A convenient enantioselective CBS-reduction of arylketones in flow-microreactor systems

Article abstract of DOI:10.1039/c6ob00336b

A convenient, versatile, and green CBS-asymmetric reduction of aryl and heteroaryl ketones has been developed by using the microreactor technology. The study demonstrates that it is possible to handle borane solution safely within microreactors and that the reaction performs well using 2-MeTHF as a greener solvent.

Full text of DOI:10.1039/c6ob00336b

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A Convenient Enantioselective CBS-Reduction of Arylketones in
Flow-Microreactor Systems
Sonia De Angelis,a Maddalena De Renzo,a Claudia Carlucci,a Leonardo Degennaro,*,a and Renzo
Luisi*,a
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
A convenient, versatile, and green CBS-asymmetric reduction of aryl and heteroaryl ketones has been developed
by using the microreactor technology. The study demonstrates that it is possible to handle safely the borane
solution within microreactors and that the reaction performs well using 2-MeTHF as greener solvent.
www.rsc.org/
environmental impact of the pharmaceutical industry. Thus, the
search for new conditions in terms of solvent, temperature,
Introduction
stoichiometry and work-up operations as well as the use of flow
technologies would help to reduce its burden.7
In recent years microreactors and continuous flow technologies have
been playing an important role both in academic research and in the
industrial field, acting as a viable alternative to batch processes, and
offering, in many cases, more sustainable synthetic routes.1,2 These
technologies reduce the wide gap between the academic and
industrial development, allowing for an improvement of safety
concerns and chemistry performance in terms of yield and
selectivity. The use of continuous processes, within "micro- or meso-
reactors", provides access to a wider profile of reaction conditions
not accessible by traditional "batch" systems.
The needs for new technologies is also due to increasingly stringent
regulations concerning the emission of wastes and the related
environmental impact.8
In continuation of our research projects in the field of microreactor
technology,9 we became interested into the development of a
continuous flow process for the asymmetric reduction of prochiral
arylketones.
The asymmetric reduction of prochiral ketones, to produce
enantioenriched alcohols, is an important step in the synthesis of
many pharmaceutical molecules (Figure 1).4b
In fact, the high surface/volume ratio in microreactors allows for a
rapid heat transfer and high thermal control. Usually, reactions
conducted under cryogenic conditions in batch (i.e. -78 °C), could be
conducted at higher temperature (i.e. 0 °C) in microreactors. In
addition, pressure and temperature can be easily handled in flow.
The production in continuous flow has recently attracted the interest
of the chemical and pharmaceutical industry, as it ensures lower
costs, improved reliability, safety and sustainability. Recently a
pharmaceutical roundtable study demonstrated the importance of
continuous processes in the design of ꢀGreener Processesꢁ.3
CF
3
O
N
O
N
H
O
N
H
Dapoxetine
Fluo xetine
Atomoxetine
NH
N
N
O
H
O
S
F C
3
N
N
N
H
O
O
N
O
An interesting example is the continuous production of aliskiren
hemifumarate, a direct renin inhibitor.4 The production plant
realised was able to perform reactions, separations, crystallization,
drying and formulation up to the final tablets, all through a highly
controlled and modular process. The production in continuous flow
can be extended to a broader range of active pharmaceutical
ingredients (API),5 and the number of applications of flow technology
in the production of API or other pharmaceutical products, is rapidly
growing.6 This aspect is particularly important considering the high
O
CF
3
Duloxetine
Aprepitant
Revastigmine
F
Figure 1. Drugs involving asymmetric reduction steps in their
synthesis.
