 140.4,
128.6, 128.2, 128.1, 127.9, 127.8, 126.8, 126.8, 126.7, 59.0,
58.4, 57.9, 57.7, 57.6, 57.1, 55.2, 55.2, 51.9, 51.7, 33.9, 19.3,
19.23, 16.0, 14.1, 13.9. HRMS (ESI) m/z: [M+H]+ Calcd for
C14H22NO 310.2165; Found 310.2159.
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N-Benzyl-N-methyl-1-(3-((trityloxy)methyl)oxiran-2-
yl)methanamine (2k): Prepared according to General Proce-
dure B using N-benzylmethylamine (4.2 mmol, 0.509 g, 0.542
mL),
and
(3-((trityloxy)methyl)oxiran-2-yl)methyl
4-
methylbenzenesulfonate (2.0 mmol, 1.00 g). Purification by
column chromatography on silica gel (0–30% EtOAc in hex-
ane) afforded the title compound as a yellowish oil (0.867 g,
1.93 mmol, 96%). 1H-NMR (CDCl3, 300 MHz) δH: 7.44 (6H, d, J
= 7.8 Hz, 6 × C[13]-H), 7.30 – 7.21 (14H, m, Ar-H), 3.55 (1H, AB
d, J= 13.0 Hz, C[5]-H), 3.41 (1H, d, J= 13.0 Hz, C[5]-H), 3.32
(1H, dd, J = 10.5 Hz, 6.0 Hz, C[10]-H), 3.18 (2H, m, C[1]-H, C[2]-
H), 3.10 (1H, dd, J = 10.5, 4.5 Hz, C[10]-H), 2.57 (1H, dd, J =
13.5, 3.5 Hz, C[3]-H), 2.21 (3H, s, 3 × C[4]-H), 2.18 (1H, dd, J =
13.5, 6.0 Hz, C[3]-H). 13C{1H} NMR (CDCl3, 75 MHz), C: 143.7
(C[12]), 138.5 (C[6]), 129.0 (C[13]), 128.6 (C[14]), 128.2
(C[7]), 127.9 (C[8]), 127.1 (C[15]), 127.1 (C[9]), 86.9 (C[11]),
62.4 (C[10]), 62.2 (C[5]), 55.4 (C[3]), 55.1 (C[1]), 54.2 (C[2]),
42.7 (C[4]). HRMS (ESI) m/z: [M+H]+ Calcd for C31H32NO2
450.2433; found 450.2443.
Tert-butyl
(4-methoxybenzyl)((3-propyloxiran-2-
yl)methyl)carbamate (2h): Prepared according to General
Procedure C using tert-butyl (4-methoxybenzyl)carbamate
(1.85 mmol, 440 mg), and (3-propyloxiran-2-yl)methyl 4-
methylbenzenesulfonate (1.85 mmol, 500 mg). Purification by
column chromatography on Florisil (0–20% EtOAc in hexane)
afforded the title compound as a yellowish oil (436 mg, 1.30
mmol, 70%). 1H-NMR (CDCl3, 300 MHz) δH: 7.17 (2H, d, J= 7.2
Hz, 2 × C[9]-H), 6.85 (2H, d, J= 7.2 Hz, 2 × C[10]-H), 4.53 (1H,
AB d, J= 15.0 Hz, C[7]-H), 4.37 (1H, d, J= 15.0 Hz, C[7]-H), 3.78
(3H, s, 3 × C[12]-H), 3.63-2.65 (4H, m, C[1]-H, C[2]-H, 2 × C[3]-
H), 1.60-1.35 (13H, m, 9 × C[6]-H, 2 × C[13]-H, 2 × C[14]-H),
0.94 (3H, t, J= 6.8 Hz, 3 × C[15]-H). 13C{1H} NMR (CDCl3, 75
MHz), C: 158.9 (C[11]), 155.6 (C[4]), 130.3 (C[9]), 129.3
(C[8]), 128.8 (C[9]), 113.9 (C[10]), 80.0 (C[5]), 57.4 (C[1]),
56.8 (C[2]), 55.2 (C[12]), 50.8 (C[7]), 50.3 (C[7]), 47.8 (C[3]),
33.7 (C[13]), 28.5 (C[6]), 19.2 (C[14]), 13.9 (C[15]). HRMS
(ESI+) for C19H29NNaO4 ([M+Na]+): calculated 358.1989; found
358.1982. HRMS (ESI) m/z: [M+H-tBu]+ Calcd for C15H22NO4
280.1543; Found 280.1533.
N-Benzyl-N-ethyl-1-(3-((trityloxy)methyl)oxiran-2-
yl)methanamine (2l): Prepared according to General Proce-
dure B using N-ethylbenzylamine (4.2 mmol, 0.568 g, 0.625
mL),
and
(3-((trityloxy)methyl)oxiran-2-yl)methyl
4-
methylbenzenesulfonate (2.0 mmol, 1.00 g). Purification by
column chromatography on silica gel (0–20% EtOAc in hex-
ane) afforded the title compound as a yellowish oil (0.713 g,
1.54 mmol, 77%). 1H-NMR (CDCl3, 300 MHz) δH: 7.44 (6H, d, J
= 7.8 Hz, 6 × C[14]-H), 7.30 – 7.20 (14H, m, Ar-H), 3.67 (1H, AB
d, J= 13.0 Hz, C[6]-H), 3.49 (1H, d, J= 13.0 Hz, C[6]-H), 3.29
(1H, dd, J = 10.5 Hz, 6.0 Hz, C[11]-H), 3.18 – 3.10 (2H, m, C[1]-
H, C[2]-H), 3.08 (1H, dd, J = 10.5, 4.5 Hz, C[11]-H), 2.61 – 2.54
(2H, m, C[3]-H, C[4]-H), 2.52 – 2.45 (1H, m, C[4]-H), 2.30 (1H,
dd, J = 13.5, 6.0 Hz, C[3]-H), 0.98 (3H, t, J = 7.2 Hz, 3 × C[5]-H).
13C{1H} NMR (CDCl3, 75 MHz), C: 143.8 (C[13]), 139.4 (C[7]),
128.8 (C[9]), 128.7 (C[14]), 128.2 (C[8]), 127.9 (C[15]), 127.1
(C[16]), 126.9 (C[10]), 86.9 (C[12]), 62.3 (C[11]), 58.3 (C[6]),
55.3 (C[3]), 54.3 (C[1]), 51.5 (C[2]), 47.9 (C[4]), 11.8 (C[5]).
HRMS (ESI) m/z: [M+H]+ Calcd for C32H34NO2 464.2590;
Found 464.2596.
Tert-butyl (4-trifluoromethylbenzyl)((3-propyloxiran-
2-yl)methyl)carbamate (2i): Prepared according to General
Procedure
C
using
tert-butyl
(4-
(trifluoromethy)benzyl)carbamate (1.85 mmol, 510 mg), and
(3-propyloxiran-2-yl)methyl 4-methylbenzenesulfonate (1.85
mmol, 500 mg). Purification by column chromatography on
Florisil (0–10% EtOAc in hexane) afforded the title compound
2i as a yellowish oil (520 mg, 1.39 mmol, 76%). 1H-NMR
1
(CDCl3, 300 MHz) δH: H-NMR (CDCl3, 300 MHz) δH: 7.58 (2H,
d, J= 7.8 Hz, 2 × C[9]-H), 7.41-7.30 (2H, m, 2 × C[10]-H), 4.66
(1H, AB d, J= 15.0 Hz, C[7]-H), 4.49 (1H, AB d, J= 15.0 Hz, C[7]-
H), 3.82-2.66 (4H, m, C[1]-H, C[2]-H, 2 × C[3]-H), 1.55-1.40
(13H, m, 9 × C[6]-H, 2 × C[13]-H, 2 × C[14]-H), 0.94 (3H, t, J=
6.8 Hz, 3 × C[15]-H). 13C{1H} NMR (CDCl3, 75 MHz), C: 155.5
(C[4]), 142.6 (q, J= 1.8 Hz, C[9]), 130.0 (C[8]), 127.7 (q, J= 31
Hz, C[11]), 127.3, 125.5 (q, J= 3.6 Hz, C[10]), 129.9 (q, J= 273
Hz, C[12]), 80.6 (C[5]), 56.9 (C[1]), 56.7 (C[2]), 51.2 (C[7]),
50.7 (C[7]), 48.5 (C[3]), 33.6 (C[13]), 28.4 (C[6]), 19.2 (C[14]),
13.9 (C[15]). HRMS (ESI) m/z: [M+H-tBu]+ Calcd for
C15H19F3NO3 318.1312; Found 318.1327.
