Development of a Continuous Flow Synthesis of 2-Substituted Azetines and 3-Substituted Azetidines by Using a Common Synthetic Precursor

Article abstract of DOI:10.1021/acs.joc.1c01297

The generation and functionalization, under continuous flow conditions, of two different lithiated four-membered aza-heterocycles is reported. N-Boc-3-iodoazetidine acts as a common synthetic platform for the genesis of C3-lithiated azetidine and C2-lithiated azetine depending on the lithiation agent. Flow technology enables easy handling of such lithiated intermediates at much higher temperatures compared to batch processing. Flow technology combined with cyclopentylmethyl ether as an environmentally responsible solvent allows us to address sustainability concerns.

Full text of DOI:10.1021/acs.joc.1c01297

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Development of a Continuous Flow Synthesis of 2‑Substituted
Azetines and 3‑Substituted Azetidines by Using a Common
Synthetic Precursor
Marco Colella,§ Pantaleo Musci,§ Debora Cannillo, Mauro Spennacchio, Andrea Aramini,
Leonardo Degennaro,* and Renzo Luisi*
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ABSTRACT: The generation and functionalization, under con-
tinuous flow conditions, of two different lithiated four-membered
aza-heterocycles is reported. N-Boc-3-iodoazetidine acts as a
common synthetic platform for the genesis of C3-lithiated
azetidine and C2-lithiated azetine depending on the lithiation
agent. Flow technology enables easy handling of such lithiated
intermediates at much higher temperatures compared to batch
processing. Flow technology combined with cyclopentylmethyl
ether as an environmentally responsible solvent allows us to
address sustainability concerns.
for taming, controlling, and using highly reactive organo-
metallic intermediates.14 The benefits of flow microreactor
technology as a pivotal synthetic “toolbox” for enabling new
and previously inaccessible reactivity patterns or for controlling
safety concerns of old-fashioned chemistry are nowadays well-
documented.15,16 Furthermore, flow technology holds the
potential to be a green technology addressing the quest for
sustainability coming from modern society.17 Leveraging on
our experience in the field, we report herein a greener and
more sustainable approach for the functionalization of the
azetidine ring under continuous flow conditions.18 Examples of
C3-functionalization of azetidines, via the corresponding C3-
metalated intermediates, have been reported by several authors
(Scheme 1, a) that, however, used this strategy in cross-
coupling reactions in the presence of transition metals.19−23
The C2-functionalization of 2-azetines has been exploited only
recently by Hodgson24 and Didier25 to generate the
corresponding 2-lithium azetine intermediates under cryogenic
conditions and without using a green solvent. Herein, a
sustainable continuous flow protocol has been developed
starting from a common readily available precursor to access
C3-functionalized azetidines and C2-functionalized 2-azetines.
Both synthetic sequences foresee a metalation (lithiation) step
INTRODUCTION
■
Nitrogen-bearing heterocycles are ubiquitous and essential in a
plethora of biologically relevant molecules and natural
products.1 Piperidines and pyrrolidines are in the top five
among the 25 most frequently employed nitrogen heterocycles,
respectively, at the first and fifth position. In this ranking, the
four-membered heterocyclic core is represented by the well-
known β-lactams (i.e., azetidine-2-ones), especially as bicyclic
fused systems are mostly employed as antibacterial agents.
However, although less investigated than the corresponding
higher homologues belonging to the class of N-containing
heterocycles, the azetidine ring is present in several biologically
relevant compounds.2,3 The peculiar molecular rigidity and
robustness (e.g., chemical stability) are the main features that
justify the introduction of azetidine motifs in medicinal
chemistry design. Moreover, beneficial effects on the
pharmacokinetic profile after the introduction of this strained
ring have also been reported.4 The importance of the azetidine
ring is showcased by the recent introduction into the market of
several medicines such as azelnipidine (Calblock),5 cobimeti-
nib (Cotellic),6 baricitinib (Olumiant),7 and others (Figure
1).8,9
The first reported synthesis of the azetidine ring dates to
1888,10 but interest in developing efficient synthetic method-
ologies for creating functionalized azetidines was raised only
recently. On the other hand, such a relatively unexplored motif
continues to stimulate organic chemists’ creativity.11 Our
research group is involved in developing synthetic tactics
involving metalated (i.e., lithiated) azetidines as useful
intermediates for creating molecular diversity.12,13 In addition,
we became interested in the use of flow technology as a tool
Special Issue: Enabling Techniques for Organic Syn-
thesis
Received: June 3, 2021
https://doi.org/10.1021/acs.joc.1c01297
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© XXXX American Chemical Society
A

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Figure 1. Examples of azetidine-containing biologically active compounds.
Scheme 1
(Scheme 1, c) and employ cyclopentylmethyl ether as green
solvent.26
secondary akyllithiums requires a precise control of the
reaction parameters (i.e., temperature as low as −100 °C),
rapid quenching in the order of seconds, and precise order of
addition of reactants to avoid undesired side reactions.28 With
this in mind, we envisaged that the lithiated species 1a-Li,
generated by iodine−lithium exchange from 1 using
hexyllithium,29 would undergo protonation (i.e., quenching)
by reaction with 1 itself or with 1-iodohexane, furnishing side
products 2, 3, and 1-hexene, respectively (Scheme 2, b).
According to Knochel’s report, such side-reaction pathways
could be favored generating 1a-Li in the presence of an excess
of 1. Hence, an inversion addition protocol, in which 1 is
added to an organolithium solution, was fundamental.
Moreover, the process needed to be conducted at low
temperatures (<−78 °C).
RESULTS AND DISCUSSION
■
We started our investigation by using 1-Boc-3-iodoazetidine 1
as a cheap (2.7 eur/g)27 and readily available starting material,
evaluating the lithium/iodine exchange reaction leading to 1a-
Li. Quenching of 1a-Li with an electrophile gives access to C3-
functionalized 1-Boc-azetidines. To the best of our knowledge,
protocols for the generation of azetidine lithiated at C3 have
not been reported. A possible reason could be ascribed to the
expected high reactivity of the putative secondary organo-
lithium generated by lithium/iodine exchange. Knochel
recently reported the generation of secondary alkyllithium
reagents employed in very elegant stereocontrolled processes.
Moreover, it was reported that the generation and use of
B
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external quenching conditions, and adding the electrophile
after the generation of the lithiated species 1a-Li. As reported
in Table 1, using 2-MeTHF as the solvent (entry 1), 1a-Li
could be efficiently intercepted using benzophenone as the
electrophile to furnish adduct 4a in 64% yield. In striking
contrast, the use of CPME resulted in a modest 18% yield of
4a, jointly to a predominant 49% of protonated azetidine 2
(entry 2). Another experiment conducted at −50 °C in CPME
proved that the process cannot be effectively executed in this
solvent (entry 3). Adopting the internal quenching protocol
using CPME as the solvent at −78 °C returned a 62% yield of
4a and only 10% of byproduct 2 (entry 4). However, running
the reaction at −50 °C in internal quenching mode was
detrimental likely because of the thermal sensitivity of 1a-Li
(entry 5). Despite the poor performance of CPME under batch
conditions, we reasoned that this might have been the right
solvent to use under flow conditions for the following reasons.
CPME has a high boiling point (106 °C) and low propensity
to form peroxides, displays chemical stability under acidic and
basic conditions, is cheaper than 2-MeTHF, and can be used as
received without anhydrification. In addition, the very low
solubility in water allows us to reduce the amount of organic
solvent for workup procedures.31 For these reasons, to develop
a greener process, we focused on the use of CPME and flow
technology for the C3-functionalization of N-Boc azetidine.
The continuous flow C3-lithiation/trapping sequence was
performed using a flow system consisting of two stainless steel
T-shaped micromixers (M1 and M2) and two stainless steel
microtube reactors (R1 and R2), and the CPME solutions of 1,
HexLi, and benzophenone were introduced by syringe pumps
(Table 2).