The most used methods involve bio-catalysis, heterogeneous
catalysis with transition metals, use of stoichiometric amounts of
chiral hydrides and homogenous asymmetric reduction based on
oxazaborolidine.10
Herein we report the study on the development of a sustainable
asymmetric reduction of arylketones under homogeneous
conditions by using a microfluidic device, 2-MeTHF as greener
solvent and without employing any additive. The Corey, Bakshi and
a. Department of Pharmacy ꢀ Drug Sciences, University of Bari ꢁA. Moroꢂ; FLAME-
Lab ꢀ Flow Chemistry and Microreactor Technology Laboratory, Via E. Orabona 4,
I-70125. E-mail renzo.luisi@uniba.it; leonardo.degennaro@uniba.it; Phone: (+39)-
080-5442762; fax: (+39)-080-5442739;
Electronic Supplementary Informa on (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
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Shibata (CBS) oxazaborolidine was employed as the catalyst to Figure 2. Scheme and equipment for a continuous flow CBS
control the enantioselectivity.11
asymmetric reduction.
One of the main problems in CBS asymmetric reductions is the use of The optimization study was executed using a 2 inlets 1000 mL glass
hazardous borane reagents difficult to handle on large scale and chip microreactor fed with a 0.2M 2-MeTHF solution of 1-phenyl-3-
potentially benefiting from microreactor technology. Modified chloropropan-1-one 1a, chosen as model substrate, and the progress
protocols have been introduced which, however, use genotoxic alky of the reduction monitored by an ATR probe at steady state
halides12 or large amount of N,N-diethylaniline (DEAN)13 and N-t-Bu- conditions. A 0.3M solution of BH3 (85% 2-MeTHF, 15% THF), and
N-trimethylsilylamine as stabilizer for the borane.14 Recently, oxazaborolidine 2 was introduced for the asymmetric reduction.
Sanderson and coworkers developed a multi-steps flow synthesis of Stoichiometry and residence time were adjusted according to the
fluoxetine where the CBS asymmetric reduction of an arylketone was flow rate of the feeding solutions and response of the ATR probe.
the stereo-determining step. Under optimised conditions, the Results for this optimization study are reported in Table 1.
reduction was accomplished in 10 minutes with 3 equivalents of We started the study running the reactor at room temperature (24
borane-DEAN, 30% of catalyst, CH2Cl2/toluene as solvents and -7 °C) by using 2.5 equivalents of borane and 25 mol % of CBS catalyst
°C.15
(Table 1, entry 1). Under such reaction conditions, the reaction was
complete in 10 minutes and the expected alcohol 3a was obtained
with 95% yield and a 91:9 enantiomeric ratio. Next, the amount of
catalyst was reduced to 12 mol % and again a full conversion was
Results and discussion
We evaluated the possibility to develop a greener and continuous observed while maintaining high enantioselectivity (Table 1, entry 2).
flow process for CBS asymmetric reduction of ketones, using chip- However, reducing the amount of chiral catalyst to 8 mol %, and the
microreactors and employing a more sustainable solvent such as 2- amount of borane up to 1.5 equivalents (Table 1, entries 3,4), was
MeTHF.16 This is one of the ethereal solvents recommended for its detrimental for both yield (70%) and enantioselectivity (85:15). With
low solubility in water (14g/100g at 23 °C), the relatively low boiling the aim to improve the reaction performance, the temperature
point (80 °C), deriving from renewable sources and amenable to be effect was also considered. Running the flow reactor under the
recycled. In particular 2-MeTHF can be obtained from levulinic acid conditions of entry 2 but at 0 °C (Table 1, entry 5) again a full
or by hydrogenation of furfural which is, in turn, obtained from corn conversion was observed (>95% yield) jointly to a very good
cobs and sugar cane, through an intramolecular cyclisation of enantioselectivity (er: 93:7). Lowering the amount of the catalyst to
pentoses.17 Compared to THF, 2-MeTHF has a higher boiling point, 5 mol % and using 1.5 equivalents of borane led to a good conversion
lower solubility in water, allowing reactions at higher temperatures (90% yield) with a modest enantiomeric ratio of 75:25 (Table 1, entry
and giving superior performance in biphasic reactions, easiness to 6). Increasing the loading of the catalyst to 8 mol % and using 1.5
dry, and it is less irritating to eyes and respiratory system.18 The equivalents of borane, gave 94% yield of 3a and an enatiomeric ratio
microfluidic device employed in this study is reported in Figure 2. of 91:9 (Table 1, entry 7). Reducing the catalyst to 5 mol % using 2
Exploiting the advantages of microreactors, we explored the equivalents of borane resulted in lower yield (85%) while maintaining
possibility to handle the commercially available solution of BH3 (1M the enantioselectivity (Table 1, entry 8) thus showing that the
in THF), without using any additive and to perform an in-line FT-IR amount of the catalyst is an important factor.