N,N-Dibenzyl-1-(3-((trityloxy)methyl)oxiran-2-
yl)methanamine (2m): Prepared according to General Pro-
cedure B using dibenzylamine (4.2 mmol, 0.828 g, 0.808 mL),
and
(3-((trityloxy)methyl)oxiran-2-yl)methyl
4-
methylbenzenesulfonate (2.0 mmol, 1.00 g). Purification by
column chromatography on silica gel (0–10% EtOAc in hex-
ane) afforded the title compound as a yellowish oil (894 mg,
1.70 mmol, 85%). 1H-NMR (CDCl3, 300 MHz) δH: 1H-NMR
Tert-butyl (4-tert-butyl benzyl)((3-propyloxiran-2-
yl)methyl)carbamate (2j): Prepared according to General
Procedure C using tert-butyl (4-(tert-butyl)benzyl)carbamate
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(CDCl3, 300 MHz) δH: 7.41 (6H, d, J = 7.5 Hz, 6 × C[12]-H), 7.33
J= 10.1 Hz, 5.6 Hz, C[13]-H), 3.23-3.07 (3H, m, C[1]-H , C[2]-H ,
1
2
3
4
5
6
7
8
– 7.20 (19H, m, Ar-H), 3.71 (2H, AB d, J= 13.7 Hz, 2 × C[4]-H),
3.47 (2H, d, J= 13.7 Hz, 2 × C[4]-H), 3.24 (1H, dd, J = 9.9 Hz, 5.5
Hz, C[9]-H), 3.20 – 3.11 (2H, m, C[1]-H, C[2]-H), 3.05 (1H, dd, J
= 9.9 Hz, 3.9 Hz, C[9]-H), 2.59 (1H, dd, J = 13.7, 3.1 Hz, C[3]-H),
2.18 (1H, dd, J = 13.7 Hz, 6.2 Hz, C[3]-H). 13C{1H} NMR (CDCl3,
75 MHz), C: 143.7 (C[11]), 139.1 (C[5]), 128.8 (C[6]), 128.6
(C[13]), 128.2 (C[7]), 127.8 (C[12]), 127.1 (C[14]), 126.9
(C[8]), 86.9 (C[10]), 62.2 (C[9]), 58.6 (C[4]), 55.3 (C[1]), 54.2
(C[1]), 51.6 (C[2]). HRMS (ESI) m/z: [M+H]+ Calcd for
C37H36NO2 526.2746; Found 526.2733.
C[13]-H), 2.60 (1H, dd, J= 13.5 Hz, 3.3 Hz, C[3]-H), 2.22 (3H, s,
3 × C[4]-H), 2.16 (1H, dd, J= 13.5 Hz, 6.4 Hz, C[3]-H). 13C{1H}
NMR (CDCl3, 75 MHz), C: 159.6 (C[8]), 143.7 (C[15]), 140.3
(C[6]), 129.2 (C[10]), 128.6 (C[16]), 127.9 (C[17]), 127.1
(C[18]), 121.3 (C[11]), 114.3 (C[7]), 112.6 (C[9]), 86.9 (C[14]),
62.4 (C[5]), 62.1 (C[13]), 55.4 (C[3]), 55.2 (C[12]), 55.2 (C[1]),
54.1 (C[2]), 42.8 (C[4]). HRMS (ESI) m/z: [M+H]+ Calcd for
C32H34NO3 480.2533; Found 480.2535.
N-(4-Fluorobenzyl)-N-methyl-1-(3-
((trityloxy)methyl)oxiran-2-yl)methanamine (2q): Pre-
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
Tert-butyl
benzyl((3-((trityloxy)methyl)oxiran-2-
pared according to General Procedure
fluorophenyl)-N-methylmethanamine (2.1 mmol, 0.292 g),
and (3-((trityloxy)methyl)oxiran-2-yl)methyl 4-
B using 1-(4-
yl)methyl)carbamate (2n): Prepared according to General
Procedure C using tert-butyl (benzyl)carbamate (1.2 mmol,
316
mg),
and
(3-propyloxiran-2-yl)methyl
(3-
4-
methylbenzenesulfonate (1.0 mmol, 0.50 g). Purification by
column chromatography on silica gel (10–45% EtOAc in hex-
ane) afforded the title compound as a yellowish oil (0.365 g,
0.78 mmol, 78%). 1H-NMR (CDCl3, 300 MHz) δH: 7.44 (6H, d, J
= 7.4 Hz, 6 × C[13]-H), 7.32 – 7.19 (11H, m, Ar-H), 6.95 (2H, t, J
= 8.5 Hz, 2 × C[8]-H), 3.51 (1H, AB d, J= 13.0 Hz, C[5]-H), 3.38
(1H, d, J= 13.0 Hz, C[5]-H), 3.32 (1H, dd, J = 10.3 Hz, 6.0 Hz,
C[10]-H), 3.15 – 3.12 (2H, m, C[1]-H, C[2]-H), 3.08 (1H, dd, J =
10.0 Hz, 4.7 Hz, C[10]-H), 2.55 (1H, dd, J = 13.5, 3.4 Hz, C[3]-
H), 2.20 (3H, s, 3 × C[4]-H), 2.20 – 2.10 (1H, m, C[3]-H).
13C{1H} NMR (CDCl3, 75 MHz), C: 161.9 (d, J= 243 Hz, C[9]),
143.7 (C[12]), 134.3 (d, J= 2.8 Hz, C[6]) 130.4 (d, J= 7.9 Hz,
C[7]), 128.6 (C[13]), 127.9 (C[14]), 127.1 (C[15]), 115.0 (d, J=
21.1 Hz, C[8]), 86.9 (C[11]), 62.2 (C[10]), 61.5 (C[5]), 55.3
(C[3]), 55.0 (C[1]), 54.1 (C[2]), 42.6 (C[4]). HRMS (ESI) m/z:
[M+H]+ Calcd for C31H31FNO2 468.2333; Found 468.2325.
((trityloxy)methyl)oxiran-2-yl)methyl
methylbenzenesulfonate (1.2 mmol, 601 mg). Purification by
column chromatography on Florisil (0–20% EtOAc in hexane)
afforded the title compound as a yellowish oil (372 mg, 0.70
mmol, 58%). 1H-NMR (CDCl3, 300 MHz) δH: 7.41 (6H, d, J = 7.8
Hz, 6 × C[15]-H), 7.30 – 7.18 (12H, m, Ar-H), 7.11 – 7.05 (2H,
m, Ar-H), 4.59 (1H, AB d, J= 15.5 Hz, C[7]-H), 4.32-4.26 (1H, m,
C[7]-H), 3.68 – 2.78 (6H, m, C[1]-H, C[2]-H, 2 × C[3]-H, 2 ×
C[12]-H), 1.44 (9H, s, 2 × C[6]-H). 13C{1H} NMR (CDCl3, 75
MHz), C: 155.6 (C[4]), 143.6 (C[14]), 138.9 (C[8]), 138.1
(C[8]), 128.6 (C[15]), 128.4 (C[10]), 127.9 (C[9]), 127.9
(C[16]), 127.3 (C[11]), 127.1 (C[17]), 87.0 (C[13]), 80.2 (C[5]),
62.3 (C[12]), 54.9 (C[1]), 54.3 (C[2]), 50.9 (C[7]), 45.0 (C[3]),
28.4 (C[6]). HRMS (ESI) m/z: [M+H]+ Calcd for C35H38NO4
536.2801; Found 536.2816.
N-(4-Methoxybenzyl)-N-methyl-1-(3-
((trityloxy)methyl)oxiran-2-yl)methanamine (2o): Pre-
pared according to General Procedure
methoxyphenyl)-N-methylmethanamine (2.1 mmol, 0.318 g),
and (3-((trityloxy)methyl)oxiran-2-yl)methyl 4-
N-Methyl-1-(naphthalen-2-yl)-N-((3-
((trityloxy)methyl)oxiran-2-yl)methyl)methanamine
(2r): Prepared according to General Procedure B using N-
methyl-1-(naphthalen-2-yl)methanamine (2.1 mmol, 0.360 g),
B using 1-(4-
and
(3-((trityloxy)methyl)oxiran-2-yl)methyl
4-
methylbenzenesulfonate (1.0 mmol, 0.50 g). Purification by
column chromatography on silica gel (10–40% EtOAc in hex-
ane) afforded the title compound as a yellowish oil (0.363 g,
0.76 mmol, 76%). 1H-NMR (CDCl3, 500 MHz) δH: 7.44 (6H, d, J
= 7.4 Hz, 6 × C[14]-H), 7.32 – 7.19 (9H, m, Ar-H), 7.16 (2H, d,
J= 5.1 Hz, 2 × C[7]-H), 6.81 (2H, d, J= 5.1 Hz, 2 × C[8]-H), 3.79
(1H, s, 3 × C[10]-H). 3.49 (1H, AB d, J= 12.9 Hz, C[5]-H), 3.38 –
3.26 (2H, m, C[5]-H, C[11]-H), 3.21-3.14 (2H, m, C[1]-H, C[2]-
H), 3.10 (1H, dd, J= 6.3 Hz, 2.7 Hz, C[11]-H), 2.55 (1H, dd, J=
13.2 Hz, 3.3 Hz, C[3]-H), 2.20 (3H, s, 3 × C[4]-H), 2.20 – 2.10
(1H, m, C[3]-H). 13C{1H} NMR (CDCl3, 75 MHz), C: 158.7
(C[9]), 143.7 (C[13]), 130.5 (C[6]), 130.2 (C[7]), 128.6 (C[14]),
127.9 (C[15]), 127.1 (C[16]), 113.6 (C[8]), 86.9 (C[12]), 62.2
(C[11]), 61.7 (C[5]), 55.2 (C[3]), 55.2 (C[10]), 55.1 (C[1]), 54.2
(C[2]), 42.6 (C[4]). HRMS (ESI) m/z: [M+H]+ Calcd for
C32H34NO3 480.2533; Found 480.2523.
methylbenzenesulfonate (1.0 mmol, 0.500 g). Purification by
column chromatography on silica gel (0–5% MeOH in DCM)
afforded the title compound as a yellowish oil (0.332 g, 0.67
mmol, 67%). 1H-NMR (CDCl3, 300 MHz) δH: 8.25 – 8.22 (1H,
m, C[9]-H), 7.84 – 7.79 (1H, m, C[12]-H), 7.79 – 7.72 (1H, m,
C[14]-H), 7.49 – 7.42 (8H, m, Ar-H), 7.37 – 7.33 (2H, m, Ar-H),
7.32 – 7.18 (9H, m, Ar-H), 3.98 (1H, dd, J=13.2 Hz, C[5]-H),
3.78 (1H, dd, J=13.2 Hz, C[5]-H), 3.33 (1H, dd, J= 9.9 Hz, 4.8 Hz
C[16]-H), 3.25 – 3.15 (2H, m, C[1]-H, C[2]-H), 3.33 (1H, dd, J=
9.9 Hz, 3.5 Hz C[16]-H), 2.71 – 2.59 (1H, m, C[3]-H), 2.29 –
2.25 (4H, C[3]-H, 3 × C[4]-H). 13C{1H} NMR (CDCl3, 300 MHz),
C: 143.7 (C[18]), 134.4 (C[6]), 133.8 (C[8]), 132.4 (C[13]),
128.6 (C[19]), 128.4 (C[20]), 128.0 (C[15]), 127.9 (C[12]),
127.4 (C[9]), 127.1 (C[21]), 125.8 (C[14]), 125.6 (C[7]), 125.1
(C[10]), 124.6 (C[11]), 86.9 (C[17]), 62.1 (C[16]), 60.7 (C[5]),
55.7 (C[3]), 55.2 (C[1]), 55.1 (C[2]), 42.9 (C[4]). HRMS (ESI)
m/z: [M+H]+ Calcd for C35H34NO2 500.2584; Found 500.2576.
