Flow microreactor synthesis of 2,2-disubstituted oxetanes via 2-phenyloxetan-2-yl lithium

Article abstract of DOI:10.1515/chem-2016-0041

A mild and sustainable synthesis of 2,2-disubstituted oxetanes has been achieved through the use of a fow microreactor system. By controlling the residence time a highly unstable intermediate such as 2-phenyloxetan-2-yl lithium can be generated and trappe

Full text of DOI:10.1515/chem-2016-0041

Open Chem., 2016; 14: 377–382
Invited Paper
Open Access
Leonardo Degennaro*, Aiichiro Nagaki, Yuya Moriwaki, Giuseppe Romanazzi,
Maria Michela Dell’Anna, Jun-ichi Yoshida, Renzo Luisi
Flow microreactor synthesis of 2,2-disubstituted
oxetanes via 2-phenyloxetan-2-yl lithium
DOI 10.1515/chem-2016-0041
received November 11, 2016; accepted December 29, 2016.
Among the strategies for accessing oxetane rings,
there are generally two synthetic approaches that have the
Abstract:
A mild and sustainable synthesis of 2,2- widest application, although some interesting alternative
disubstituted oxetanes has been achieved through the use synthetic approaches have been recently suggested by
of a flow microreactor system. By controlling the residence Bull’s group [7-11]. The first approach entails a ring-closing
time a highly unstable intermediate such as 2-phenyloxetan- etherification reaction [12,13], namely an intramolecular
2-yl lithium can be generated and trapped with various Williamson ether synthesis, and the second one involves the
electrophiles affording in moderate to good yields Paternò-Büchi reaction [14,15], namely a photochemical [2+2]
2-substituted-2-phenyloxetanes at higher temperatures with cycloaddition of carbonyl compounds to alkenes. Following
respect to macrobatch-mode where ‒78 °C is required.
these approaches, the preparation of more elaborated
oxetanes bearing a higher degree of functionalization can
be sometimes a very laborious work. Therefore, the study
on synthesis of oxetane containing molecules is yet an open
issue showing the need for new synthetic methods for the
rapid preparation of valuable functionalized oxetanes. In
this context, a recent work by Capriati and co-workers [16]
(scheme 1) demonstrated, for the first time, a direct method
Keywords: oxetanes, organolithium, flow chemistry,
microreactor system, residence time
1 Introduction
Oxetane rings have an important role as the main core to obtain 2-substituted-2-phenyloxetanes (2) by electrophilic
in naturally occurring compounds as well as versatile quenching of the 2-lithiated derivative 1-Li, although the latter
motifs both in the total synthesis of natural products [1] was found to be thermally and configurationally unstable.
and in synthetic organic chemistry. [2] They have also In fact, at temperature higher than ‒78 °C, 1-Li was found
received considerable attention as versatile elements in to mainly undergo decomposition with the formation of a
drug discovery [3,4] and their preparation has offered complex reaction mixture of unidentified products. However,
opportunities for the discovery of novel chemical it should be pointed out that in the reactivity of oxetanes
transformations [5]. Moreover, oxetanes are also versatile towards alkyllithiums, it was already known that the
starting materials for a wide variety of ring-expansion nucleophilic substitution at C-2 can compete with α-lithiation
reactions [6].
[17] as well as oxetane moiety could undergo ring opening
reactions [18,19].
More recently, Capriati’s group [20], has shown that
2-substituted-2-phenyloxetanes, obtained as shown above,
can be functionalized regioselectively on phenyl group via
anortho-lithiationreactionusings-BuLiasabase, opening
new possibilities for the synthesis of oxetane derivatives.
Next, Ley and co-workers [21], within this context, have
successfully shown that oxetanes bearing a pyridine at C2
can be lithiated regioselectively on pyridine moiety using
n-BuLi as a base affording new functionalized pyridine
oxetane building blocks.
*Corresponding author: Leonardo Degennaro: Department of
Pharmacy – Drug Sciences, University of Bari “A. Moro”; FLAME-Lab
– Flow Chemistry and Microreactor Technology Laboratory, Via E.
Orabona 4, 70125, Bari Italy, E-mail: leonardo.degennaro@uniba.it
Renzo Luisi: Department of Pharmacy – Drug Sciences, University
of Bari “A. Moro”; FLAME-Lab –Flow Chemistry and Microreactor
Technology Laboratory, Via E. Orabona 4, 70125, Bari Italy
Aiichiro Nagaki, Yuya Moriwaki, Jun-ichi Yoshida: Department of
Synthetic Chemistry and Biological Chemistry, Graduate School of
Engineering, Kyoto University, Nishikyo-ku, Kyoto 615-8510, Japan
Giuseppe Romanazzi, Maria Michela Dell’Anna: DICATECh,
Politecnico di Bari, Via E. Orabona 4, 70125, Bari Italy
By taking in account the paucity of examples,
employing 2-aryloxetanes as starting material for the
© 2016 Leonardo Degennaro et al., published by De Gruyter Open.