analysis to speed up the optimization process.19
Table 1 Optimization study in continuous flow microreactor of the
CBS asymmetric reduction of 3-chloro-1-phenylpropan-1-one 1.
a
b
BH3
(equiv) (%) (°C)
CBS
T
tR
Yieldc
(%)
> 95
> 95
70
70
> 95
90
94
85
> 95
23
28
Entry
Solvent
erd
(min)
10
10
10
10
10
10
10
15
5
1
2
3
4
5
6
7
8
9
2.5
2.5
2
1.5
2.5
1.5
1.5
2
25
12
8
RT 2-MeTHF
RT 2-MeTHF
RT 2-MeTHF
RT 2-MeTHF
91:9
91:9
85:15
85:15
93:7
75:25
91:9
89:11
90:10
91:9
8
12
5
0
0
2-MeTHF
2-MeTHF
2-MeTHF
2-MeTHF
THF
8
0
5
0
2.5
2
25
20
10
RT
RT
RT
10
11
THF
THF
10
20
1
90:10
aentry 1-8: solvent mixture of 2-MeTHF 85% and THF 15% (deriving from
commercial solution of BH3 1M in THF). bResidence time. cDetermined by 1H-
NMR using internal standard. dDetermined by HPLC using a chiral stationary
phase.
It is worth mentioning that under steady state conditions, reached
by flowing twice the volume of the microreactor, the reaction was
complete in 10 minutes under various conditions. The in-line
2 | J. Name., 2012, 00, 1-3
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monitoring offers several advantages reducing the optimization time because of a competing b-elimination.24 We tested the Noyori
and allowing for the automation of a continuous process.20,21
asymmetric reduction, in batch conditions, using 1a as starting
The progress of the reaction was followed by monitoring the material, but only the corresponding product of b-elimination was
disappearance of the C=O stretching signal at 1690 cm-1 and observed.25 Lower yields and enantioselectivity were observed in the
appearance of new signals in the range 1400-1350 cm-1, ascribable reduction of indanone leading to 3l, and in the reduction of aryl
to the reduction product.22 In Figure 3 is reported the IR profile for ketone bearing ortho substituents as in the case of 3n. Heteroaryl
the asymmetric reduction of 1a under optimised conditions (Table 1, ketones could be effectively reduced under flow conditions as in the
entry 7).
case of 3o. Pyridyl derivative 3p was obtained as racemic mixture
while compound 3q was obtained enantioenriched, as established by
the optical rotation value.
O
Ar
R
1a-q
OH
2-MeTHF
Ar
3a-q
R
H
Ph
T = 0 °C
N
B
+
BH3
t
R = 10 min
Ph
O
2
Me
OH
OH
OH
Cl
Cl
(S)
(S)
Cl
(S)
Cl
F
3a
3b
3c
er = 90:10
94%
er = 97:3
75%
er = 87:13
80%
OH
OH
OH
Cl
Cl
(S)
Cl
(S)
(S)
H3CO
H3C
Br
3d
3e
3f
er = 92:8
97%
er = 94:6
90%
er = 93:7
66%
OH
(S)
OH
OH
Cl
Cl
Cl
Cl
(S)
Cl
(S)
F
3g
3h
3i
er = 80:20
66%
er = 93:7
95%
er = 92:8
52%
Figure 3.
OH
OH
OH
OH
(R)
For sake of comparison, THF was employed to perform the same
reaction into continuous flow microreactor (Table 1, entries 9-11). As
reported in Table 1, the reaction performs well only using 25 mol %
of catalyst and 2.5 equivalent of borane (entry 9). Lowering the
loading of the catalyst caused a drop of the yields while maintaining
the enantioselectivity (entries 10-11). The reason of this different
behavior between THF and 2-MeTHF is unclear at the moment.