N-(3-Methoxybenzyl)-N-methyl-1-(3-
((trityloxy)methyl)oxiran-2-yl)methanamine (2p): Pre-
N-Benzyl-N-methyl-1-(3-phenyloxiran-2-
yl)methanamine (2s): Prepared according to General Proce-
dure B using N-methylbenzylamine (2.76 mmol, 0.335 g, 0.356
pared according to General Procedure
methoxyphenyl)-N-methylmethanamine (2.1 mmol, 0.318 g),
and (3-((trityloxy)methyl)oxiran-2-yl)methyl 4-
methylbenzenesulfonate (1.0 mmol, 0.50 g). Purification by
column chromatography on silica gel (10–40% EtOAc in hex-
ane) afforded the title compound as a yellowish oil (0.424 g,
0.88 mmol, 88%). 1H-NMR (CDCl3, 300 MHz) δH: 7.46 (6H, d, J
= 7.4 Hz, 6 × C[16]-H), 7.31 – 7.15 (10H, m, Ar-H), 6.86 – 6.75
(3H, m, Ar-H), 3.78 (3H, s, 3 × C[12]-H) 3.54 (1H, AB d, J= 13.2
Hz, C[5]-H), 3.38 (1H, AB d, J= 13.2 Hz, C[5]-H), 3.32 (1H, dd,
B
using 1-(3-
mL),
and
(3-phenyloxiran-2-yl)methyl
4-
methylbenzenesulfonate (1.31 mmol, 0.40 g). Purification by
column chromatography on silica gel (10–30% EtOAc in hex-
ane) afforded the title compound as a yellowish oil (0.205 g,
0.81 mmol, 62%). 1H-NMR (CDCl3, 300 MHz) δH: 7.37 – 7.21
(10H, m, C[7-9, 11-13]-H), 3.66 (1H, AB d, J= 13.0, Hz, C[5]-H),
3.63 – 3.60 (1H, m, C[1]-H), 3.55 (1H, AB d, J= 13.0, Hz, C[5]-
H), 3.20 – 3.12 (1H, m, C[2]-H), 2.80 (1H, dd, J= 13.3 Hz, 3.9 Hz,
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 17
C[3]-H), 2.58 (1H, dd, J= 13.3 Hz, 6.2 Hz, C[3]-H), 2.35 (3H, s, 3
Procedure B using isoindoline (4.2 mmol, 0.500 g), and (3-
((trityloxy)methyl)oxiran-2-yl)methyl 4-
methylbenzenesulfonate (2.0 mmol, 1.00 g). Purification by
× C[4]-H). 13C{1H} NMR (CDCl3, 75 MHz), C: 138.6 (C[6]),
137.3 (C[10]), 129.0 (C[7]), 128.5 (C[11]), 128.3 (C[8]), 128.1
(C[13]), 127.1 (C[9]), 125.6 (C[12]), 62.6 (C[5]), 61.4 (C[1]),
59.0 (C[2]), 56.9 (C[3]), 43.0 (C[4]). HRMS (ESI) m/z: [M+H]+
Calcd for C17H20NO 254.1539; Found 254.1536.
1
2
3
4
5
6
7
8
column chromatography on Florisil (0–40% EtOAc in hexane)
1
afforded 2w as a yellowish oil (0.780 g, 1.74 mmol, 87%). H-
NMR (CDCl3, 300 MHz) δH: 7.49 – 7.46 (6H, d, J = 7.8 Hz, 6 ×
C[11]-H), 7.33 – 7.17 (13H, m, Ar-H), 3.98 – 3.90 (4H, m, 4 ×
C[4]-H), 3.43 (1H, dd, J= 10.2 Hz, 5.7 Hz, C[8]-H) 3.30 – 3.21
(2H, m, C[1]-H, C[2]-H) 3.15 (1H, dd, J= 10.2 Hz, 4.5 Hz, C[8]-
H) 2.91 (1H, dd, J= 12.9 Hz, 3.6 Hz, C[3]-H), 2.51 (1H, dd, J=
12.9 Hz, 6.6 Hz, C[3]-H). 13C{1H} NMR (CDCl3, 75 MHz), C:
143.7 (C[10]), 139.9 (C[5]), 128.6 (C[12]), 127.9 (C[11]),
127.2 (C[6]), 126.8 (C[7]), 122.3 (C[13]), 87.0 (C[9]), 62.1
(C[4]), 59.3 (C[8]), 55.4 (C[1]), 54.4 (C[2]), 53.8 (C[3]). HRMS
(ESI) m/z: [M+H]+ Calcd for C31H30NO2 448.2271; found
448.2293.
N-Benzyl-N-ethyl-1-(3-phenyloxiran-2-
yl)methanamine (2t): Prepared according to General Proce-
dure B using N-benzylethylamine (2.76 mmol, 0.373 g, 0.411
mL),
and
(3-phenyloxiran-2-yl)methyl
4-
9
methylbenzenesulfonate (1.31 mmol, 0.40 g). Purification by
column chromatography on silica gel (15–30% EtOAc in hex-
ane) afforded the title compound 2t as a yellowish oil (0.260
g, 0.97 mmol, 74%). 1H-NMR (CDCl3, 300 MHz) δH: 7.38 – 7.20
(10H, m, C[7-9, 12-14]-H), 3.75 (1H, AB d, J= 13.8, Hz, C[5]-H),
3.67 – 3.57 (2H, m, C[1]-H C[5]-H), 3.12 (1H, m, C[2]-H) 2.43
(1H, dd, J= 13.8, Hz, 3.9 Hz, C[3]-H), 2.70 – 2.59 (3H, m, C[2]-H,
2 × C[4]-H), 1.10 (3H, t, J= 6.9, Hz, 3 × C[5]-H). 13C{1H} NMR
(CDCl3, 75 MHz), C: 139.4 (C[7]), 137.4 (C[11]), 128.8 (C[8]),
128.4 (C[12]), 128.2 (C[9]), 128.1 (C[14]), 126.9 (C[10]),
125.6 (C[13]), 61.6 (C[1]), 58.6 (C[2]), 57.0 (C[6]), 55.1 (C[3]),
48.2 (C[4]), 11.9 (C[5]). HRMS (ESI) m/z: [M+H]+ Calcd for
C18H22NO 268.1696; Found 268.1703.
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
Synthesis of 2-phenylazetidines
(1-Methyl-2-phenylazetidin-3-yl)methanol (1a): Pre-
pared according to General Procedure D using 2a (1.39 mmol,
300 mg). Purification by column chromatography on silica gel
(0–20% MeOH in DCM) afforded the title compound (1a) as a
1
yellowish oil (261 mg, 1.47 mmol, 87%). H-NMR (CDCl3, 500
MHz) δH: 7.38 (2H, d, J= 7.8 Hz, Ar-H), 7.32 (2H, t, J= 7.5 Hz, Ar-
H), 7.24 (1H, t, J= 7.3 Hz, Ar-H), 3.74 (1H, d, J= 7.8 Hz, C[1]-H),
3.70 (2H, t, J= 4.5 Hz, 2 × C[9]-H), 3.57 (1H, t, J= 6.8 Hz, C[3]-
H), 2.75 (1H, t, J= 7.5 Hz, C[3]-H), 2.59 (1H, td, J= 7.0 Hz, 5.9
Hz, C[2]-H), 2.34 (3H, s, 3 × C[8]-H). 13C{1H} NMR (CDCl3, 75
MHz), C: 141.9 (C[4]), 128.4 (C[5]), 127.4 (C[7]), 126.7 (C[6]),
73.3 (C[1]), 63.2 (C[9]), 55.6 (C[3]), 44.4 (C[8]), 42.5 (C[2]).
HRMS (ESI) m/z: [M+H]+ Calcd for C11H16NO 178.1264; Found
178.1239.
N,N-Dibenzyl-1-(3-phenyloxiran-2-yl)methanamine
(2u): Prepared according to General Procedure B using
dibenzylamine (2.76 mmol, 0.544 g, 0.531 mL), and (3-
phenyloxiran-2-yl)methyl 4-methylbenzenesulfonate (1.31
mmol, 0.400 g). Purification by column chromatography on
silica gel (0–20% EtOAc in hexane) afforded 2u as a yellowish
oil (0.313 g, 95 mmol, 72%). 1H-NMR (CDCl3, 300 MHz) δH:
7.44 – 7.18 (15H, m, C[6-8, 10-12]-H), 3.81 (2H, AB d, J= 13.7,
Hz, 2 × C[4]-H), 3.63 (2H, AB d, J= 13.7, 2 × C[4]-H), 3.58 – 3.53
(1H, m, C[1]-H), 3.20 – 3.10 (1H, m, C[2]-H), 2.87 (1H, dd, J=
13.8 Hz, 3.7 Hz, C[3]-H) 2.63 (1H, dd, J= 5.8 Hz, 14.1 Hz C[3]-
H). 13C{1H} NMR (CDCl3, 75 MHz), C: 139.2 (C[5]), 137.3
(C[9]), 128.8 (C[6]), 128.4 (C[10]), 128.3 (C[7]), 128.1 (C[12]),
127.0 (C[8]), 125.6 (C[11]), 61.6 (C[1]), 58.9 (C[4]), 56.7
(C[2]), 55.2 (C[3]). HRMS (ESI) m/z: [M+H]+ Calcd for
C23H24NO 330.1852; Found 330.1852.