This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivs 3.0 License.
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378ꢀ
ꢀ Leonardo Degennaro et al.
P2 (φ = 1000 μm, L = 50 cm) and P3 (φ = 1000 μm,
L = 100 cm)) was used. A solution of oxetane (0.05 M) in
THF (flow rate: 6.00 mL min-1) and a solution of sec-BuLi
(0.40 M) in n-hexane (flow rate: 1.50 mL min-1) were
introduced to M1. The resulting solution was passed
through R1 and was mixed with a solution of electrophile
(0.30 M) in THF (flow rate: 1.75 mL min-1) in M2. The
resulting solution was passed through R2. Afer a steady
state was reached, the product solution was collected
for 60 s while being quenched with H2O. Sat. aq. NH4Cl
(5 ml) and brine (20 ml) were added and the reaction
mixture was extracted with ethyl acetate (3 x 20 mL). The
combined organic extract was dried over Na2SO4. Organic
layer was analyzed by gas chromatography and isolated
by flash chromatography.
Scheme 1.
synthesisof2,2-disubstitutedoxetanes,andcontinuingour
research interests [22-27] in the field of flow microreactor
chemistry [28-30] and flash chemistry [31,32], we wondered
if Capriati’s protocol for the preparation of 2-substituted-
2-phenyloxetanes (2) by electrophilic quenching of 1-Li,
could be conducted under mild and sustainable conditions
employing flow microreactor systems. We reasoned
that within a microreactor system, we should have been
able to control the thermal (and chemical) instability
of 1-Li avoiding its decomposition. In fact, in the last
decade microreactors and continuous flow technologies
are emerging as a viable alternative to macrobatch
processes both in academic research and in the industrial
field, offering even more sustainable synthetic routes.
Furthermore, organolithium compounds are generally
very unstable and they have to be generated at very low
temperatures and the reactions are sometimes difficult
or impossible to control in batch-mode systems because
they are ofen extremely fast and highly exothermic. In
this context, flow chemistry could open new possibilities
in organic synthesis involving organolithiums. Therefore,
the use of a flow microreactor, by controlling residence
time and temperature, allows the overcoming of these
drawbacks [33,34]. The proper control of the residence
time in microreactors can be fundamental to increase
yields and selectivities in organic reactions compared to
macrobatch-mode [35].
Deprotonation of 2-Phenyloxetane (1)
Followed by Reaction with Chlorotrimethylsi-
lane in a Flow Microreactor System.
2-phenyl-2-trimethylsilyl oxetane (2a). The crude
product was purified by flash chromatography (hexane/
ethyl acetate 100:0 to 9:1); 85% yield. 1H NMR (400 MHz,
CDCl3) δ, 0.02 (s, 9 H), 2.66-2.73 (m, 1 H), 3.06-3.12 (m,
1 H), 4.67-4.71 (m, 2 H), 7.06-7.33 (m, 5 H); 13C NMR
(100 MHz, CDCl3) δ, -5.1, 31.6, 68.8, 86.8, 123.2, 125.1, 127.7,
147.8. Analytical data in agreement with those reported in
the literature. [16]
Deprotonation of 2-Phenyloxetane (1)
Followed by Reaction with Iodomethane in a
Flow Microreactor System.
2-methyl-2-phenyloxetane (2b): the crude product was
purified by flash chromatography (hexane/ethyl acetate
20:1 to 4:1); 78% yield, colorless oil; IR (neat) 2967, 2880,
1
1444, 1283, 965, 701 cm-1; H NMR (CDCl3) δ, 7.28-7.22 (m,
2 Experimental Procedure
4H), 7.15-7.11 (m, 1H), 4.53-4.48 (m, 1H), 4.42-4.38 (m, 1H),
2.71-2.60 (m, 2H), 1.61 (s, 3H); 13C NMR (CDCl3) δ, 148.2,
128.2, 126.6, 123.6, 86.6, 64.5, 35.6, 30.7. Analytical data in
agreement with those reported in the literature. [36]
Typical Procedure for Deprotonation Reaction
of 2-Phenyloxetane Followed by Reaction
with Electrophiles in Flow Microreactor
Systems.
Deprotonation of 2-Phenyloxetane (1)
Followed by Reaction with Pivaldehyde
in a Flow Microreactor System.