Remarkably, these results demonstrate that the asymmetric
reduction can be effectively run in continuous flow mode using a
reduced amount of chiral catalyst, with respect to batch mode, using
a greener solvent such as the 2-MeTHF and without any additive.
Next, the scope of the process was investigated using several
prochiral ketones of interest in medicinal chemistry programs
(Scheme 2). The optimised conditions (Table 1, entry 7) were
effective for the asymmetric reduction of aromatic ketones 1b-f
leading to the corresponding chloroalcohols 3b-f with good yields
and excellent enantiomeric ratios. In the case of 3,4-dichlorophenyl
substituted ketone 1g, 3 equivalents of BH3 and 10 mol % of catalyst
were needed to obtain a better yield (75%) and enantiomeric ratio
(er: 80:20). It is worth pointing out that the CBS-reduction is the best
strategy for the preparation of chiral 1-aryl-3-chloropropanols of the
kind of 3a-h, important for the synthesis of chiral four membered
heterocycles23 and APIs.4 In fact, Yus recently reported that a Noyori-
type asymmetric reduction was not effective with sulfinylhaloimines
(S)
Cl
Cl
(S)
(S)
H3CO
3m
er = 90:10
85%
3j er = 93:7
75%
3k er = 96:4
86%
3l er = 84:16
40%
OH
OH
OH
(R)
OH
S
(S)
Me
Me
CH3
(S)
N
(Z)
(Z)
N
3q er = 80:20
3p er = 50:50
3o er = 83:17
3n
er = 70:30
75%
>99%
90%
70%
Scheme 2. Scope for the continuous flow CBS asymmetric reduction
of prochiral ketones. Conditions: ketone (0.2 M) in 2-MeTHF, flow
rate: 50¼L/min, (R)-CBS catalyst (8%), BH3 (0.3 M, 85% 2-MeTHF, 15%
THF), flow rate: 50¼L/min. Yields of isolated product are reported.
As mentioned previously, the enantioselective reduction of ketones
to alcohols can represent an important step in the synthesis of
several bioactive molecules and the availability of flow-methodology
could be useful from a sustainability point of view. Thus, this
continuous flow asymmetric reduction was tested in a microfluidic
system including an in-line work up and a liquid/liquid separator at
the output of the chip microreactor (Scheme 3). This integrated flow
device allows to exploit the low solubility in water of 2-MeTHF.
Nevertheless, the liquid/liquid separator was unable to perform a
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clear separation of the organic phase without introducing a small General procedure for the enantioselective synthesis of alcohols
amount of AcOEt as organic solvent. The microfluidic system 3a-q in flow. The general procedure refers to the reduction of 1a.
reported in Scheme 3, allows to recover >90% of the desired chloro The process could be executed using Asia® syringe pumps by Syrris
alcohol 3b and could be run for hours. However, for long runs, it was that continuously deliver solutions of reactants from stock
necessary to maintain the temperature of the BH3 solution at 0 °C containers of suitable volume (minimum 50 mL). The following
during the infusion, to minimise decomposition and loss of the solutions were prepared and filtered with PTFE filters with a porosity
reducing agent.26
of 0.2 mm: (i) 10 mL, 0.2 M in 2-MeTHF of ketone 1a (2 mmol, 337.2
mg); (ii) 10 mL, 0.3 M of BH3 in 85% 2-MeTHF, obtained by diluting
with 2-MeTHF a 1 M commercial solution of BH3 in THF. To solution
(ii), the catalyst (R)-CBS 2 (8 mol% with respect to ketone 1a) was
added, and cooled at 0° C with an ice bath. Those solutions were
pumped into the microreactor kept at 0° C with an ice bath at a flow
rate of 50 mL/min. The solutions were delivered simultaneously into
the ꢀow system and collected under steady state conditions (after 20
minutes) for 1h (0.6 mmol of ketone). At the output of the
microreactor, the flowing solution (100¼L/min) was poured in acidic
water (10%aq HCl) to deactivate the excess of borane. The catalyst
may be removed during the purification on silica gel or by washing
with a saturated solution of sodium bicarbonate NaHCO3 (10 mL).