(1-Ethyl-2-phenylazetidin-3-yl)methanol (1b): Pre-
pared according to General Procedure D using 2b (1.70 mmol,
325 mg). Purification by column chromatography on silica gel
(0–10% MeOH in DCM) afforded the title compound (1b) as a
1
yellowish oil (302 mg, 1.58 mmol, 93%). H-NMR (CDCl3, 300
MHz) δH: 7.38 (2H, d, J= 7.1 Hz, 2 × C[5]-H), 7.28 (2H, t, J= 7.1
Hz, 2 × C[6]-H), 7.23 – 7.19 (1H, m, C[7]-H), 3.78 – 3.70 (2H, d
+ bs, J= 7.8 Hz, C[1]-H, OH), 3.62 – 3.52 (2H, m, 2 × C[10]-H),
3.50 (1H, t, J= 6.9 Hz, C[3]-H) 2.69 – 2.59 (2H, m, C[3]-H, C[8]-
H) 2.54 – 2.40 (2H, m, C[2]-H, C[8]-H) 0.90 (3H, t, J= 7.8 Hz,
C[9]-H). 13C{1H} NMR (CDCl3, 75 MHz), C: 142.5 (C[4]), 128.3
(C[5]), 127.2 (C[7]), 126.7 (C[6]), 71.7 (C[1]), 62.8 (C[10]),
53.5 (C3]), 52.8 (C[8]), 42.2 (C[2]), 12.5 (C[9]). HRMS (ESI)
m/z: [M+H]+ Calcd for C12H17NO 192.1383; Found 192.1389.
N-Methyl-1-(3-propyloxiran-2-yl)-N-(2-
(trifluoromethyl)benzyl)methanamine (2v): Prepared
according to General Procedure
B using N-methyl-1-(2-
(trifluoromethyl)phenyl)methanamine (4.27 mmol, 0.845 g),
and (3-propyloxiran-2-yl)methyl 4-methylbenzenesulfonate
(2.03 mmol, 0.550 g). Purification by column chromatography
on silica gel (0–30% EtOAc in hexane) afforded the title com-
pound as a yellowish oil (0.517 g, 1.80 mmol, 89%). 1H-NMR
(CDCl3, 300 MHz) δH: 7.83 (1H, J= 7.8 Hz, C[8]-H), 7.61 (1H, d,
J= 7.8 Hz, C[11]-H), 7.52 (1H, t, J= 7.6 Hz, C[10]-H), 7.32 (1H, t,
J= 7.6 Hz, C[11]-H), 3.76 (1H, AB d, J= 14.7 Hz, C[5]-H), 3.68
(1H, d, J= 14.7 Hz, C[5]-H), 2.95 – 2.81 (1H, m, C[2]-H), 2.76 –
2.62 (2H, m C[1]-H, C[3]-H), 2.47 (1H, AB dd, J= 13.2 Hz, 6.2
Hz, C[3]-H), 2.32 (3H, s, 3 × C[4]-H), 1.56 – 1.39 (4H, m, 2 ×
C[13]-H, 2 × C[14]-H), 0.96 (3H, t, J= 6.9 Hz, 3 × C[15]-H).
13C{1H} NMR (75 MHz, CDCl3) δC: 138.4 (q, J= 1.5 Hz, C[6]),
131.8 (C[9]), 130.4 (C[11]), 128.5 (q, J= 30 Hz, C[7]), 126.8
(C[10]), 125.7 (q, J= 6 Hz, C[8]), 124.5 (q, J= 273 Hz, C[12]),
59.7 (C[3]), 58.0 (q, J= 1.7 Hz, C[5]), 57.9, 57.1 (C[2]), 56.8
(C[1]), 43.1 (C[4]), 33.9 (C[13]), 19.3 (C[14]), 13.9 (C[15]).
HRMS (ESI) m/z: [M+H]+ Calcd for C14H22NO 288.1564; Found
288.1572.
(1-Benzyl-2-phenylazetidin-3-yl)methanol (1c): Prepared
according to General Procedure D using 2c (1.70 mmol, 431
mg). Purification by column chromatography on silica gel (40–
80% EtOAc in hexane) afforded the title compound (1c) as a
yellowish oil (105 mg, 0.29 mmol, 25%). Pure TFA salt of 1c
can be isolated by preparative HPLC (using 0.1% TFA in 1 L
water and acetonitrile). 1H-NMR (DMSO-d6, 500 MHz) δH:
10.27 (1H, bs, NH), 7.47 – 7.41 (4H, m, Ar-H), 7.41 – 7.35 (6H,
m, Ar-H), 5.29 (1H, bs, C[1]-H), 5.17 (1H, bs, OH), 4.46 (2H, bs,
2 × C[8]-H), 3.92 (2H, bs, 2 × C[3]-H), 3.60 – 3.55 (2H, m, 2 ×
C[13]-H), 3.25 (1H, bs, C[2]-H). 13C{1H} NMR (DMSO-d6, 126
MHz), C: 142.4 (C[4]), 138.2 (C[9]), 128.8 (C[10]), 128.3
(C[5]), 128.2 (C[11]), 127.2 (C[7]), 126.9 (C[12]), 126.7 (C[6]),
71.0 (C[1]), 63.4 (C[13]), 61.9 (C[8]), 53.5 (C[3]), 43.2
(C[2]).HRMS (ESI) m/z: [M+H]+ Calcd for C17H19NO 254.1539;
Found 254.1530.
2-((3-((Trityloxy)methyl)oxiran-2-
yl)methyl)isoindoline (2w): Prepared according to General
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Page 11 of 17
The Journal of Organic Chemistry
(1-Methyl-2-phenylazetidin-3-yl)butan-1-ol (1d): Pre-
(C[9]), 144.3 (C[4]), 128.3 (C[11]), 128.2 (C[6]), 127.4 (C[12]),
127.0 (C[13]), 127.0 (C[5]), 126.9 (C[7]), 71.0 (C[15]), 69.8
(C[1]), 68.4 (C[8]), 51.0 (C[3]), 46.4 (C[2]), 37.3 (C[16]), 22.1
(C[12]), 18.6 (C[17]), 14.0 (C[18]). HRMS (ESI) m/z: [M+H]+
Calcd for C21H27NO 310.2165; Found 310.2174.
1
2
3
4
pared according to General Procedure D using 2d (0.91 mmol,
200 mg). Purification by column chromatography on silica gel
(40–100% EtOAc in hexane) afforded the title compound (1d)
1
as a yellowish oil (172 mg, 0.78 mmol, 86%). H-NMR (CDCl3,
300 MHz) δH: 7.40 (2H, d, J= 7.2 Hz, 2 × C[5]-H), 7.33 (2H, t, J=
7.3 Hz, 2 × C[6]-H), 7.29 – 7.22 (1H, m, C[7]-H), 3.75 (1H, d, J=
8.1 Hz, C[1]-H), 3.70 – 3.62 (1H, m, C[9]-H), 3.55 (1H, t, J= 6.6
Hz, C[3]-H), 2.83 (1H, dd, J= 8.7 Hz, 6.8 Hz, C[3]-H), 2.55 – 2.44
(2H, m, C[2]-H, OH), 2.33 (3H, s, 3 × C[8]-H), 1.40 – 1.20 (4H,
m, 2 × C[10]-H, 2 × C[11]-H), 0.84 (3H, t, J= 6.6 Hz, 3 × C[12]-
H). 13C{1H} NMR (CDCl3, 75 MHz), C: 141.8 (C[4]), 128.4
(C[5]), 127.5 (C[7]), 127.2 (C[6]), 72.8 (C[1]), 71.3 (C[9]), 54.4
(C[3]), 46.0 (C[2]), 44.2 (C[8]), 37.4 (C[10]), 18.6 (C[11]), 14.0
(C[12]). HRMS (ESI) m/z: [M+H]+ Calcd for C14H22NO
220.1701; Found 220.1696.
1
5
6
7
8
1g_diastereomer II: H-NMR (CDCl3, 300 MHz) δH: 7.12 –
6.98 (7H, m, Ar-H), 6.98 – 6.90 (3H, m, Ar-H), 3.74 (1H, d, J=
7.8 Hz, C[1]-H), 3.70 – 3.55 (2H, m, C[3]-H, C[15]-H), 3.41 (1H,
q, J= 6.5 Hz C[8]-H), 2.93 (1H, t, J= 7.2 Hz, C[3]-H), 2.54 – 2. 38
(1H, m, C[2]-H), 1.55 (1H, bs, OH), 1.35 – 1.15 (7H, m, 3 ×
C[14]-H, 2 × C[16]-H, 2 × C[17]-H), 0.81 (1H, t, J= 6.8 Hz 3 ×
C[18]-H). 13C{1H} NMR (CDCl3, 300 MHz), C: 142.6 (C[4/9]),
142.4 (C[4/9]), 128.0 (C[11]), 127.5 (C[6/C12/C13]), 127.5
(C[6/C12/C13]), 126.7 (C[5]), 126.5 (C[7]), 71.9 (C[15]), 70.4
(C[1]), 68.3 (C[8]), 52.0 (C[3]), 45.4 (C[2]), 37.3 (C[16]), 20.4
(C[12]), 18.5 (C[17]), 13.9 (C[18]). HRMS (ESI) m/z: [M+H]+
Calcd for C14H22NO 310.2165; Found 310.2169.