Scheme 2. Self-Quenching of Secondary Alkyllithiums
Table 1
a
b
bc
,
entry
solvent
T (°C) time (min) 4a yield (%) 2 yield (%)
1
2
3
4
5
2-MeTHF
CPME
CPME
CPME
CPME
−78
−78
−50
−78
−50
1
1
1
0
0
64
18
<5
62
33
49
47
10
24
d
d
24
b
a
Time before quenching with the electrophile. Yields calculated by
1H NMR of the crude reaction mixture using CH2Br2 as the internal
standard. The amount of azetine 3 and 1-hexene was difficult to
c
d
evaluate due to the volatility of those compounds. Reaction ran in
Initial attempts to conduct the flow sequence in the range of
temperatures −30 to +25 °C resulted in clogging of the system
or low yields of the desired product. To overcome this
problem we decided to adopt −50 °C as the ideal temperature
for the iodine/lithium exchange reaction. As reported in Table
2, by using a short residence time (in the range of 82 up to 330
ms) we were able to effectively generate and intercept the C3-
lithiated azetidine 1a-Li. Interestingly, 4a could be obtained in
80% yield using 82 ms as the residence time in R1, observing
internal quenching conditions.
Aimed at developing a more sustainable protocol, our idea
was to generate 1a-Li by taking advantage of the flow
technology and by using a primary alkyllithium (i.e., HexLi) for
the iodine/lithium exchange reaction using a green solvent
(i.e., 2-MeTHF or CPME).30 We started our investigation by
testing the generation of 1a-Li at −78 °C in batch under
Table 2
a
b
bc
,
entry
HexLi (equiv)
electrophile (equiv)
tR1 (ms)
4a, yield (%)
2, yield (%)
1
2
3
4
2
1
1
1
2
330
330
82
40
64
52
80
30
10
20
<5
1.5
1.5
1.5
82
a
b
Time before quenching with the electrophile. Yields calculated by 1H NMR of the crude reaction mixture using CH2Br2 as the internal standard.
c
The amount of azetine 3 and 1-hexene was difficult to evaluate due to the volatility of those compounds.
C
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Scheme 3. Scope for the Continuous Flow Synthesis of C3-Funtionalized Azetidines
only traces of byproduct 2 (Table 2, entry 4). Longer residence
times (entries 1 and 2) provided lower yields of 4a while
promoting the protonation of 1a-Li to furnish 2. Remarkably,
the use of flow technology resulted in a much better
performance of the reaction with respect to batch processing
(compare Table 1, entries 3 and 5, and Table 2, entry 4). In
addition, the short residence time realized in the flow system
gives the opportunity to generate a secondary organolithium
reagent from the safer (primary) HexLi, avoiding the more
reactive t-BuLi considered the “must be used” reagent for this
kind of chemistry.
With the optimal condition in hands, the scope of the
reaction was investigated. As reported in Scheme 3, the flow
setup allowed to prepare several C3-funtionalized azetidines
4b−r with good to excellent yields. The flow synthesis was
effective with both ketones and aldehydes and occurred with
high chemoselectivity as in the case of 4d potentially prone to
undergoing a competitive Br/Li exchange reaction or as in the
case of 4f susceptible of β-elimination. The use of α,β-
unsaturated carbonyls resulted in a chemo-selective 1,2-
addition returning products 4g,h in very good yields.
The slightly lower yields observed with aromatic ketones
(furnishing 4e and 4f) could be the result of a competitive
enolization as well as a different electrophilicity of the
carbonyls due to the aromatic ring. The reaction gave
successful results with imines (4m), carbocyclic and hetero-
cyclic ketones (4n,o), as well as enolizable aldehydes (4p).
Moreover, compounds bearing a silyl and a boron functionality
could be prepared in satisfactory yields (4q,r) by silylation and
borylation reactions. Under optimized conditions, the process
is complete in less than 12 s, producing 0.224 mmol/min of
the desired product. In the case of 4a, 5 min of continuous
collection furnished 380 mg of the product, securing an
estimated productivity of 4.56 g/h.
Next, we investigated the possibility to use the same 3-iodo
azetidine 1 as a common synthetic platform for a β-
elimination/lithiation/electrophilic trapping sequence to ac-
cess C2-functionalized azetines. Hodgson23 and Didier24
D
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demonstrated that azetines could be deprotonated at C2 in
THF at −78 °C by using sec-BuLi as the lithiation agent. Our
idea was to use 1 as starting material for a one-pot β-
elimination/lithiation sequence. We reasoned that the use of
an alkyllithium would have been problematic due to a
competitive iodine/lithium exchange reaction. For this reason,
we selected, lithium diisopropylammide (LDA, pKa ∼ 35) as a
suitable non-nucleophilic base capable of promoting β-
elimination of 1 and C2-lithiation of the resulting azetine
3.32 Aimed at developing a sustainable process, the entire
sequence was developed under continuous flow conditions and
using CPME as the green solvent (Scheme 4).
trophilic trapping sequence under more sustainable conditions
(i.e., continuous flow, 0 °C and using a green solvent), the
scope of the synthetic sequence was investigated (Scheme 5).
Several C2-functionalized azetines 5b−r were prepared in
good to excellent yields using this one-flow approach from 1
(Scheme 5). Aromatic ketones as well as aldehydes and α,β-
unsaturated carbonyls were found to be suitable reaction
partners and reacted with high chemoselectivity when in the
presence of additional functional groups (namely, halogens as
in the case of 5d, 5f, or 5l; double bonds as in the case of
5g,h). The use of imines, enolizable aldehydes, and strained
carbocyclic and heterocyclic ketones was also feasible,
furnishing azetines 5m−q in good yields (Scheme 5).
Remarkably, silylation reaction occurred with good yield,
furnishing azetine 5r. This flow process occurred in less than
20 s providing a productivity of 0.3 mmol/min of azetines 5.
By using acetophenone as the electrophile, continuous
collection for 5 min furnished 525 mg of azetine 5e, which
would correspond to a productivity of 6.3 g/h.
Scheme 4. Optimization of the Continuous Flow β-
Elimination/Lithiation/Electrophilic Trapping Sequence
Unfortunately, it was not possible to introduce an alkyl
group at the C-2 position of the azetine and at the C-3 position
of azetidine by using alkyl halides, likely because of a
competitive Li/halide exchange and β-elimination reaction
occurring between the formed organolithium and the alkyl
halide. Attempts using MeI returned unsubstituted azetine and
azetidine.
CONCLUSIONS
■
In conclusion, to the best of our knowledge, this work reports
the first flow synthesis of C3-functionalized azetidines and C2-
functionalized azetines starting from the same precursor,
adopting different lithiation conditions. In addition, CPME
has been employed as a green and sustainable solvent that
could be used as received without requiring additional
anhydrification steps. The developed process is safer, robust,
and more sustainable if compared to the available batch
methods for the preparation of similar molecules. Further
applications of the prepared molecules will be reported in due
course.
EXPERIMENTAL SECTION
■
Proton, carbon, and fluorine NMR spectra were recorded on an
Agilent 500 spectrometer (500 MHz for H, 126 MHz for 13C, 470
1
MHz for 19F) and on a Varian Mercury 300 spectrometer (300 MHz
for 1H, 75 MHz for 13C, 282 MHz for 19F). Chemical shifts are
reported in ppm (δ), and the center of the residual solvent signal was
used as the internal standard which was related to TMS with δ 7.26
ppm (1H in CDCl3), δ 77.00 ppm (13C in CDCl3). The multiplicity of
the signals is reported as s (singlet), d (doublet), t (triplet), q
(quartet), quin (quintet), bs (broad signal), m (multiplet). Spin−spin
coupling constants (J) are given in hertz. As far as possible, complete
and unambiguous assignment of all resonances was performed by
combined application of standard NMR techniques, such as HSQC
and COSY experiments. To minimize decomposition, NMR spectra
of azetines were recorded with CDCl3 aged on solid K2CO3. Infrared
spectra (FT-IR) were obtained by using a PerkinElmer 283
Spectrometer. High-resolution mass spectrometry (HRMS) spectra
were recorded on an Agilent 6530 accurate mass Q-TOF instrument.