The crude was extracted with ethyl acetate (3 x 2 mL), dried over
magnesium sulfate, ꢁltered and concentrated under reduced
pressure. Pure products are obtained after column chromatography
(hexane/ethyl acetate 8:2-9:1). Alternatively, the process can be
executed using traditional syringe pumps and 10 or 20 mL gas-tight
syringes (SGE) under the same conditions reported above. In this
case, in order to reduce gas evolution (presumably borane), it is
necessary to maintain the temperature at about 0° C during the
infusion by keeping the syringe in contact with a plastic bag ꢁlled
with ice replaced when required. Data for isolated products reported
below matched those reported in the literature (references given).
O
Cl
AcOEt
50 L/min
1b
Aqueous waste
F
0.2 M
50 L/min
2-MeTHF
Back Pressure
Organic phase
OH
0.3 M
0 °C
tR = 10 min
50 L/min
Water
150 L/min
H
Ar
N
B
+ BH3
Ar
O
2
Cl
R
F
>90% Recovery in the organic phase
er >95:5
Scheme 3. Integrated microfluidic device for CBS asymmetric
reduction.
Conclusions
In summary, a sustainable, versatile, fast and environmentally
friendly CBS-asymmetric reduction of aryl and heteroaryl
ketones has been developed by using the microreactor
technology. The study demonstrates that it is possible to handle
safely the borane solution within microreactors and that the
reaction performs well using 2-MeTHF as greener alternative to
traditional solvents. In addition, the use of flow technology
allows for a reduction of the amount of the chiral catalyst, avoid
the use of an additive such as DEAN (N,N-diethylaniline) and the
in-line monitoring and work up procedures helped to optimise
the process.
(S)-3-Chloro-1-phenylpropan-1-ol (3a)27 White solid, m.p. 30-32 °C
1
(94% yield, 92 mg). H NMR (CDCl3, 500 MHz): ´ 7.38-7.28 (m, 5H),
4.95 (dd, 1H, J = 4.6 e 8.5 Hz), 3.77-3.72 (m, 1H), 3.59-3.54 (m, 1H),
2.28-2.22 (m, 1H), 2.13-2.07 (m, 1H), 1.99-1.94 (bs, 1H, exchange
with D2O). [±]19D = -25° (c = 1, CHCl3). 13C NMR (CDCl3, 125 MHz): ´
143.9, 128.9, 128.1, 126.0, 71.6, 41.9, 41.7. FT IR (KBr, cm-1) ½ 3060,
2878, 1620, 1612, 1596, 1452, 1215, 1190, 1042, 1020, 988.
Experimental section
The enantiomeric ratio was determined by HPLC using a chiral
column Lux- 1 Cellulose [hexane/i-PrOH (90:10)]; flow 0.5 mL/min; »
= 220 nm; er 90:10 (tR major = 15.729 min, tR minor = 16.774 min).
(S)-3-Chloro-1-(4-fluorophenyl)propan-1-ol (3b) Colorless oil (75%
yield, 85 mg) 1H NMR (CDCl3, 500 MHz): ´ 7.34 (dd, 2H, J = 5.3 e 8.6
Hz), 7.05 (t, 2H, J = 8.6 Hz), 4.94 (dd, 1H, J = 4.5 e 8.6 Hz), 3.76-3.71
(m, 1H), 3.57-3.52 (m, 1H), 2.25-2.18 (m, 1H), 2.09-2.02 (m, 1H), 1.93-
1.70 (bs, 1H, exchange with D2O). [±]20D = -25.7° (c = 1, CHCl3). 13C
NMR (CDCl3, 125 MHz): d 162 (dd, J = 247.9 Hz), 139.49, 127.45,
115.50 (dd, J = 21.3), 70.68, 41.59, 41.49, 29.70. FT IR (NaCl, cm-1): ½
3381, 2032, 1891, 1715, 1605, 1511, 1224, 1054, 836, 661.