A flow microreactor system consisting of two T-shaped
micromixers (M1 (φ = 250 μm) and M2 (φ = 500 μm)), two
microtubereactors(R1andR2(φ=1000μm,L=200cm))and 2,2‐dimethyl‐1‐(2‐phenyloxetan‐2‐yl)propan‐1‐ol
three tube pre-cooling units (P1 (φ = 1000 μm, L = 100 cm), (2c). The crude product (anti:syn = 67:33 (determined
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Flow microreactor synthesis of 2,2-disubstituted oxetanesꢀ
ꢀ379
by 1H NMR)) was purified by flash chromatography 3 Results and Discussion
(hexane/ethyl acetate 20:1 to 4:1): inseparable mixture of
diastereoisomers (dr = 67:33); 63% yield, yellow solid, mp On the basis of previous experience of generating
1
96 - 97 °C (Et2O). H NMR (400 MHz, CDCl3) δ, 0.61 (s, 3 H highly unstable oxiranyl [37-39] and aziridinyl lithium
minor), 0.64 (s, 3 H major), 2.52 - 2.59 (m, 1 H minor), 2.72 - species [40,41] under flow chemistry, our study began by
2.78 (m, 1 H major), 2.98 (d, J = 8.4 Hz, 1 H minor, exchanges assembling a flow microreactor system that consisted
with D2O), 3.22 (d, J = 2.8 Hz, 1 H major, exchanges with of two T-shaped micromixers (M1 and M2) and two
D2O), 3.29 - 3.43 (m, 1 H minor + 1 H major), 3.52 (d, J = microtube reactors (R1 and R2) as shown in figure 1.
2.8 Hz, 1 H major, s afer exchange with D2O), 3.61 (d, J = A solution of 2-phenyloxetane 1 and a solution of s-BuLi
8.4 Hz, 1 H minor, s afer exchange with D2O), 4.39 - 4.52 were introduced to micromixer M1 by syringe pumps.
(m, 2 H minor + 2 H major), 7.27 - 7.43 (m, 5 H minor + 5 The mixture passed through microtube reactor R1, with
H major); 13C NMR (100 MHz, CDCl3) δ, 27.2 (minor), 27.4 variable length; the resulting solution of generated
(major), 28.6 (major), 31.6 (minor), 33.9 (minor), 34.6 2-phenyloxetan-2-yllithium 1-Li and
a
solution of
(major), 66.0 (minor), 66.3 (major), 83.0 (minor), 83.7 chlorotrimethylsilane were respectively introduced to
(major), 91.5 (minor), 91.9 (major), 125.3 (minor), 126.0 micromixer M2. The resulting mixture was then passed
(major), 126.9 (minor), 127.5 (major), 127.9 (minor), 127.9 through microtube reactor R2 with fixed length (tR2
(major), 143.9 (major), 144.5 (minor). The spectral data 2.20 s) affording the desired product 2a.
=
were identical to those reported in the literature [16].
In particular, the reaction was carried out by varying
the residence time (tR1) from 0.38 to 25 s changing the
length of microtube reactor R1, while maintaining a fixed
flow rate, and varying the temperature of cooling bath
from –50 to –20 °C. Therefore, both deprotonation and
quenching with chlorotrimethylsilane were conducted at
the same temperature. The effects of an accurate control
Deprotonation of 2-Phenyloxetane (1)
Followed by Reaction with Acetone
in a Flow Microreactor System.
2‐(2‐phenyloxetan‐2‐yl)propan‐2‐ol (2d). The crude of both reaction temperature (T) and residence time (tR1)
product was purified by flash chromatography (hexane/ on the yield of 2a are highlighted in Figure 2.
ethyl acetate 20:1 to 4:1). Colorless oil, 55% yield. 1H NMR
By conducting the reaction using shorter residence
(600 MHz, CDCl3) δ, 0.97 (s, 3 H), 1.15 (s, 3 H), 2.53 - 2.57 (m, times (i.e. between 0.38 and 2.5 s), we obtained low or
1 H), 3.40 - 3.45 (m, 1 H), 4.43 - 4.47 (m, 1 H), 4.50 - 4.54 (m, moderate yields of 2a. On the other hand, employing
1 H), 7.34 - 7.38 (m, 5 H); 13C NMR (150 MHz, CDCl3) δ, 21.8, higher residence times (i.e. between 2.5 and 25 s), at
1
23.1, 29.5, 65.6, 73.8, 93.3, 125.9, 126.8, 127.4, 144.0. H and temperatures between –50 and –30 °C, 2a was obtained
13C data in agreement with those reported in the literature. from moderate to high yield, but at temperatures higher
[16]
than –30 °C the yields decreased significantly. The
assembled flow microreactor system has indeed provided
an effective reactor for the generation and reactions of
2-phenyloxetan-2-yl lithium 1-Li without decomposition by
using a residence time of 12.5 s and efficient temperature
control at –40 °C, which is an impracticable temperature
in batch-mode. In particular, the systematic tuning of
Deprotonation of 2-Phenyloxetane (1)
Followed by Reaction with Benzophenone in
a Flow Microreactor System.