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-Ethyl-2-phenylazetidin-3-yl)butan-1-ol (1e): Pre-
pared according to General Procedure D using 2e (0.89 mmol,
200 mg). Purification by column chromatography on silica gel
(40–100% EtOAc in hexane) afforded the title compound (1e)
Tert-butyl
3-(1-hydroxybutyl)-2-(4-
methoxyphenyl)azetidine-1-carboxylate (1h) : Prepared
according to General Procedure D using 2h (0.60 mmol, 200
mg). Purification by preparative HPLC (using 0.4 g NH4HCO3
in 1 L water and acetonitrile) afforded the title compound (1h,
84 mg, 0.25 mmol, 42%) as a yellowish oil and 9h (72 mg,
0.21 mmol, 36%) as a yellowish oil.
1
as a yellowish oil (178 mg, 0.76 mmol, 89%). H-NMR (CDCl3,
300 MHz) δH: 7.42 (2H, d, J= 7.3 Hz, 2 × C[5]-H), 7.33 (2H, t, J=
7.3 Hz, 2 × C[6]-H), 7.29 – 7.22 (1H, m, C[7]-H), 3.80 (1H, d, J=
8.1 Hz, C[1]-H), 3.75 – 3.65 (1H, m, C[10]-H), 3.53 (1H, t, J= 6.9
Hz, C[3]-H), 2.76 (1H, t, J= 6.9 Hz, C[3]-H), 2.67 – 2.54 (1H, m,
C[2]-H), 2.54 – 2.37 (2H, m, 2 × C[8]-H), 1.63 (1H, bs, OH), 1.35
– 1.26 (4H, m, 2 × C[11]-H, 2 × C[12]-H), 0.93 – 0.83 (6H, m, 3
× C[9]-H, 3 × C[13]-H). 13C{1H} NMR (CDCl3, 75 MHz) C: 142.9
(C[4]), 128.3 (C[5]), 127.2 (C[7]), 127.1 (C[6]), 71.4 (C[1]),
71.2 (C[10]), 52.7 (C[3]), 52.1 (C[8]), 46.1 (C[2]), 37.4 (C[11]),
18.6 (C[12]), 14.0 (C[9]), 12.7 (C[13]). HRMS (ESI) m/z:
[M+H]+ Calcd for C15H24NO 234.1852; found 234.1862.
Tert-butyl
3-(1-hydroxybutyl)-2-(4-
methoxyphenyl)azetidine-1-carboxylate (1h): 1H-NMR
(CDCl3, 300 MHz) δH(ppm): 1H NMR (300 MHz, CDCl3) δH: 7.28
(2H, d, J = 8.2 Hz, 2 × C[6]-H), 6.88 (2H, d, J = 8.2 Hz, 2 × C[5]-
H), 4.87 (1H, d, J = 5.7 Hz, C[1]-H), 3.99 (1H, t, J = 8.4 Hz, C[3]-
H), 3.88 (t, J = 7.4 Hz, C[3]-H), 3.81 (4H, s, 3 × C[8]-H, C[12]-H),
2.48 – 2.35 (1H, m, C[2]-H), 1.81 (1H, bs, OH), 1.55 – 1.16
(13H, m, 9 × C[11]-H, 2 × C[13]-H, 2 × C[14]-H), 0.90 (t, J = 6.0
Hz, 3 × C[15]-H). 13C{1H} NMR (CDCl3, 75 MHz), C: 159.0
(C[7]), 156.7 (C[9]), 133.9 (C[4]), 127.5 (C[5]), 113.9 (C6]),
79.5 (C[10]), 71.8 (C[12]), 66.0 (C[1]), 55.3 (C[8]), 48.0 (C[3]),
44.9 (C[2]), 37.0 (C[13]), 28.3 (C[11]), 18.7 (C[14]), 14.0
(C[15]). HRMS (ESI) m/z: [M+H]+ Calcd for C19H30NO4
336.2169; Found 336.2175.
(1-Benzyl-2-phenylazetidin-3-yl)butan-1-ol (1f): Pre-
pared according to General Procedure D using 2f (0.97 mmol,
286 mg). Purification by column chromatography on silica gel
(0–10% MeOH in DCM) afforded the title compound (1f) as a
1
yellowish oil (203 mg, 0.71 mmol, 71%). H-NMR (CDCl3, 300
MHz) δH: 7.45 (2H, d, J= 6.9 Hz, 2 × C[5]-H), 7.38 – 7.15 (8H, m,
Ar-H), 4.00 (1H, d, J= 7.9 Hz, C[1]-H), 3.81 (1H, AB d, J= 12.9
Hz, C[8]-H), 3.74-3.64 (1H, m, C[14]-H), 3.44 (1H, AB d, J= 12.9
Hz, C[8]-H), 3.42-3.35 (1H, m, C[3]-H), 2.85 (1H, t, J= 7.8 Hz,
C[3]-H), 2.50 – 2.35 (1H, m, C[2]-H), 1.61 (1H, bs, OH), 1.38 –
1.20 (4H, m, 2 × C[15]-H, 2 × C[16]-H), 0.84 (3H, t, J= 6.9 Hz, 3
× C[17]-H). 13C{1H} NMR (CDCl3, 75 MHz), C: 142.4 (C[4]),
138.3 (C[9]), 128.8 (C[10]), 128.3 (C[5]), 128.1 (C[11]), 127.3
(C[7]), 127.1 (C[12]), 126.9 (C[6]), 71.2 (C[1]), 70.3 (C[13]),
61.7 (C[8]), 52.2 (C[3]), 46.8 (C[2]), 37.4 (C[14]), 18.6 (C[15]),
14.0 (C[16]). HRMS (ESI) m/z: [M+H]+ Calcd for C20H26NO
296.2009; found 296.2008.
Tert-butyl
(E)-(3-hydroxyhex-1-en-1-yl)(4-
1
methoxybenzyl)carbamate (9h): H-NMR (CDCl3, 300 MHz)
δH: H NMR (300 MHz, CDCl3) δH: 7.30 – 7.02 (1H, bs, C[6]-H),
1
7.12 (2H, d, J= 8.1 Hz, 2 × C[12]-H), 6.83 (2H, d, J= 8.4 Hz, 2 ×
C[13]-H), 4.82 (1H, bs, C[5]-H), 4.64 (2H, bs, 2 × C[10]-H), 4.05
(1H, bs, C[4]-H), 3.79 (3H, s, 3 × C[15]-H), 1.61 – 1.17 (13H, m,
2 × C[2]-H, 2 × C[3]-H, 9 × C[9]-H), 0.87 (3H, t, J = 7.2 Hz, 3 ×
C[1]-H). 13C{1H} NMR (CDCl3, 75 MHz), C: 158.6 (C[14]),
129.3 (C[6]), 128.9 (C[11]), 127.8 (C[12]), 113.9 (C[13]),
112.2 (C[5]), 81.6 (C[8]), 72.1 (C[4]), 55.3 (C[15]), 47.0
(C[10]) 39.9 (C[3]), 28.2 (C[9]), 18.8 (C[2]), 13.9 (C[1]). HRMS
(ESI) m/z: [M+H]+ Calcd for C19H30NO4 336.2169; Found
336.2178.
1-(2-Phenyl-1-(1-phenylethyl)azetidin-3-yl)butan-1-ol
(1g): Prepared according to General Procedure D using 2g
(0.97 mmol, 300 mg). Purification by column chromatography
on silica gel (10–100% EtOAc in hexane) afforded the title
compound (1g_diastereomer I; 139 mg, 0.45 mmol, 46%)
and (1g_diastereomer II; 85 mg, 0.28 mmol,%) as a yellowish
oil (in overall 70% yield). 1g_diastereomer I: 1H-NMR
(CDCl3, 300 MHz) δH: 7.58 (2H, d, J= 7.4 Hz, C[5]-H), 7.42 –
7.20 (8H, m, Ar-H), 4.03 (1H, d, J= 7.7 Hz, C[1]-H), 3.72 – 3.60
(1H, m, C[15]-H), 3.46 (1H, q, J= 6.5 Hz, C[8]-H), 3.19 (1H, t, J=
7.5 Hz, C[3]-H), 2.66 (1H, t, J= 7.5 Hz, C[3]-H), 2.35 – 2.20 (1H,
m, C[2]-H), 1.44 (1H, bs, OH), 1.32 – 1.15 (4H, m, 2 × C[16]-H,
2 × C[17]-H), 0.94 (3H, d, J= 6.5 Hz, 3 × C[14]-H), 0.82 (3H, t, J=
6.4 Hz, 3 × C[18]-H). 13C{1H} NMR (CDCl3, 300 MHz), C: 144.7
Tert-butyl
3-(1-hydroxybutyl)-2-(4-tert-
butylphenyl)azetidine-1-carboxylate (1j): Prepared ac-
cording to General Procedure D using 2j (1.25 mmol, 450 mg).
Purification by preparative HPLC (using 0.4 g NH4HCO3 in 1 L
water and acetonitrile) afforded the title compound (1j, 198
mg, 0.55 mmol, 47%) as a yellowish oil and 9j (143 mg, 0.43
mmol, 34%) as a yellowish oil.