The ethereal solvents employed in this study (CPME, THF, and
2MeTHF) have a water content ≤0.50% (K. F.) as reported by
specification from the supplier and were used as received. The
solution of lithium diisopropylamide (2 M in THF/heptane/
ethylbenzene) and the solution of n-hexyllithium (2.3 M in hexane)
were purchased from Merck and titrated prior to use. Other chemicals
were purchased from suppliers and used as received. TLC was carried
Parameters such as the residence time in R1 and the
temperature were evaluated in the optimization study (Scheme
4). Under the optimal conditions, the sequence for the
conversion of 1 into 3-Li required 9.4s at 0 °C furnishing, after
trapping with benzophenone as the model electrophile, C2-
functionalized azetine 5a in 89% yield. The 3D plot clearly
shows that high yields (i.e., >80%) could be obtained at lower
temperature (−40 °C) using longer residence times (up to
20s). In striking contrast, acceptable yields of 5a (in the range
60−80%) were observed using shorter residence times (2.3s)
and higher temperature (20 °C). It is worth pointing out that
the same one-pot sequence performed at 0 °C in batch made
returned 60% yield of 5a and 30% of 3 and required internal
quenching conditions.33 Delighted with the possibility to
effectively execute the one-pot β-elimination/lithiation/elec-
E
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Scheme 5. Scope for the Continuous-Flow Synthesis of C2-Functionalized Azetines
out on 0.25 mm precoated silica gel thick plates (Merck) with a
fluorescence indicator F-254; the spots were visualized under UV light
(λ = 254 nm) and/or KMnO4 (aq) as revealing agent.
for the quenching step (M2 through hole = 1000 μm, R2 inner
diameter ϕ = 1000 μm, length L = 200 cm). Three precooling units
(P1, P3 (inner diameter ϕ = 1000 μm, length L = 50 cm) and P2
(inner diameter ϕ = 1000 μm, length L = 25 cm)) were used.
General Procedure 1 (GP1) for Flow Synthesis of 3-
Substituted Azetidines 4. Flow set up A was employed. The
flow microreactor was dipped in a cooling bath (−50 °C). The
solution of 1-Boc-3-iodoazetidine 1 (0.07 M in CPME, flow rate: 4
mL/min) and the solution of n-hexyllithium (0.42 M in CPME, flow
rate: 1 mL/min) were delivered into M1 by syringe pumps. The
resulting solution passed through R1 (82 ms) and then was
introduced to M2, where it was mixed with the solution of
electrophile. The resulting solution passed through R2 (10.4 s).
After the system reached the steady state (1 min), the output solution
was collected for 2 min while being quenched with water. The
aqueous phase was separated, the organic layer was dried on Na2SO4
and filtered, and the solvent was removed under vacuum. The yield
was determined by NMR using dibromomethane as internal standard.
Flash column chromatography (SiO2) led to the desired product. The
employed solution of n-hexyllithium (0.42 M in CPME) was prepared
from the commercial solution of n-hexyllithium (2.3 M in hexane)
Stainless steel T-shaped micromixers and stainless steel microtube
reactors were employed. The microtubes were cut into appropriate
lengths and connected to the micromixers with stainless steel fittings
to build a customized flow microreactor. Solutions of the reaction
components were injected into the flow microreactor system using
Harvard PHD 2000 syringe pumps equipped with gastight syringes.
Flow Set Up A. Two stainless steel T-shaped micromixers (M1
and M2) and two stainless steel microtube reactors (R1 and R2) were
employed for the lithiation of azetidine 1 (M1 through hole = 250
μm, R1 inner diameter ϕ = 500 μm, length L = 3.5 cm) and for the
quenching step (M2 through hole = 1000 μm, R2 inner diameter ϕ =
1000 μm, length L = 200 cm). Three precooling units (P1, P3 (inner
diameter ϕ = 1000 μm, length L = 50 cm) and P2 (inner diameter ϕ
= 1000 μm, length L = 25 cm)) were used.
Flow Set Up B. Two stainless steel T-shaped micromixers (M1
and M2) and two stainless steel microtube reactors (R1 and R2) were
employed for the genesis and lithiation of azetine 3 (M1 through hole
= 250 μm, R1 inner diameter ϕ = 1000 μm, length L = 100 cm) and
F
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and titrated prior to use. Following the general procedure 1 (GP1),
continuous collection for 5 min furnished, after column chromatog-
raphy, 380 mg (1.1 mmol) of azetidine 4a.
1592, 1565, 1475, 1419, 1366, 1254, 1145, 1075, 995, 781, 767, 700.
HRMS calcd for C21H24BrNNaO3 [M + Na]+: 440.0837; found
440.0825.
General Procedure 2 (GP2) for Flow Synthesis of 2-
Substituted Azetines 5. Flow set up B was employed. The flow
microreactor was dipped in a cooling bath (0 °C). The solution of 1-
Boc-3-iodoazetidine 1 (0.0875 M in CPME, flow rate: 4 mL/min)
and the solution of lithium diisopropylamide (0.7 M in CPME, flow
rate: 1 mL/min) were delivered into M1 by syringe pumps. The
resulting solution passed through R1 (9.4 s) and then was introduced
to M2, where it was mixed with the solution of electrophile. The
resulting solution passed through R2 (10.4 s). After the system
reached the steady state (1 min), the output solution was collected for
2 min while being quenched with water. The aqueous phase was
separated, the organic layer was dried on Na2SO4 and filtered, and the
solvent was removed under vacuum. The yield was determined by
NMR using dibromomethane as internal standard. To minimize
decomposition, NMR spectra were recorded with CDCl3 aged on
solid K2CO3. Flash column chromatography (SiO2) led to the desired
product. In the case of products 5a−d and 5f,g, the crude mixture was
washed with hexane/diethyl ether 9:1 (5 mL) and filtrated on Gooch
yielding a white powder. The employed solution of LDA (0.7 M in
CPME) was prepared form the commercial solution of LDA (2 M in
THF/heptane/ethylbenzene) and titrated prior to use. Following the
general procedure 2 (GP2), continuous collection for 5 min
furnished, after column chromatography, 525 mg (1.9 mmol) of
azetine 5e.
tert-Butyl 3-(1-Hydroxy-1-phenylethyl)azetidine-1-carboxylate
4e. Following GP1 with acetophenone as electrophile, compound
4e was obtained as a white waxy solid (44% yield, 68 mg). Rf = 0.5
1
(7:3 hexane/ethyl acetate). H NMR (500 MHz, CDCl3): δ 7.42−
7.40 (m, 2H, Ar-H), 7.34 (t, J = 7.7 Hz, 2H, Ar-H), 7.27−7.24 (m,
1H, Ar-H), 4.03−3.93 (m, 2H, NCH2), 3.75−3.65 (m, 2H, NCH2),
3.00−2.94 (m, 1H, CH), 1.49 (s, 3H, CH3COH), 1.41 (s, 9H, 3 ×
CH3). 13C{1H} NMR (126 MHz, CDCl3): δ 156.6, 146.0, 128.6,
127.3, 124.8, 79.4, 73.4, 49.8, 39.1, 28.5, 27.4. IR (film)/cm−1: 3428,
2975, 1682, 1477, 1417, 1367, 1142, 909, 760, 701. HRMS calcd for
C16H23NNaO3 [M + Na]+: 300.1576; found 300.1571.
tert-Butyl 3-(3-Chloro-1-(4-fluorophenyl)-1-hydroxypropyl)-
azetidine-1-carboxylate 4f. Following GP1 with 3-chloro-4′-
fluoropropiophenone as electrophile, compound 4f was obtained as
a white waxy solid (41%, 79 mg). Rf = 0.5 (7:3 hexane/ethyl acetate).
1H NMR (300 MHz, CDCl3): δ 7.40−7.30 (m, 2H, Ar-H), 7.12−6.97
(m, 2H, Ar-H), 4.11−3.91 (m, 2H, NCH2), 3.67−3.54 (m, 2H,
NCH2), 3.45 (ddd, J = 10.9, 8.5, 7.1 Hz, 1H, CH2CH2Cl), 3.26 (ddd,
J = 10.9, 8.3, 5.8 Hz, 1H, CH2CH2Cl), 3.04−2.93 (m, 1H,
NCH2CH), 2.70 (bs, 1H, OH), 2.28−2.10 (m, 2H, CH2CH2Cl),
1.41 (s, 9H, 3 × CH3). 13C{1H} NMR (75 MHz, CDCl3): δ 162.2 (d,
1JCF = 246.6 Hz), 156.5, 138.2 (d, 4JCF = 3.1 Hz), 127.0 (d, 3JCF = 8.0
Hz), 115.7 (d, 2JCF = 21.4 Hz), 79.7, 75.6, 49.3, 42.6, 39.9, 39.1, 28.5.