General
The 1H NMR, 13C NMR spectra were recorded with a Bruker 500,
Varian Inova 600 MHz or 400 MHz; all chemical shift values are
reported in ppm (´); the CDCl3 was used as solvent. The high-
performance liquid chromatography HPLC was performed with chiral
stationary phases 5u Lux Cellulose -1 250 x 4.60 mm and CHIRALPAK
AD- H ø 0.46 cm x 25 cm. The gas chromatography GC was performed
with chiral column Cyclodex B 30m x 0.25mm x 0.25µm; inlet: (250°C)
Split at 75 mL/min. The IR spectra have been carried out with a
PERKIN
- ELMER 283 spectrophotometer. The thin layer
chromatography (TLC) was performed using silica gel plates (Merck)
with fluorescence indicator F-254 and the visualisation was carried
out with UV light (254nm). The flow apparatus is the FRX-400TM
system by Syrris. Two Asia Syringe Pumps, equipped with Asia Green
Syringes (250µL), glass chip microreactors (1000 µl ꢂ 3 inlet; 1000 µl
-2 inlet) and a chip header were used. All the modules were
connected by PTFE tubing and end fittings.
The enantiomeric ratio was determined by HPLC using a chiral
column Lux- 1 Cellulose [hexane/i-PrOH (90:10)]; flow 0.5 mL/min; »
= 220 nm; er 97:3 (tR major = 13.130 min, tR minor = 12.385 min).
(S)-3-Chloro-1-(4-chlorophenyl)propan-1-ol (3c)28 Colorless oil (80%
yield, 98 mg) 1H NMR (CDCl3, 500 MHz): ´ 7.34 (d, 2H, J = 8.6 Hz), 7.32
(d, 2H, J = 8.6 Hz), 4.95 (dd, 1H, J = 4.6 e 8.6 Hz), 3.77-3.72 (m, 1H),
3.58-3.53 (m, 1H), 2.24-2.17 (m, 1H), 2.09-2.03 (m, 1H), 1.94-1.81(bs,
1H, exchange with D2O). [±]20D = -10.6° (c = 1, CHCl3) (Literature data:
4 | J. Name., 2012, 00, 1-3
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[±]20D = -15.6° c = 1, CHCl3). 13C NMR (CDCl3, 125 MHz): d 142.34, with D2O). FT IR (NaCl, cm-1): ½ 3400, 2923, 1721, 1455, 1259, 1051,
133.71, 128.94, 127.29, 70.78, 41.67, 41.56. FT IR (NaCl, cm-1): ½ 856, 800, 747, 699.
3380, 2963, 1904, 1709, 1597, 1491, 1287, 1198, 1063, 927, 827, 735. The enantiomeric ratio was determined by HPLC using a chiral
The enantiomeric ratio was determined by HPLC using a chiral column Lux- 1 Cellulose [hexane/i-PrOH (90:10)]; flow 1 mL/min; » =
column Lux- 1 Cellulose [hexane/i-PrOH (90:10)]; flow 0.5 mL/min; » 254 nm; er 93:7 (tR major = 19.15 min, tR minor = 23.11 min).
= 220 nm; er 87:13 (tR major = 13.871 min, tR minor = 14.861 min).
(S)-4-Chloro-1-(4-fluorophenyl)butan-1-ol (3i)31 Colorless oil (52%
(S)-3-Chloro-1-(4-bromophenyl)propan-1-ol (3d)28 Colorless oil yield, 63 mg) 1H NMR (CDCl3, 500 MHz): ´ 7.33 (dd, 2H, J = 5.2 e 8.5
(97% yield, 145 mg) 1H NMR (CDCl3, 500 MHz): ´ 7.49 (d, 2H, J = 8.1 Hz), 7.05 (t, 2H, J = 8.5 Hz), 4.73 (dd, 1H, J = 5.4 e 7.2 Hz), 3.61-3.53
Hz), 7.25 (d, 2H, J = 8.1 Hz), 4.94 (dd, 1H, J = 4.6 e 8.6 Hz), 3.77-3.72 (m, 2H), 1.96-1.75 (m, 5H, 2 x CH2 e 1H OH). [±]20D = 40° (c = 1, CHCl3).