Tert-butyl
3-(1-hydroxybutyl)-2-(4-tert-
butylphenyl)azetidine-1-carboxylate (1j): 1H-NMR (CDCl3,
500 MHz) δH: 7.35 (2H, d, J = 8.3 Hz, 2 × C[6]-H), 7.27 (2H, d, J
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 17
= 6.9 Hz, 2 × C[5]-H), 4.92 (1H, bs, C[1]-H), 3.99 (1H, t, J = 8.3
1-(1-Ethyl-2-phenylazetidin-3-yl)-2-(trityloxy)ethan-
1
2
3
4
5
6
7
8
Hz, C[3]-H), 3.92 (1H, dd, J = 8.3 Hz, 6.4 Hz, C[3]-H), 3.79 (1H,
s, C[13]-H), 2.43 (1H, bs, C[2]-H), 2.38 – 2.22 (1H, bs, OH), 1.53
– 1.08 (22H, m, 9 × C[9]-H, 9 × C[12]-H, 2 × C[14]-H, 2 × C[15]-
H), 0.92 (3H, t, J = 6.9 Hz, 3 × C[16]-H). 13C{1H} NMR (CDCl3,
126 MHz), C: 156.8 (C[10]), 150.3 (C[7]), 138.7 (C[4]), 125.8
(C[5]), 125.3 (C[6]), 79.5 (C[11]), 71.5 (C[13]), 66.1 (C[1]),
48.9 (C[3]), 44.6 (C[2]), 36.9 (C[14]), 34.5 (C[8]), 31.4 (C[9]),
28.3 (C[12]), 18.8 (C[15]), 14.0 (C[16]). HRMS (ESI) m/z:
[M+H]+ Calcd for C22H32NO4 362.2690; Found 362.2687.
1-ol (1l): Prepared according to General Procedure D using 2l
(1.0 mmol, 463 mg). Purification by column chromatography
on silica gel (20–60% EtOAc in hexane) afforded the title
compound (1l) as a yellowish solid (371 mg, 0.80 mmol,
80%). 1H-NMR (CDCl3, 300 MHz) δH : 7.39 – 7.32 (8H, m, Ar-
H), 7.32 – 7.18 (12H, m, Ar-H), 3.93 (1H, td, J = 6.9 Hz, 3.2 Hz,
C[10]-H), 3.85 (1H, d, J = 7.8 Hz, C[1]-H), 3.39 (1H, d, J = 7.0 Hz,
C[3]-H), 3.02 (1H, dd, J = 9.2 Hz, 3.5 Hz C[11]-H), 2.90 (1H, dd,
J = 9.2 Hz, 7.7 Hz, C[11]-H), 2.64 – 2.51 (2H, m, C[3]-H, C[8]-H),
2.48 – 2.35 (2H, m, C[2]-H, C[8]-H),2.17 (1H, bs, OH) 0.87 (3H,
t, J = 7.2 Hz, 3 × C[9]-H). 13C{1H} NMR (CDCl3, 75 MHz), C:
143.7 (C[13]), 143.1 (C[4]), 128.6 (C[14]), 128.2 (C[5]), 127.9
(C[15]), 127.9 (C[7]), 127.1 (C[16]), 127.0 (C[6]), 86.8 (C[12]),
72.7 (C[10]), 71.9 (C[1]), 65.6 (C[11]), 52.7 (C[3]), 52.3 (C[8]),
42.9 (C[2]), 12.7 (C[9]). HRMS (ESI) m/z: [M+H]+ Calcd for
C32H34NO2 464.2590; Found 464.2586.
9
Tert-butyl
(E)-(3-hydroxyhex-1-en-1-yl)(4-
tert-
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
butyl)carbamate (9j): 1H-NMR (CDCl3, 300 MHz) δH: 7.32
(2H, d, J= 8.5 Hz, 2 × C[13]-H), 7.11 (2H, d, J= 8.5 Hz, 2 × C[12]-
H), 7.18+7.03 (0.5 + 0.5 H, bs. C[6]-H), 4.81 (1H, bs, C[5]-H),
4.66 (2H, bs, 2 × C[10]-H), 4.05 (1H, bs, C[4]-H), 1.67 (1H, bs,
OH), 1.52 – 1.22 (22H, m, 2 × C[2]-H, 2 × C[3]-H, 9 × C[9]-H, 9
× C[19]-H), 0.84 (3H, t, J = 7.5 Hz, 3 × C[1]-H). 13C{1H} NMR
(CDCl3, 75 MHz), C: 149.9 (C[9]), 138.6 (C[11]), 134.2 (C[14]),
129.3 (C[6]), 126.3 (C[14]), 125.4 (C[13]), 112.3 (C[5]), 81.6
(C[8]), 72.1 (C[4]), 47.4 (C[10]), 39.8 (C[3]), 34.4 (C[15]), 31.4
(C[9]), 28.2 (C[16]), 18.7 (C[2]), 14.0 (C[1]). HRMS (ESI) m/z:
[M+H]+ Calcd for C22H32NO4 362.2690; Found 362.2683.
1-(1-Benzyl-2-phenylazetidin-3-yl)-2-
(trityloxy)ethan-1-ol (1m): Prepared according to General
Procedure D using 2m (1.0 mmol, 525 mg). Purification by
column chromatography on silica gel (0–25% EtOAc in hex-
ane) afforded the title compound (1m) as a yellowish solid
(252 mg, 0.80 mmol, 48%). 1H-NMR (CDCl3, 300 MHz) δH:
7.41 – 7.32 (8H, m, Ar-H), 7.32 – 7.18 (17H, m, Ar-H), 4.03 (1H,
d, J = 7.6 Hz, C[1]-H), 3.99 – 3.89 (1H, m, C[13]-H), 3.79 (1H,
AB d, J= 13.0 Hz, C[8]-H), 3.38 (2H, d, J= 13.0 Hz, C[8]-H), 3.26
(1H, t, J = 7.0 Hz, C[3]-H), 3.01 (1H, dd, J = 9.4 Hz, 7.0 Hz C[14]-
H), 2.90 (1H, dd, J = 9.4 Hz, 7.5 Hz C[14]-H), 2.68 (1H, dd, J =
8.3 Hz, 7.0 Hz, C[3]-H), 2.50 – 2.38 (1H, m, C[2]-H), 2.27 (1H,
bs, OH). 13C{1H} NMR (CDCl3, 75 MHz), C: 143.7 (C[16]),
142.6 (C[4]), 138.3 (C[9]), 128.7 (C[10]), 128.6 (C[17]), 128.2
(C[6]), 128.2 (C[11]), 127.9 (C[18]), 127.9 (C[7]), 127.1
(C[19]), 127.1 (C[5]), 126.9 (C[12]), 86.8 (C[15]), 72.8 (C[13]),
71.2 (C[1]), 65.6 (C[14]), 61.7 (C[8]), 52.6 (C[3]), 43.6 (C[2]).
HRMS (ESI) m/z: [M+H]+ Calcd for C37H36NO2 526.2746;
Found 526.2744.
1-(1-Methyl-2-phenylazetidin-3-yl)-2-
(trityloxy)ethan-1-ol (1k)
1.0 mmol scale synthesis:
Prepared according to General Procedure D using 2k (1.0
mmol, 449 mg). Purification by column chromatography on
silica gel (40–100% EtOAc in hexane) afforded the title com-
pound (1k) as a yellowish solid (341 mg, 0.76 mmol, 76%).
The scale-up synthesis:
Potassium tert-butoxide (40 mmol, 4.49 g, 2.0 equiv.) was
dissolved in dry THF (50 mL) and cooled to -78 °C, using dry
ice in acetone, in a Schlenk flask (200 mL) under nitrogen
atmosphere. Diisopropylamine (40 mmol, 4.05 g, 5.65 mL, 2.0
equiv.) followed by a 1.59 M hexane solution of BuLi (46
mmol, 29 mL, 2.3 equiv.) were added dropwise into the solu-
tion (yellowish). The reaction mixture was stirred for 20
minutes at -78 °C. Oxirane (2k, 8.98 g, 20 mmol, 1.0 equiv.) in
dry THF (100 mL) was added dropwise, the dark red mixture
was stirred at -78 °C for 2 hours. The cold reaction mixture
was poured carefully into the mixture of diethyl ether (100
mL) and water (50.0 mL) then it was allowed to warm up to
room temperature. The phases were separated, the aqueous
phase was extracted with diethyl ether (3 × 100 mL). The
combined organic layers were washed with brine (1 × 200
mL), dried over sodium sulfate, filtered and concentrated
under reduced pressure. The crude mixture (8.4 g) was puri-
fied by flash chromatography on silica gel (50–100% EtOAc in
hexane) afforded 1k as an off-white solid (7.01 g, 15.7 mmol,
78%). 1H-NMR (CDCl3, 300 MHz) δH: 7.34 (8H, t, J= 9.2 Hz, Ar-
H), 7.34 (8H, t, J= 7.8 Hz, Ar-H), 7.24 – 7.19 (4H, m, Ar-H), 3.92
(1H, td, J = 7.2 Hz, 3.8 Hz, C[9]-H), 3.84 (1H, d, J = 7.8 Hz, C[1]-
H), 3.42 (1H, t, J = 7.0 Hz, C[3]-H), 3.00 (1H, dd, J = 9.2 Hz, 3.6
Hz C[10]-H), 2.90 (1H, dd, J = 9.2 Hz, 8.5 Hz, C[10]-H), 2.71
(1H, t, J = 7.4 Hz, C[3]-H), 2.53 – 2.47 (1H, m, C[2]-H), 2.29 (3H,
s, 3 × C[8]-H ). 13C{1H} NMR (CDCl3, 75 MHz), C: 143.7
(C[12]), 142.3 (C[4]), 128.6 (C[13]), 128.3 (C[5]), 127.9
(C[14]), 127.2 (C[7]), 127.1 (C[15]), 127.0 (C[6]), 86.8 (C[11]),
73.5 (C[9]), 72.6 (C[1]), 65.7 (C[10]), 54.5 (C[3]), 44.2 (C[8]),
43.1 (C[2]). HRMS (ESI) m/z: [M+H]+ Calcd for C31H32NO2
450.2433; Found 450.2424.