19F NMR (282 MHz, CDCl3): δ −115.17 (s, 1F). IR (film)/cm−1:
tert-Butyl 3-(Hydroxydiphenylmethyl)azetidine-1-carboxylate
4a. Following GP1 with benzophenone as electrophile, compound
4a was obtained as a white waxy solid (80%, 152 mg). Rf = 0.4 (8:2
3401, 1677, 1604, 1508, 1478, 1424, 1367, 1225, 1159, 834, 770.
HRMS calcd for C17H23ClFNNaO3 [M + Na]+: 366.1248; found
366.1231.
1
hexane/ethyl acetate). H NMR (300 MHz, CDCl3): δ 7.33−7.19
tert-Butyl (E)-3-(1-Hydroxy-1,3-diphenylallyl)azetidine-1-carbox-
ylate 4g. Following GP1 with (E)-chalcone as electrophile,
compound 4g was obtained as a white waxy solid (60%, 123 mg)
Rf = 0.26 (8:2 hexane/ethyl acetate). 1H NMR (500 MHz, CDCl3): δ
7.44 (d, J = 7.4 Hz, 2H, Ar-H), 7.37 (dt, J = 7.7, 4.0 Hz, 4H, Ar-H),
7.33−7.28 (m, 3H, Ar-H), 7.27−7.23 (m, 1H, Ar-H), 6.66 (d, J = 16.0
Hz, 1H, CH = CH), 6.38 (d, J = 16.0 Hz, 1H, CH = CH), 4.03−3.94
(m, 2H, NCH2), 3.86 (dd, J = 8.7, 6.1 Hz, 1H, NCH2), 3.79 (t, J = 8.6
Hz, 1H, NCH2), 3.33−3.12 (m, 1H, CH), 1.42 (s, 9H, 3 × CH3).
13C{1H} NMR (126 MHz, CDCl3): δ 156.6, 143.7, 136.4, 132.5,
129.5, 128.8, 128.7, 128.1, 127.7, 126.8, 125.6, 79.5, 76.2, 50.4, 49.3,
37.5, 28.5. IR (film)/cm−1: 3428, 2981,2103, 1649, 1478, 1419, 1265,
1145, 970, 746. HRMS calcd for C23H27NNaO3 [M + Na]+:
388.1889; found 388.1892.
(m, 10 H, Ar-H), 3.98−3.85 (m, 4H, 2 × NCH2), 3.63−3.51 (m, 1H,
CH), 1.41 (s, 9H, 3 × CH3). 13C{1H} NMR (126 MHz, CDCl3): δ
156.5, 145.4, 128.6, 127.5, 126.1, 79.5, 78.4, 50.0, 37.8, 28.6. IR
(film)/cm−1: 3451, 2973, 1689, 1485, 1414, 1365, 1257, 1146, 991,
697. HRMS calcd for C21H25NNaO3 [M + Na]+: 362.1732; found
362.1730.
tert-Butyl 3-(Bis(4-fluorophenyl)(hydroxy)methyl)azetidine-1-
carboxylate 4b. Following GP1 with 4,4′-difluorobenzophenone as
electrophile, compound 4b was obtained as a white waxy solid (77%,
1
162 mg). Rf = 0.4 (8:2 hexane/ethyl acetate). H NMR (300 MHz,
CDCl3): δ 7.32−7.21 (m, 4H, Ar-H overlapping CHCl3 signal),
7.05−6.93 (m, 4H, Ar-H), 3.95−3.82 (m, 4H, 2 × NCH2), 3.55−3.45
(m, 1H, CH), 1.41 (s, 9H, 3 × CH3). 13C{1H} NMR (75 MHz,
CDCl3): δ 162.1 (d, 1JCF = 246.8 Hz), 156.5, 141.1 (d, 4JCF = 3.2 Hz),
3
2
tert-Butyl (E)-3-(1-hydroxy-3-phenylallyl)azetidine-1-carboxylate
4h. Following GP1 with (E)-cinnamaldehyde as electrophile,
compound 4h was obtained as a white waxy solid (61%, 99 mg) Rf
127.9 (d, JCF = 8.1 Hz), 115.4 (d, JCF = 21.4 Hz), 79.7, 76.9, 49.9,
37.9, 28.5. 19F NMR (282 MHz, CDCl3): δ −114.95 − −115.05 (m,
2F). IR (film)/cm−1: 3447, 3404, 2972, 1687, 1602, 1504, 1415,
1147, 991, 828. HRMS calcd for C21H22F2NO3 [M − H]−: 374.1568;
found 374.1570.
1
= 0.3 (7:3 hexane/ethyl acetate). H NMR (300 MHz, CDCl3): δ
7.41−7.20 (m, 5H, Ar-H), 6.62 (d, J = 15.9 Hz, 1H, CH = CH), 6.12
(dd, J = 15.9, 6.9 Hz, 1H, CH = CH), 4.38 (t, J = 7.1 Hz, 1H,
CHOH), 4.02−3.86 (m, 3H, NCH2), 3.72 (dd, J = 8.7, 5.4 Hz, 1H,
NCH2), 2.71−2.60 (m, 1H, NCH2CH), 2.35 (bs, 1H, OH), 1.43 (s,
9H, 3 × CH3). 13C{1H} NMR (75 MHz, CDCl3): δ 156.6, 136.4,
132.2, 129.1, 129.0, 128.8, 128.1, 126.7, 79.6, 74.5, 51.4, 34.1, 28.5. IR
(film)/cm−1: 3400, 2974, 2885, 1677, 1478, 1419, 1366, 1298, 1256,
1143, 968, 858, 750, 693. HRMS calcd for C17H23NNaO3 [M + Na]+:
312.1576; found 312.1572.
tert-Butyl 3-(Hydroxydi-p-tolylmethyl)azetidine-1-carboxylate
4c. Following GP1 with 4,4′-dimethylbenzophenone as electrophile,
compound 4c was obtained as a white waxy solid (91%, 187 mg). Rf =
0.4 (8:2 hexane/ethyl acetate). 1H NMR (300 MHz, CDCl3): δ
7.21−7.05 (m, 8H, Ar-H), 3.98−3.82 (m, 4H, 2 × NCH2), 3.60−3.47
(m, 1H, NCH2CH), 2.47 (s, 1H, OH), 2.31 (s, 6H, 2 × Ar-CH3),
1.41 (s, 9H, 3 × CH3). 13C{1H} NMR (75 MHz, CDCl3): δ 156.5,
142.7, 137.0, 129.2, 126.0, 79.4, 77.3, 49.9, 37.8, 28.6, 21.1. IR (film)/
cm−1: 3430, 2974, 2923, 1681, 1511, 1420, 1366, 1169, 1145, 1019,
936, 814, 764. HRMS calcd for C23H29NNaO3 [M + Na]+: 390.2045;
found 390.2038.
tert-Butyl 3-(Hydroxy(phenyl)methyl)azetidine-1-carboxylate 4i.
Following GP1 with benzaldehyde as electrophile, compound 4i was
obtained as a white waxy solid (58% yield, 85 mg). Rf = 0.3 (7:3
1
hexane/ethyl acetate). H NMR (300 MHz, CDCl3): δ 7.43−7.19
tert-Butyl 3-((3-Bromophenyl)(hydroxy)(phenyl)methyl)-
azetidine-1-carboxylate 4d. Following GP1 with 3-bromobenzophe-
none as electrophile, compound 4d was obtained as a white waxy
(m, 5H, Ar-H), 4.74 (d, J = 7.9 Hz, 1H, CHOH), 4.01−3.91 (m, 2H,
NCH2), 3.77 (t, J = 8.7 Hz, 1H, NCH2), 3.63 (dd, J = 8.8, 5.7 Hz, 1H,
NCH2), 2.86−2.77 (m, 1H, NCH2CH), 2.70 (bs, 1H, OH), 1.41 (s,
9H, 3 × CH3). 13C{1H} NMR (75 MHz, CDCl3): δ 156.6, 142.2,
128.8, 128.2, 126.3, 79.5, 76.0, 51.8, 51.0, 35.6, 28.5. IR (film)/cm−1:
3403, 2974, 1701, 1677, 1478, 1420, 1366, 1254, 1144, 1053, 992,
859, 770, 756, 701. HRMS calcd for C15H21NNaO3 [M + Na]+:
286.1419; found 286.1412.