Diphenyl(2‐phenyloxetan‐2‐yl)methanol(2e).Thecrude
product was purified by flash chromatography (hexane/
ethyl acetate 20:1 to 4:1); white solid, mp 98 oC (Et2O), 70%
1
yield. H NMR (400 MHz, CDCl3) δ, 2.56 - 2.63 (m, 1 H),
3.20 - 3.27 (m, 1 H), 4.06 - 4.12 (m, 1 H), 4.38 - 4.43 (m, 1 H),
7.15 - 7.31 (m, 11 H), 7.58 - 7.61 (m 2 H), 7.75 - 7.77 (m, 2 H); 13C
NMR (150 MHz, CDCl3) δ, 32.4, 66.1, 80.5, 93.1, 126.9, 127.0,
127.1, 127.2, 127.3, 127.47, 127.50, 127.8, 142.9, 143.0, 143.6;
GC‐MS (70 eV) m/z (%) 316 (M+ , 2), 270 (5), 183 (47), 133
(100), 105 (90), 77 (47). Analytical data in agreement with
those reported in the literature. [16]
Figure 1: A flow microreactor system for the deprotonation of
2-Phenyloxetane (1) with s-BuLi followed by reaction with
chlorotrimethylsilane. M1, M2: T-shaped micromixer. R1, R2:
microtube reactor.
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380ꢀ
ꢀ Leonardo Degennaro et al.
In order to increase the yield of 2a, we attempted
a further tuning of the reaction conditions by changing
the molarity of a solution of s-BuLi (from 0.5 M to 0.6 M).
We found that the yield of 2a slightly depends on the
amount of the base. However, with 3 equiv of s-BuLi, 2a
was obtained in 85% yield.
Next, on the basis of the optimized conditions
(1.0 equiv of 1, 3.0 equiv of s-BuLi, 3.0 equiv of electrophile,
tR1 = 12.50 s, tR2 = 2.20 s at ‒40 °C), we examined the
nucleophilicity of 1-Li towards various electrophiles
in order to prepare different 2,2-disubstituted-oxetane
derivatives as reported in Table 1.
By using electrophiles such as chlorotrimethylsilane
and MeI (entry 1 and 2), the corresponding 2-substituted-
2-phenyloxetanes 2a and 2b were obtained in good yield.
An aliphatic aldehyde such as pivalaldehyde (entry 3)
also reacted affording the expected addition product 2c
in good yield although, with diastereoselectivity poor
(dr=67:33)asobservedinbatch. [16]Withanacetone(entry
4), the corresponding hydroxyalkylated products 2d was
obtained in moderate yield suggesting that enolisation
could in principle compete with the addition reaction.
On the other hand, when enolisation is not possible as
in the case of benzophenone (entry 5), the corresponding
hydroxyarylated products 2e was even obtained in lower
yield.
Figure 2: Effects of reaction temperature (T) and residence time (tR1)
on the yield of 2a under the flow conditions reported in figure 1.
Table 1: Deprotonation of 2-phenyloxetane 1 followed by reactions
with electrophiles using a flow microreactor system under the
optimized conditions.
Entry
Electrophile
Product
Yielda
1
85
2
3
78
4 Conclusions
63b
The use of a flow microreactor system, enabled the
generation of 2-lithiated oxetane species such as 1-Li
and its trapping with representative electrophiles. In
particular, by controlling the residence time, the highly
unstable intermediate 1-Li could be generated and trapped
with electrophiles at higher temperatures with respect
to batch-mode (i.e -40 °C instead of -78 °C) obtaining 2,2-
disubstituted oxetanes (2a-e) in moderate to good yields.
Under flow conditions, it is worth noting that the accurate
control of reaction parameters such as residence time and
temperature proved to be fundamental for achieving a
more sustainable reaction, that normally need to be carried
out in bath-mode at much lower temperatures. This work
could eventually open the possibility for a sustainable flow
synthesis of substituted oxetanes in pharmaceutical field.
4
5
55
36
a Isolated yield afer column chromatoghraphy. b Overall isolated
yield of inseparable mixture of diastereomers; diastereomeric ratio
= 67:33 (determined by 1H NMR spectroscopy).
the residence time (tR1) has proved, as generally expected Acknowledgements: This work has been realized under
in flash chemistry, to be a key parameter for achieving the framework of the National Project “FIRB - Futuro in
a reaction with good yield and selectivity.
Ricerca” (code: CINECA RBFR083M5N) coordinated by R.L.
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Flow microreactor synthesis of 2,2-disubstituted oxetanesꢀ
[18] Yamaguchi H., Nobayashi Y., and Hirao I., A ring opening
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