Tert-butyl
3-(1-hydroxy-2-(trityloxy)ethyl)-2-
phenylazetidine-1-carboxylate (1n): Prepared according to
General Procedure D using 2n (1.0 mmol, 535 mg). Purifica-
tion by column chromatography on silica gel (0–20% EtOAc in
hexane) afforded the title compound (1n) as a yellowish solid
(215 mg, 0.40 mmol, 40%). 1H-NMR (CDCl3, 300 MHz) δH:
7.41 – 7.35 (6H, m, Ar-H), 7.32 – 7.20 (14H, m, Ar-H), 5.06 (1H,
m, C[1]-H), 4.05 – 3.95 (1H, m, C[11]-H), 3.89 (1H, J = 8.4 Hz,
C[3]-H), 3.68 (1H, dd, J = 8.4 Hz, 6.2 Hz C[3]-H), 3.12 (1H, dd,
J= 9.4 Hz, 3.6 Hz C[12]-H), 3.00 (1H, dd, J= 9.4 Hz, 7.4 Hz
C[12]-H), 2.55 – 2.25 (1H, m, C[2]-H), 1.30 (9H, bs, 9 × C[10]-
H). 13C{1H} NMR (CDCl3, 126 MHz), C: 156.5 (C[8]), 143.5
(C[14]), 141.8 (C[4]), 128.5 (C[15]), 128.3 (C[5]), 127.9
(C[16]), 127.2 (C[17]), 127.1 (C[7]), 125.9 (C[6]), 87.0 (C[13]),
79.5 (C[9]), 72.0 (C[11]), 65.3 (C[12]), 60.4 (C[1]), 53.8 (C[3]),
41.6 (C[2]), 28.3 (C[10). HRMS (ESI) m/z: [M+H]+ Calcd for
C35H38NO4 536.2801; Found 536.2805.
1-(2-(4-Methoxyphenyl)-1-methylazetidin-3-yl)-2-
(trityloxy)ethan-1-ol (1o): Prepared according to General
Procedure D using 2o (0.63 mmol, 300 mg). Purification by
column chromatography on silica gel (0–20% MeOH in DCM)
afforded the title compound (1o) as a yellowish solid (260 mg,
0.54 mmol, 76%). 1H-NMR (CDCl3, 300 MHz) δH: 7.45 – 7.36
(6H, m, 6 × C[14]-H), 7.33 – 7.24 (11H, m, Ar-H), 6.80 (2H, d, J=
8.6 Hz, 2 × C[6]-H), 3.96 – 3.88 (1H, m, C[10]-H), 3.77 (3H, s, 3
× C[8]-H), 3.72 (1H, d, J= 7.5, Hz, C[1]-H), 3.37 (1H, t, J= 6.9 Hz,
C[3]-H), 3.00 (1H, dd, J= 9.6 Hz, 3.6 Hz, C[11]-H), 2.88 (1H, dd,
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J= 9.6 Hz, 7.2 Hz, C[11]-H), 2.63 (1H, t, J= 6.9 Hz, C[3]-H), 2.50
1-Methyl-2-phenylazetidin-3-yl(phenyl)methanol
– 2.38 (1H, m, C[2]-H), 2.26 (3H, s, 3 × C[9]-H). 13C{1H} NMR
(CDCl3, 75 MHz), C: 158.9 (C[7]), 143.7 (C[13]), 134.4 (C[4]),
128.6 (C[14]), 128.2 (C[5]), 127.9 (C[15]), 127.1 (C[16]),
113.7 (C[6]), 86.8 (C[12]), 73.1 (C[1]), 72.5 (C[10]), 65.7
(C[11]), 55.3 (C[8]), 54.4 (C[3]), 44.0 (C[9]), 43.3 (C[2]).
HRMS (ESI) m/z: [M+H]+ Calcd for C32H34NO3 480.2533;
Found 480.2538.
(1s_trans): Prepared according to General Procedure D using
2s (0.87 mmol, 220 mg). Purification by preparative HPLC
(using 0.4 g NH4HCO3 in 1 L water and acetonitrile) afforded
the title compound 1s_trans (51 mg, 0.20 mmol, 23%) as a
yellowish oil and 1s_cis (15 mg, 0.06 mmol, 7%) as a yellow-
ish oil, 10_trans (48 mg, 0.23 mmol, 19%) as a yellowish oil,
10_cis (30 mg, 0.23 mmol, 12%) as a yellowish oil. Crude
product: LC MS area%: 1s_trans: 31%, 1s_cis: 11%, 10_trans:
33%, 10_cis: 25%
1
2
3
4
5
6
7
8
1-(2-(3-Methoxyphenyl)-1-methylazetidin-3-yl)-2-
(trityloxy)ethan-1-ol (1p): Prepared according to General
Procedure D using 2p (0.83 mmol, 400 mg). Purification by
column chromatography on silica gel (0–20% MeOH in DCM)
afforded the title compound (1p) as a yellowish solid (290 mg,
0.60 mmol, 72%). 1H-NMR (CDCl3, 300 MHz) δH: 7.40 – 7.32
(6H, m, 6 × C[14]-H), 7.31 – 7.12 (11H, m, Ar-H), 6.98 (1H, s,
C[5]-H), 6.88 (1H, d, J= 7.5 Hz, C[8]-H), 6.76 (1H, dd, J= 7.5 Hz,
1.8 Hz C[7]-H), 3.92 (1H, td, J= 6.6 Hz, 3.6 Hz, C[12]-H), 3.80 –
3.75 (4H, m, C[1]-H, 3 × C[10]-H), 3.38 (1H, t, J= 6.9 Hz, C[3]-
H), 3.02 (1H, dd, J= 9.3 Hz, 3.6 Hz, C[13]-H), 2.92 (1H, dd, J=
9.0 Hz, 7.2 Hz, C[13]-H), 2.64 (1H, t, J= 6.9 Hz, C[3]-H), 2.51 –
2.42 (1H, m, C[2]-H), 2.29 (3H, s, 3 × C[11]-H). 13C{1H} NMR
(CDCl3, 75 MHz), C: 159.7 (C[6]), 143.9 (C[4]), 143.7 (C[15]),
129.2 (C[8]), 128.6 (C[16]), 127.8 (C[17]), 127.1 (C[18]),
119.4 (C[9]), 113.1 (C[7]), 112.1 (C[5]), 86.8 (C[14]), 73.5
(C[1]), 72.7 (C[12]), 65.7 (C[13]), 55.2 (C[10]), 54.5 (C[3]),
44.2 (C[11]), 43.1 (C[2]). HRMS (ESI) m/z: [M+H]+ Calcd for
C32H34NO3 480.2533; Found 480.2521.
9
Trans-1-methyl-2-phenylazetidin-3-
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yl(phenyl)methanol (1s_trans): 1H-NMR (DMSO-d6, 500
MHz) δH: 7.25 – 7.09 (10H, m, aromatic H), 5.44 (1H, bs, OH),
4.60 (1H, d, J= 5.9 Hz, C[9]-H), 3.82 (1H, d, J= 7.8 Hz, C[1]-H),
3.29 (1H, t, J= 6.8 Hz, C[3]-H), 2.91 (1H, dd, J= 8.4 Hz, 6.4 Hz,
C[3]-H), 2.45 – (1H, m, C[2]-H), 2.22 (3H, s, 3 × C[8]-H).
13C{1H} NMR (DMSO-d6, 126 MHz), C: 143.9 (C[10]), 142.5
(C[4]), 127.9 (C[11/C5]), 127.9 (C[11/C5]), 126.9 (C[13]),
126.7 (C[7]), 126.5 (C[12]), 126.2 (C[6]), 72.6 (C[9]), 71.2
(C[1]), 54.4 (C[3]), 47.8 (C[2]), 44.0 (C[8]). HRMS (ESI) m/z:
[M+H]+ Calcd for C17H20NO 254.1539; Found 254.1544.
Cis-1-methyl-2-phenylazetidin-3-yl(phenyl)methanol
(1s_cis): 1H-NMR (CDCl3, 500 MHz) δH: 7.28 – 7.18 (8H, m,
aromatic H), 7.08 – 7.04 (2H, m, aromatic H), 4.36 (1H, dd, J=
5.1 Hz, 3.5 Hz, C[9]-H), 3.34 (1H, d, J= 10.7 Hz, C[3]-H), 3.13
(1H, d, J= 9.2 Hz, C[2]-H), 3.09 (1H, dd, J= 9.2 Hz, 3.2 Hz, C[1]-
H), 2.81 (1H, dd, J= 10.7 Hz, 5.9 Hz, C[3]-H), 2.50 (1H, bs, OH),
2.20 (3H, s, 3 × C[8]-H). 13C{1H} NMR (CDCl3, 126 MHz), C:
141.1, 140.4, 128.6, 128.5, 128.1, 127.7, 127.6, 126.7, 79.9
(C[1]), 77.9 (C[9]), 66.1 (C[2]), 65.7 (C[3]), 40.4 (C[8]). HRMS
(ESI) m/z: [M+H]+ Calcd for C17H20NO 254.1539; Found
254.1529.