1
solid (89%, 208 mg). Rf = 0.6 (7:3 hexane/ethyl acetate). H NMR
(300 MHz, CDCl3): δ 7.51 (s, 1H, Ar-H), 7.38−7.09 (m, 8H, Ar-H),
3.99−3.75 (m, 4H, 2 × NCH2), 3.61−3.45 (m, 1H, CH), 2.70 (s, 1H,
OH), 1.40 (s, 9H, 3 × CH3). 13C{1H} NMR (75 MHz, CDCl3): δ
156.5, 147.7, 144.7, 130.5, 130.1, 129.3, 128.8, 127.9, 126.1, 124.8,
122.8, 79.6, 77.3, 49.8, 37.6, 28.5. IR (film)/cm−1: 3411, 2975, 1678,
G
https://doi.org/10.1021/acs.joc.1c01297
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Featured Article
tert-Butyl 3-((4-Chlorophenyl)(hydroxy)methyl)azetidine-1-car-
boxylate 4l. Following GP1 with 4-chlorobenzaldehyde as electro-
phile, compound 4l was obtained as a white waxy solid (65% yield,
1478, 1455, 1427, 1391, 1365, 1301, 1251, 1117, 998, 906, 813.
HRMS calcd for C16H25NNaO2Si [M + Na]+: 314.1552; found
314.1553.
1
108 mg). Rf = 0.4 (6:4 hexane/ethyl acetate). H NMR (500 MHz,
Lithium (1-(tert-Butoxycarbonyl)azetidin-3-yl)trimethoxyborate
4r. Following GP1 and using triisopropyl borate as the electrophile,
the reaction mixture was concentrated under reduced pressure and
the residual solid washed (2 × 2 mL) with a mixture of ethyl acetate/
methanol 3:1 (v/v) to afford compound 4r as an insoluble white waxy
CDCl3): δ 7.31−7.23 (m, 4H, Ar-H), 4.72 (dd, J = 7.8, 3.2 Hz, 1H,
CHOH), 3.95−3.90 (m, 2H, NCH2), 3.76 (t, J = 8.7 Hz, 1H, NCH2),
3.61 (dd, J = 8.8, 5.7 Hz, 1H, NCH2), 3.01 (bs, 1H, OH), 2.80−2.71
(m, 1H, NCH2CH), 1.40 (s, 9H, 3 × CH3). 13C{1H} NMR (126
MHz, CDCl3): δ 156.6, 140.8, 133.8, 128.9, 127.7, 79.7, 75.0, 51.5,
35.6, 28.5. IR (film)/cm−1: 3401, 2975, 1674, 1479, 1417, 1366, 1254,
1145, 1089, 1014, 832, 770. HRMS calcd for C15H20ClNNaO3 [M +
Na]+: 320.1029; found 320.1024.
1
solid (70%, 105 mg). H NMR (500 MHz, CD3OD): δ 3.92−3.79
(m, 4H, NCH2), 3.35 (s, 9H, 3 × OCH3), 1.82−1.71 (m, 1H,
NCH2CH), 1.41 (s, 9H, 3 × CH3). 13C{1H} NMR (126 MHz,
CD3OD): δ 157.0, 78.3, 52.5, 51.2, 47.6, 27.5, 17.1. 11B NMR (160
MHz, CD3OD): δ 2.93. IR (film)/cm−1: 2973, 2935, 2879, 1664,
1478, 1422, 1365, 1137, 916, 860, 768. HRMS calcd for C11H23BNO5
[M − Li]− 260.1675; found 260.1681.
tert-Butyl 3-(((tert-Butoxycarbonyl)amino)(phenyl)methyl)-
azetidine-1-carboxylate 4m. Following GP1 with tert-butyl
(phenylmethylene)carbamate as electrophile, compound 4m was
obtained as a white waxy solid (53% yield, 108 mg). Rf = 0.3 (7:3
hexane/ethyl acetate). 1H NMR (500 MHz, CDCl3): δ 7.32 (t, J = 7.3
Hz, 2H, Ar-H), 7.28−7.24 (m, 1H, Ar-H), 7.23−7.20 (m, 2H, Ar-H),
4.89 (bs, 1H, CHNHBoc), 4.00 (t, J = 8.5 Hz, 1H, NCH2), 3.88−3.78
(m, 2H, NCH2), 3.62−3.57 (m, 1H, NCH2), 2.87 (bs, 1H,
NCH2CH), 1.42 (s, 9H, 3 × CH3), 1.41 (bs, 9H, 3 × CH3).
13C{1H} NMR (75 MHz, CDCl3): δ 156.4, 155.6, 140.5, 129.0, 127.9,
tert-Butyl 4-(Hydroxydiphenylmethyl)azete-1(2H)-carboxylate
5a. Following GP2 with benzophenone as electrophile, compound
5a was obtained as a white waxy solid (89%, 210 mg) by treatment of
the reaction mixture with hexane/diethyl ether 9:1 (5 mL) and
subsequent filtration on Gooch. 1H NMR (500 MHz, CDCl3): δ 7.44
(d, J = 7.5 Hz, 4H, Ar-H), 7.32 (t, J = 7.4 Hz, 4H, Ar-H), 7.26−7.25
(m, 2H, Ar-H overlapping CHCl3 signal), 5.09 (s, 1H, NCH2CH),
4.32 (s, 2H, NCH2CH), 1.39 (bs, 9H, 3 × CH3). 13C{1H} NMR (126
MHz, CDCl3): δ 153.8, 152.7, 143.3, 128.1, 127.5, 127.0, 110.4, 81.5,
76.4, 55.4, 28.3. IR (film)/cm−1 3430, 2964, 1720, 1370, 1450, 1263,
1117, 1100, 1018, 727. HRMS calcd for C21H23NNaO3 [M + Na]+:
360.1576; found 360.1572.
126.7, 80.0, 79.6, 57.1, 51.4, 34.0, 28.5, 28.5. IR (film)/cm−1: 3330,
2976, 2885, 1704, 1694, 1682, 1410, 1366, 1248, 1166, 1050, 861,
772, 736, 701. HRMS calcd for C20H30N2NaO4 [M + Na]+: 385.2103;
found 385.2095.
tert-Butyl 3-(1-Hydroxycyclohexyl)azetidine-1-carboxylate 4n.
Following GP1 with cyclohexanone as electrophile, compound 4n
was obtained as a white waxy solid (75% yield, 107 mg). Rf = 0.4 (7:3
tert-Butyl 4-(bis(4-fluorophenyl)(hydroxy)methyl)azete-1(2H)-
carboxylate 5b. Following GP2 with 4,4′-difluorobenzophenone as
electrophile, compound 5b was obtained as a white waxy solid (87%,
227 mg) by treatment of the reaction mixture with hexane/diethyl
ether 9:1 (5 mL) and subsequent filtration on Gooch. 1H NMR (500
MHz, CDCl3): δ 7.38 (dd, J = 8.4, 5.5 Hz, 4H, Ar-H), 7.00 (t, J = 8.7
Hz, 4H, Ar-H), 5.07 (s, 1H, NCH2CH), 4.31 (s, 2H, NCH2), 1.40 (s,
1
hexane/ethyl acetate). H NMR (300 MHz, CDCl3): δ 3.91−3.77
(m, 4H, NCH2), 2.60−2.50 (m, 1H, NCH2CH), 1.66−1.36 (m, 7H,
CH2), 1.42 (s, 9H, 3 × CH3), 1.31−1.16 (m, 3H, CH2). 13C{1H}
NMR (75 MHz, CDCl3): δ 156.6, 79.3, 70.3, 49.5, 38.2, 34.5, 28.6,
25.7, 21.7. IR (film)/cm−1: 3435, 1682, 1478, 1419, 1366, 1255, 1165,
1140, 994, 962, 859, 771. HRMS calcd for C14H25NNaO3 [M + Na]+:
278.1732; found 278.1728.