1-(2-(4-Fluorophenyl)-1-methylazetidin-3-yl)-2-
(trityloxy)ethan-1-ol (1q): Prepared according to General
Procedure D using 2q (0.43 mmol, 200 mg). Purification by
column chromatography on silica gel (40–100% EtOAc in
hexane) afforded the title compound (1q) as a yellowish solid
(160 mg, 0.35 mmol, 80%). 1H-NMR (CDCl3, 300 MHz) δH:
7.38 – 7.21 (17H, m, aromatic H), 6.92 (2H, t, J= 8.8 Hz, 2 ×
C[6]-H), 3.97 – 3.85 (1H, m, C[9]-H), 3.77 (1H, d, J= 7.8, Hz,
C[1]-H), 3.37 (1H, t, J= 6.9 Hz, C[3]-H), 2.98 (1H, dd, J= 9.6 Hz,
3.9 Hz, C[10]-H), 2.88 (1H, dd, J= 9.3 Hz, 7.5 Hz, C[10]-H), 2.66
(1H, t, J= 6.9 Hz, C[3]-H), 2.46 – 2.36 (1H, m, C[2]-H), 2.26 (3H,
s, 3 × C[8]-H). 13C{1H} NMR (CDCl3, 75 MHz), C: 162.1 (d, J=
243.3 Hz, C[7]), 143.7 (C[12]), 138.1 (d, J= 2.9 Hz, C[4]), 128.8
(C[5]), 128.6 (C[13]), 127.9 (C[14]), 127.2 (C[15]), 115.1 (d, J=
21.0 Hz, C[6]), 86.9 (C[10]), 72.7 (C[1]), 72.4 (C[9]), 65.8
(C[10]), 54.4 (C[3]), 44.1 (C[8]), 43.3 (C[2]). HRMS (ESI) m/z:
[M+H]+ Calcd for C31H31FNO2 468.2333; Found 468.2322.
Trans-1-methyl-4,5-diphenylpyrrolidin-3-ol
(10s_trans): 1H-NMR (DMSO-d6, 500 MHz) δH: 7.30 – 7.15
(8H, m, aromatic H), 7.09 – 7.06 (2H, m, aromatic H), 5.15 (1H,
d, J= 5.5 Hz, OH), 4.23 – 4.17 (1H, m, C[3]-H), 3.84 (1H, d, J= 7.8
Hz, C[1]-H), 3.15 (1H, dd, J= 12.0 Hz, 10.1 Hz, C[4]-H), 2.94
(1H, dd, J= 10.1 Hz, 5.3 Hz, C[2]-H), 2.72 (1H, dd, J= 10.1 Hz,
7.4 Hz, C[4]-H), 2.03 (3H, s, 3 × C[9]-H). 13C{1H} NMR (DMSO-
d6, 126 MHz), C: 141.2, 141.2, 128.2, 128.2, 128.1, 127.6,
127.2, 126.3, 78.1 (C[1]), 76.3 (C[3]), 64.9 (C[2]), 64.9 (C[4]),
40.1 (C[9]). HRMS (ESI) m/z: [M+H]+ Calcd for C17H20NO
254.1539; Found 254.1549.
Cis-1-methyl-4,5-diphenylpyrrolidin-3-ol
(10s_cis):
1-(1-Methyl-2-(naphthalen-2-yl)azetidin-3-yl)-2-
(trityloxy)ethan-1-ol (1r): Prepared according to General
Procedure D using 2r (0.4 mmol, 200 mg). Purification by
column chromatography on silica gel (40–100% EtOAc in
hexane) afforded the title compound (1r) as a yellowish solid
(104 mg, 0.21 mmol, 52%). 1H-NMR (CDCl3, 300 MHz) δH:
8.28 (1H, d, J= 8.1 Hz, C[7]-H), 7.84 (2H, t, J= 6.9 Hz, C[10]-H,
C[12]-H), 7.73 (1H, d, J= 8.1 Hz, C[13]-H), 7.46 – 7.34 (18H, m,
aromatic H), 4.59 (1H, d, J= 7.5 Hz, C[1]-H), 4.00 (1H, q, J= 5.1
Hz, C[15]-H), 3.46 (1H, t, J= 6.6 Hz, C[3]-H), 2.98 – 2.84 (2H, m,
C[3]-H, C[16]-H), 2.80 – 2.72 (1H, m, C[16]-H), 2.66 – 2.54 (1H,
m, C[2]-H), 2.29 (3H, s, 3 × C[14]-H). 13C{1H} NMR (CDCl3, 300
MHz), C: 143.6 (C[18]), 137.8 (C[4]), 133.8 (C[6]), 131.2
(C[11]), 128.6 (C[13]), 128.5 (C[19]), 127.8 (C[20]), 127.7
(C[10]), 127.1 (C[21]), 125.7 (C[7]), 125.6 (C[12]), 125.4
(C85]), 125.2 (C[9]), 123.4 (C[5]), 86.7 (C[17]), 72.3 (C[15]),
69.7 (C1]), 66.8 (C[16]), 54.4 (C[3]), 44.6 (C[14]), 44.3 (C[2]).
HRMS (ESI) m/z: [M+H]+ Calcd for C35H34NO2 500.2584;
Found 500.2560.
1H-NMR (DMSO-d6, 500 MHz) δH: 7.02 – 6.98 (4H, m, aromatic
H), 6.97 – 6.90 (4H, m, aromatic H), 6.87 – 6.84 (2H, m, aro-
matic H), 5.22 (1H, d, J= 4.5 Hz, OH), 4.36 – 4.31 (1H, m, C[3]-
H), 3.84 (1H, d, J= 7.8 Hz, C[1]-H), 3.66 (1H, dd, J= 9.8 Hz, 6.4
Hz, C[4]-H), 3.22 (1H, dd, J= 7.8 Hz, 3.0 Hz, C[2]-H), 2.35 (1H,
dd, J= 9.8 Hz, 5.6 Hz, C[4]-H), 2.15 (3H, s, 3 × C[9]-H). 13C{1H}
NMR (DMSO-d6, 125 MHz), C: 141.0, 139.3, 129.1, 127.9,
127.3, 127.2, 126.1, 125.5, 75.2 (C[3]), 72.9 (C[1]), 64.7 (C[4]),
60.6 (C[2]), 40.7 (C[9]). HRMS (ESI) m/z: [M+H]+ Calcd for
C17H20NO 254.1539; Found 254.1542.
1-Ethyl-2-phenylazetidin-3-yl)(phenyl)methanol (1t):
Prepared according to General Procedure D using 2t (0.75
mmol, 200 mg). Purification by column chromatography on
silica gel (0–20% MeOH in DCM) afforded the title compound
(1t) as a white solid (187 mg, 0.70 mmol, 93%). 1H-NMR
(CDCl3, 300 MHz) δH: 7.31 – 7.13 (10H, m, Ar-H), 4.67 (1H, d,
J= 5.4 Hz, C[10]-H) 3.90 (1H, d, J= 8.1 Hz, C[1]-H), 3.45 (1H, t,
J= 6.9 Hz, C[3]-H) 2.94 (1H, t, J= 6.9 Hz, C[3]-H) 2.68 – 2.40
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(3H, m, C[2]-H, 2 × C[8]-H), 0.91 (3H, t, J= 7.2 Hz, 3 × C[9]-H)
ACKNOWLEDGMENT
13C{1H} NMR (CDCl3, 75 MHz), C: 142.6 (C[11]), 142.5 (C[4]),
128.4 (C[5]), 128.0 (C[12]), 127.7 (C[14]), 126.9 (C[7]), 126.8
(C[6]), 126.1 (C[13]), 74.0 (C[10]), 70.6 (C[1]), 52.7 (C[3]),
52.3 (C[8]), 47.0 (C[2]), 12.6 (C[9]). HRMS (ESI) m/z: [M+H]+
Calcd for C18H22NO 268.1696; Found 268.1702.
1
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3
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5
6
7
8
This work was funded by grants provided by the Hungarian
Scientific Research Fund (OTKA K 104528). Ervin Kovács is
grateful to the National Research, Development and Innova-
tion Office (NKFIH) for Postdoctoral Excellence Award (PD
128612). We thank Mikós Nyerges, Tamás Gáti and Barbara
Balázs (Servier Research Institute of Medicinal Chemistry,
Budapest) spectroscopic assistance. We thank Gábor Turczel
for help with experiments and technical support, as well as
Imre G. Csizmadia for critical evaluation of the manuscript.
1-Benzyl-2-phenylazetidin-3-yl)(phenyl)methanol
(1u): Prepared according to General Procedure D using 2u
(0.68 mmol, 225 mg). Purification by column chromatography
on silica gel (0–10% MeOH in DCM) afforded the title com-
pound (1u) as a white solid (146 mg, 0.44 mmol, 65%). 1H-
NMR (CDCl3, 300 MHz) δH: 7.31 – 7.19 (15H, m, Ar-H), 4.72
(1H, d, J= 7.8 Hz, C[14]-H), 4.10 (1H, d, J= 7.8 Hz, C[1]-H), 3.83
(1H, AB d, J= 12.9 Hz, C[8]-H), 3.45 (1H, AB d, J= 12.9 Hz, C[8]-
H), 3.36 (1H, t, J= 6.9, Hz, C[3]-H), 3.03 (1H, t, J= 6.9 Hz, C[3]-
H), 2.70 – 2.59 (1H, m, C[2]-H), 2.09 (1H, bs, OH). 13C{1H}
NMR (CDCl3, 75 MHz), C: 142.7 (C[14]), 142.3 (C[4]), 138.6
(C[9]), 128.9 (C[10]), 128.6 (C[15]), 128.4 (C[5]), 128.3
(C[11]), 128.0 (C[17]), 127.2 (C[7]), 127.1 (C[12]), 127.0
(C[6]), 126.3 (C[17]), 74.2 (C[13]), 70.0 (C[1]), 61.9 (C[8]),
52.7 (C[3]), 48.0 (C[2]). HRMS (ESI) m/z: [M+H]+ Calcd for
C23H24NO 330.1852; Found 330.1866.
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* Ervin Kovács, e-mail: kovacs.ervin@ttk.hu
* Zoltán Mucsi, e-mail: zmucsi@femtonics.eu
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