9H, 3 × CH3). 13C{1H} NMR (126 MHz, CDCl3): δ 162.3 (d, 1JCF
=
246.1 Hz), 153.5, 152.7, 139.0 (d, 4JCF = 2.5 Hz), 128.8 (d, 3JCF = 8.2
Hz), 115.0 (d, 2JCF = 21.4 Hz), 110.6, 81.7, 75.6, 55.5, 28.3. 19F NMR
(470 MHz, CDCl3): δ −115.34 (s, 2F). IR (film)/cm−1: 3400, 2985,
2917, 1661, 1601, 1505, 1369, 1223, 1143, 834. HRMS calcd for
C21H21F2NNaO3 [M + Na]+: 396.1387; found 396.1385.
tert-Butyl 3-(1-Benzyl-4-hydroxypiperidin-4-yl)azetidine-1-car-
boxylate 4o. Following GP1 with 1-benzyl-4-piperidone as electro-
phile, compound 4o was obtained as a white waxy solid (75%, 145
mg). Rf = 0.2 (1:1 hexane/ethyl acetate). 1H NMR (500 MHz,
CDCl3): δ 7.32−7.28 (m, 4H, Ar-H), 7.27−7.22 (m, 1H, Ar-H),
3.88−3.83 (m, 4H, azetidine NCH2), 3.53 (s, 2H, CH2Ph), 2.68−
2.63 (m, 2H, piperidine CH2), 2.52 (quin, J = 7.1 Hz, 1H, NCH2CH),
2.33 (td, J = 11.4, 3.2 Hz, 2H, piperidine CH2), 1.58−1.47 (m, 4H, 2
× piperidine CH2), 1.42 (s, 9H, 3 × CH3). 13C{1H} NMR (126 MHz,
CDCl3): δ 156.6, 138.3, 129.3, 128.3, 127.2, 79.4, 68.5, 63.2, 49.86,
48.99, 48.78, 38.4, 34.1, 28.5. IR (film)/cm−1: 3430, 2936, 1681,
1416, 1366, 1344, 1255, 1143, 1031, 986, 955. HRMS calcd for
C20H30N2NaO3 [M + Na]+: 369.2154; found 369.2146.
tert-Butyl 3-(1-Hydroxyheptyl)azetidine-1-carboxylate 4p. Fol-
lowing GP1 with heptanal as electrophile, compound 4p was obtained
as a colorless oil (85%, 129 mg). Rf = 0.3 (7:3 hexane/ethyl acetate).
1H NMR (500 MHz, CDCl3): δ 3.91 (q, J = 8.4 Hz, 2H, NCH2), 3.83
(dd, J = 8.7, 5.7 Hz, 1H, NCH2), 3.71−3.63 (m, 2H, CHOH and
NCHH), 2.55−2.46 (m, 1H, NCH2CH), 2.03 (bs, 1H, OH), 1.48−
1.21 (m, 10H, 5 × CH2), 1.41 (s, 9H, OC(CH3)3), 0.87 (t, J = 6.9 Hz,
3H, CH2CH3).13C{1H} NMR (126 MHz, CDCl3): δ 156.6, 79.4,
73.1, 51.4, 50.7, 35.0, 34.6, 31.9, 29.4, 28.5, 25.6, 22.7, 14.2. IR (film)/
cm−1: 3431, 2928, 1705, 1680, 1478, 1416, 1366, 1254, 1143, 998,
943, 860, 771. HRMS calcd for C15H29NNaO3 [M + Na]+: 294.2045;
found 294.2045.
tert-Butyl 4-(Hydroxydi-p-tolylmethyl)azete-1(2H)-carboxylate
5c. Following GP2 with 4,4′-dimethylbenzophenone as electrophile,
compound 5b was obtained as a white waxy solid (89%, 228 mg) by
treatment of the reaction mixture with hexane/diethyl ether 9:1 (5
mL) and subsequent filtration on Gooch. 1H NMR (300 MHz,
CDCl3): δ 7.30 (d, J = 8.2 Hz, 4H, Ar-H), 7.11 (d, J = 8.0 Hz, 4H, Ar-
H), 5.08 (s, 1H, NCH2CH), 4.30 (s, 2H, NCH2CH), 2.32 (s, 6H, 2 ×
Ar−CH3), 1.36 (s, 9H, 3 × CH3). 13C{1H} NMR (75 MHz, CDCl3):
δ 154.1, 152.4, 140.7, 137.0, 128.7, 126.9, 110.2, 81.5, 76.2, 55.2, 28.4,
21.2. IR (film)/cm−1 3319, 2977, 2923, 1672, 1510, 1409, 1368, 1176,
1141, 1021, 812, 765. HRMS calcd for C23H27NNaO3 [M + Na]+
388.1889; found 388.1899.
tert-Butyl 4-((3-Bromophenyl)(hydroxy)(phenyl)methyl)azete-
1(2H)-carboxylate 5d. Following GP2 with 3-bromobenzophenone
as electrophile, compound 5d was obtained as a white waxy solid
(78%, 227 mg) by treatment of the reaction mixture with hexane/
1
diethyl ether 9:1 (5 mL) and subsequent filtration on Gooch. H
NMR (500 MHz, CDCl3): δ 7.64 (s, 1H, Ar-H), 7.45−7.37 (m, 3H,
Ar-H), 7.33 (t, J = 7.4 Hz, 3H, Ar-H), 7.27−7.27 (m, 1H, Ar-H
overlapping CHCl3 signal), 7.18 (t, J = 7.9 Hz, 1H, Ar-H), 5.12 (s,
1H, NCH2CH), 4.32 (s, 2H, NCH2), 1.40 (s, 9H, 3 × CH3). 13C{1H}
NMR (126 MHz, CDCl3): δ 153.1, 145.8, 142.7, 130.7, 130.1, 129.6,
128.2, 127.8, 126.9, 125.8, 122.4, 110.8, 81.9, 76.0, 55.2, 28.4. IR
(film)/cm−1: 3307, 1667, 1449, 1409, 1368, 1259, 1207, 1142, 858,
763, 693. HRMS calcd for C21H22BrNNaO3 [M + Na]+: 438.0681;
found 438.0691.
tert-Butyl 4-(1-Hydroxy-1-phenylethyl)azete-1(2H)-carboxylate
5e. Following GP2 with acetophenone as electrophile, compound
5e was obtained as a white waxy solid (95%, 183 mg) after
chromatography. Rf = 0.5 (7:3 hexane/diethyl ether +0.5% triethyl-
tert-Butyl 3-(Dimethyl(phenyl)silyl)azetidine-1-carboxylate 4q.
Following GP1 with chloro(dimethyl)phenylsilane as electrophile,
compound 4q was obtained as a colorless oil (78%, 127 mg). Rf = 0.7
1
(7:3 hexane/ethyl acetate). H NMR (500 MHz, CDCl3): δ 7.48−
7.45 (m, 2H, Ar-H), 7.40−7.33 (m, 3H, Ar-H), 4.08 (dd, J = 9.9, 8.2
Hz, 2H, NCH2), 3.85−3.81 (m, 2H, NCH2), 2.13 (tt, J = 9.9, 6.9 Hz,
1H, NCH2CH), 1.41 (s, 9H, C(CH3)3), 0.33 (s, 6H, Si(CH3)2).13C-
{1H} NMR (126 MHz, CDCl3): δ 156.4, 137.0, 133.7, 129.6, 128.1,
79.3, 51.1, 49.9, 28.5, 14.9, −5.3. IR (film)/cm−1: 2930, 2876, 1704,
H
https://doi.org/10.1021/acs.joc.1c01297
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Featured Article
amine). 1H NMR (500 MHz, CDCl3): δ 7.52 (d, J = 7.4 Hz, 2H, Ar-
H), 7.35−7.34 (m, 2H, Ar-H), 7.28−7.23 (m, 1H, Ar-H overlapping
CHCl3 signal), 5.42 (s, 1H, NCH2CH), 4.31−4.22 (m, 2H, NCH2),
1.66 (s, 3H, CH3), 1.38 (s, 9H, 3 × CH3). 13C{1H} NMR (126 MHz,
CDCl3): δ 155.4, 152.7, 144.7, 128.2, 127.2, 125.2, 107.0, 81.5, 71.5,
55.5, 28.4, 28.0. IR (film)/cm−1: 3340, 1668, 1403, 1368, 1205, 1152,
1022, 861, 764, 700. HRMS calcd for C16H21NNaO3 [M + Na]+:
298.1419; found 298.1423.
Ar-H), 5.40−5.35 (m, 1H, CHOH), 5.12 (s, 1H, NCH2CH), 4.29−
4.22 (m, 2H, NCH2), 1.49 (s, 9H, 3 × CH3). 13C{1H} NMR (126
MHz, CDCl3): δ 153.0, 151.8, 140.7, 134.3, 129.7, 128.2, 127.0,
125.0, 108.5, 81.8, 68.4, 56.1, 28.4. IR (film)/cm−1: 3367, 1667, 1598,
1477, 1410, 1368, 1257, 1139, 1054, 861, 765. HRMS calcd for
C15H18ClNNaO3 [M + Na]+: 318.0873; found 318.0877.
tert-Butyl 4-(((tert-Butoxycarbonyl)amino)(phenyl)methyl)azete-
1(2H)-carboxylate 5m. Following GP2 with tert-butyl
(phenylmethylene)carbamate as electrophile, compound 5m was
obtained as a white waxy solid (65%, 164 mg) after chromatography.
tert-Butyl 4-(3-Chloro-1-(4-fluorophenyl)-1-hydroxypropyl)-
azete-1(2H)-carboxylate 5f. Following GP2 with 3-chloro-4′-
fluoropropiophenone as electrophile, compound 5f was obtained as
a white waxy solid (80%, 191 mg) by treatment of the reaction
mixture with hexane/diethyl ether 9:1 (5 mL) and subsequent
1
Rf = 0.5 (6:4 hexane/diethyl ether + 0.5% triethylamine). H NMR
(300 MHz, CDCl3): δ 7.41−7.21 (m, 5H, Ar-H), 5.71−5.58 (d, J =
8.5 Hz, 1H, CHNHBoc), 5.51 (s, 1H, NCH2CH), 4.27 (s, 2H,
NCH2CH), 1.45 (s, 9H, 3 × CH3), 1.34 (s, 9H, 3 × CH3). 13C{1H}
NMR (75 MHz, CDCl3): δ 155.3, 151.7, 150.0, 139.1, 128.6, 127.7,
127.0, 108.7, 81.0, 79. 9, 55.5, 52.6, 28.5, 28.3. IR (film)/cm−1: 3341,
2977, 1704, 1496, 1391, 1367, 1250, 1164, 1017, 861, 699. HRMS
calcd for C20H28N2NaO4 [M + Na]+: 383.1947; found 383.1958.
tert-Butyl 4-(1-Hydroxycyclohexyl)azete-1(2H)-carboxylate 5n.
Following GP2 with cyclohexanone as electrophile, compound 5n
was obtained as a white waxy solid (59%, 105 mg) after
chromatography. Rf = 0.4 (7:3 hexane/diethyl ether + 0.5%
triethylamine). 1H NMR (500 MHz, CDCl3): δ 5.30 (s, 1H,
NCH2CH), 4.20 (s, 2H, NCH2), 1.82−1.63 (m, 6H, 3 × CH2), 1.56−
1.39 (m, 3H, CH2 overlapping 9H, 3 × CH3), 1.37−1.26 (m, 1H,
CH2). 13C{1H} NMR (126 MHz, CDCl3): δ 157.0, 152.7, 105.3,
81.1, 68.2, 55.8, 35.0, 28.5, 25.8, 22.0. IR (film)/cm−1: 3391, 2934,
1673, 1478, 1403, 1368, 1257, 1159, 1142, 1026, 1005, 861, 766.
HRMS calcd for C14H23NNaO3 [M + Na]+: 276.1576; found
276.1572.
tert-Butyl 4-(1-(tert-Butoxycarbonyl)-3-hydroxyazetidin-3-yl)-
azete-1(2H)-carboxylate 5o. Following GP2 with 1-Boc-3-azetidi-
none as electrophile, compound 5o was obtained as a pale yellow oil
(70%, 160 mg). Rf = 0.5 (7:3 hexane/ethyl acetate + 1%
triethylamine). 1H NMR (500 MHz, CDCl3): δ 5.51 (s, 1H,
NCH2CH), 4.28 (s, 2H, NCH2CH), 4.06 and 3.99 (2d, AB system, J
= 9.5 Hz, 4H, 2 × azetidine NCH2), 1.47 (s, 9H, 3 × CH3), 1.43 (s,
9H, 3 × CH3).13C{1H} NMR (126 MHz, CDCl3): δ 156.5, 153.0,
151.4, 106.3, 82.0, 79.9, 65.4, 60.8, 59.6, 56.0, 28.5, 28.4. IR (film)/
cm−1: 3338, 2977, 1705, 1672, 1478, 1407, 1368, 1251, 1150, 1080,
999, 862, 769. HRMS calcd for C16H26N2NaO5 [M + Na]+: 349.1739;
found 349.1742.
1
filtration on Gooch. H NMR (500 MHz, CDCl3): δ 7.47−7.42 (m,
2H, Ar-H), 7.07−6.99 (m, 2H, Ar-H), 5.43 (s, 1H, NCH2CH), 4.27−
4.22 (m, 2H, NCH2), 3.68 (ddd, J = 11.7, 10.9, 4.8 Hz, 1H,
CH2CH2Cl), 3.28 (td, J = 11.3, 5.0 Hz, 1H, CH2CH2Cl), 2.55 (ddd, J
= 13.3, 12.1, 4.8 Hz, 1H, CH2CH2Cl), 2.33 (ddd, J = 13.4, 12.2, 5.1
Hz, 1H, CH2CH2Cl), 1.40 (s, 9H, 3 × CH3). 13C{1H} NMR (126
1
MHz, CDCl3): δ 162.3 (d, JCF = 245.9 Hz), 153.9, 152.9, 137.5 (d,
3
2
4JCF = 3.0 Hz), 127.4 (d, JCF = 8.1 Hz), 115.2 (d, JCF = 21.4 Hz),
107.5, 81.9, 72.8, 55.8, 43.3, 39.7, 28.4. 19F NMR (470 MHz, CDCl3):
δ −115.53 (s, 1F). IR (film)/cm−1: 3307, 1667, 1600, 1507, 1409,
1369, 1225, 1155, 1139, 1014, 836, 764. HRMS calcd for
C17H21ClFNNaO3 [M + Na]+: 364.1092; found 364.1087.
tert-Butyl (E)-4-(1-Hydroxy-1,3-diphenylallyl)azete-1(2H)-car-
boxylate 5g. Following GP2 with (E)-chalcone as electrophile,
compound 5g was obtained as a white waxy solid (78%, 198 mg) by
treatment of the reaction mixture with hexane/diethyl ether 9:1 (5
mL) and subsequent filtration on Gooch. 1H NMR (500 MHz,
CDCl3): δ 7.57 (d, J = 7.5 Hz, 2H, Ar-H), 7.37 (dd, J = 14.8, 7.5 Hz,
4H, Ar-H), 7.33−7.27 (m, 3H, Ar-H), 7.22 (t, J = 7.3 Hz, 1H, Ar-H),
6.68 (d, J = 16.0 Hz, 1H, CH = CH), 6.45 (d, J = 16.0 Hz, 1H, CH =
CH), 5.36 (s, 1H, NCH2CH), 4.31 (s, 2H, NCH2CH), 1.40 (s, 9H, 3
× CH3). 13C{1H} NMR (126 MHz, CDCl3): δ 149.8, 142.1, 136.8,
131.5, 130.2, 128.6, 128.3, 127.8, 127.6, 126.9, 126.4, 109.3, 81.6,
74.6, 55.7, 28.4. IR (film)/cm−1: 3366, 2978, 1667, 1403, 1369, 1144,
903, 859, 770, 746. HRMS calcd for C23H25NNaO3 [M + Na]+:
386,1732; found 386.1722.
tert-Butyl 4-(1-Hydroxy-3-phenylallyl)azete-1(2H)-carboxylate
5h. Following GP2 with cinnamaldehyde as electrophile, compound
5h was obtained as a white waxy solid (62%, 125 mg) after
chromatography. Rf = 0.4 (7:3 hexane/diethyl ether +0.5% triethyl-
tert-Butyl 4-(1-Hydroxyheptyl)azete-1(2H)-carboxylate 5p. Fol-
lowing GP2 with heptanal as electrophile, compound 5p was obtained
as a pale yellow oil (83%, 157 mg). Rf = 0.4 (7:3 hexane/ethyl acetate
1
amine). H NMR (300 MHz, CDCl3): δ 7.44−7.39 (m, 2H, Ar-H),
7.36−7.29 (m, 2H, Ar-H), 7.28−7.21 (m, 1H, Ar-H), 6.76 (dd, J =
16.0, 1.1 Hz, 1H, CH = CH), 6.32 (dd, J = 15.9, 6.2 Hz, 1H, CH =
CH), 5.40 (s, 1H, CHOH), 5.03−4.94 (m, 1H, NCH2CH), 4.31−
4.24 (m, 2H, NCH2CH), 1.50 (s, 9H, 3 × CH3). 13C{1H} NMR (75
MHz, CDCl3): δ 152.8, 151.8, 136.7, 132.4, 128.7, 127.9, 126.8,
126.2, 107.3, 81.5, 67.5, 56.2, 28.5. IR (film)/cm−1: 3370, 2977, 1703,
1672, 1411, 1368, 1203, 1160, 1139, 1048, 967, 754, 964. HRMS
calcd for C17H21NNaO3 [M + Na]+: 310.1419; found 310.1427.
tert-Butyl 4-(Hydroxy(phenyl)methyl)azete-1(2H)-carboxylate 5i.
Following GP2 with benzaldehyde as electrophile, compound 5i was
obtained as a white waxy solid (82%, 150 mg) after chromatography.
1
+ 1% triethylamine). H NMR (500 MHz, CDCl3): δ 5.34 (s, 1H,
NCH2CH), 4.27−4.18 (m, 3H, NCH2 and CHOH), 1.73−1.66 (m,
2H, hexyl CH2), 1.48 (s, 9H, C(CH3)3), 1.34−1.27 (m, 8H, 4 × hexyl
CH2), 0.90−0.86 (m, 3H hexyl CH3). 13C{1H} NMR (126 MHz,
CDCl3): δ 153.7, 152.7, 106.1, 81.2, 66.6, 56.0, 33.4, 31.9, 29.9, 29.3,
28.5, 22.8, 14.2. IR (film)/cm−1: 3400, 2922, 2851, 1709, 1679, 1455,
1409, 1393, 1367, 1258, 1143, 863. HRMS calcd for C15H27NNaO3
[M + Na]+: 292.1889; found 292.1896.
tert-Butyl 4-(3-(Benzyloxy)-1-hydroxycyclobutyl)azete-1(2H)-car-
boxylate 5q. Following GP2 with 3-(benzyloxy)cyclobutan-1-one as
electrophile, compound 5q was obtained as a pale yellow oil (85%,
197 mg) dr >95:5. Rf = 0.4 (7:3 hexane/ethyl acetate + 1%
1
Rf = 0.4 (7:3 hexane/diethyl ether +0.5% triethylamine). H NMR
(500 MHz, CDCl3): δ 7.48−7.44 (m, 2H, Ar-H), 7.37−7.34 (m, 2H,
Ar-H), 7.33−7.29 (m, 1H, Ar-H), 5.41 (d, J = 1.9 Hz, 1H, CHOH),
5.07 (s, 1H, NCH2CH), 4.29−4.19 (m, 2H, NCH2), 1.49 (s, 9H, 3 ×
CH3). 13C{1H} NMR (126 MHz, CDCl3): δ 152.9, 152.6, 138.6,
128.4, 128.0, 126.9, 108.1, 81.5, 68.9, 55.9, 28.5. IR (film)/cm−1:
3368, 1705, 1668, 1453, 1409, 1368, 1257, 1159, 1138, 1052, 864,
698. HRMS calcd for C15H19NNaO3 [M + Na]+: 284.1263; found
284.1279.
1
triethylamine). H NMR (500 MHz, CDCl3): δ 7.36−7.31 (m, 4H,
Ar-H), 7.30−7.25 (m, 1H, Ar-H), 5.35 (s, 1H, NCH2CH), 4.43 (s,
2H, OCH2), 4.22 (s, 2H, NCH2CH), 3.75 (quin, J = 7.2 Hz, 1H,
CHOCH2), 2.73−2.66 (m, 2H, COHCH2), 2.33−2.26 (m, 2H,
COHCH2), 1.47 (s, 9H, 3 × CH3).13C{1H} NMR (126 MHz,
CDCl3): δ 154.7, 152.7, 138.2, 128.5, 128.0, 127.8, 104.9, 81.6, 70.5,
65.4, 63.2, 55.3, 41.7, 28.5. IR (film)/cm−1: 3351, 1980, 2938, 1670,
1454, 1410, 1368, 1239, 1173, 1145, 1064, 1026, 860, 698. HRMS
calcd for C19H25NNaO4 [M + Na]+: 354.1681; found 354.1689.
tert-Butyl 4-(Dimethyl(phenyl)silyl)azete-1(2H)-carboxylate 5r.
Following GP2 using chloro(dimethyl)phenylsilane as the electro-
phile, compound 5r was obtained a colorless oil (55%, 111 mg). Rf =
tert-Butyl 4-((3-Chlorophenyl)(hydroxy)methyl)azete-1(2H)-car-
boxylate 5l. Following GP2 with 3-chlorobenzaldehyde as electro-
phile, compound 5l was obtained as a white waxy solid (77%, 159
mg) after chromatography. Rf = 0.5 (6:4 hexane/diethyl ether +0.5%
1
triethylamine). H NMR (500 MHz, CDCl3): δ 7.48−7.46 (m, 1H,
1
Ar-H), 7.34 (ddd, J = 5.9, 3.7, 1.5 Hz, 1H, Ar-H), 7.31−7.27 (m, 2H,
0.5 (9:1 hexane/diethyl ether + 1% triethylamine). H NMR (500
I
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Featured Article
MHz, CDCl3): δ 7.60−7.53 (m, 2H, Ar-H), 7.41−7.30 (m, 3H, Ar-
H), 5.89 (s, 1H, NCH2CH), 4.55 (s, 2H, NCH2CH), 1.33 (s, 9H,
C(CH3)3), 0.47 (s, 6H, Si(CH3)2). 13C{1H} NMR (126 MHz,
CDCl3): δ 158.5, 152.0, 136.5, 134.2, 129.5, 127.9, 126.3, 80.4, 59.8,
28.5, −3.1. IR (film)/cm−1: 2980, 1689, 1254, 1138, 841. HRMS
calcd for C16H23NNaO2Si [M + Na]+: 312.1396; found 312.1402.
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.1c01297.
■
sı
Additional batch and flow procedures, optimization
studies, and copies of NMR spectra for all new
compounds (PDF)
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AUTHOR INFORMATION
Corresponding Authors
■
Leonardo Degennaro − FLAME-Lab, Flow Chemistry and
Microreactor Technology Laboratory, Department of
Pharmacy − Drug Sciences, University of Bari “A. Moro”,
70125 Bari, Italy; orcid.org/0000-0002-2187-9419;
Email: leonardo.degennaro@uniba.it
Renzo Luisi − FLAME-Lab, Flow Chemistry and
Microreactor Technology Laboratory, Department of
Pharmacy − Drug Sciences, University of Bari “A. Moro”,
70125 Bari, Italy; orcid.org/0000-0002-9882-7908;
Email: renzo.luisi@uniba.it
Authors
Marco Colella − FLAME-Lab, Flow Chemistry and
Microreactor Technology Laboratory, Department of
Pharmacy − Drug Sciences, University of Bari “A. Moro”,
70125 Bari, Italy
Pantaleo Musci − FLAME-Lab, Flow Chemistry and
Microreactor Technology Laboratory, Department of
Pharmacy − Drug Sciences, University of Bari “A. Moro”,
70125 Bari, Italy
Debora Cannillo − FLAME-Lab, Flow Chemistry and
Microreactor Technology Laboratory, Department of
Pharmacy − Drug Sciences, University of Bari “A. Moro”,
70125 Bari, Italy
Mauro Spennacchio − FLAME-Lab, Flow Chemistry and
Microreactor Technology Laboratory, Department of
Pharmacy − Drug Sciences, University of Bari “A. Moro”,
70125 Bari, Italy
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Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.1c01297
Author Contributions
§M.C. and P.M. contributed equally to this work.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work was supported by the Italian MIUR under the
framework of the project “SusDesFlow” FISR2020IP_01721.
■
̀
We thank Dompe Farmaceutici S.p.A. for financial support
(CT-2020 uniba). We are grateful to Mrs. Carla Muggeo and
Mr. Alessandro Simoni for the synthetic work during the early
development of this project.
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solvent and internal quenching methods (see the Supporting
Information).
L
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