(m, 1H), 3.57-3.53 (m, 1H), 2.23-2.16 (m, 1H), 2.09-2.02 (m, 1H), 1.87- 13C NMR (CDCl3, 125 MHz): 162.2 (d, J = 246 Hz), 140.0 (d, J = 3 Hz),
1.77 (bs, 1H, exchange with D2O). [±]20 = -4.27° (c = 1, CHCl3) 127.4 (d, J = 8 Hz), 115.4 (d, J = 21 Hz), 73.2, 19 44.9, 36.2, 28.8. FT IR
D
(Literature data: [±]20D = -13.3° c = 1, CHCl3). 13C NMR (CDCl3, 125 (NaCl, cm-1): ½ 3383, 1604, 1508, 1222, 1157, 1070.
MHz): d 142.86, 131.89, 127.63, 121.81, 70.82, 41.65, 41.52. FT IR The enantiomeric ratio was determined by HPLC using a chiral
(NaCl, cm-1): ½ 3465, 3184, 1562, 1450, 1114, 748, 618.
column Lux- 1 Cellulose [hexane/i-PrOH (95:5)]; flow 0.5 mL/min; » =
The enantiomeric ratio was determined by HPLC using a chiral 220 nm; er 92:8 (tR major = 22.574 min, tR minor = 23.558 min).
column Lux- 1 Cellulose [hexane/i-PrOH (90:10)]; flow 0.5 mL/min; » (S)-4-Chloro-1-(4-methoxyphenyl)butan-1-ol (3j)32 Colorless oil
1
= 220 nm; er 92:8 (tR major = 15.380 min, tR minor = 16.808 min).
(75% yield, 96 mg) H NMR (CDCl3, 500 MHz): ´ 7.27 (d, 2H, J = 8.4
(S)-3-Chloro-1-(4-methoxyphenyl)propan-1-ol (3e)29 Colorless oil Hz), 6.89 (d, 2H, J = 8.4 Hz), 4.68-4.65 (m, 1H), 3.81 (s, 3H), 3.59-3.51
(90% yield, 108 mg) 1H NMR (CDCl3, 600 MHz): ´ 7.29 (d, 2H, J = 8.5 (m, 2H), 1.95-1.73 (m, 4H), 1.66-1.53 (bs, 1H, exchange with D2O).
Hz), 6.90 (d, 2H, J = 8.5Hz), 4.89 (dd, 1H, J = 4.9 e 8.2 Hz), 3.81 (s, 3H), [±]20D = -29.13° (c = 1, CHCl3) (Literature data: [±]20D = -37.3° c = 1,
3.75-3.69 (m, 1H), 3.56-3.52 (m, 1H), 2.27-2.22 (m, 1H), 2.10-2.04 (m, CHCl3). 13C NMR (CDCl3, 125 MHz): ´ 159.2, 136.5, 127.1, 114.0,
1H), 1.94-1.86 (bs, 1H, exchange with D2O). [±]20D = -10.5° (c = 1, 73.54, 55.3, 45.0, 36.1, 29.1. FT IR (NaCl, cm-1): ½ 3211, 2955, 1462,
CHCl3)(Literature data: [±]20D = (R) +16° c = 1, CHCl3). 13C NMR (CDCl3, 1035, 832, 651.
126 MHz): ´ 195.4, 164.0, 130.6, 129.6, 114.1, 55.7, 41.1, 39.2.4 FT IR The enantiomeric ratio was determined by HPLC using a chiral
(NaCl, cmꢀ1): 3293, 2960, 2904, 1612, 1516, 1288, 1253, 1179, 1032, column Lux- 1 Cellulose [hexane/i-PrOH (90:10)]; flow 0.5 mL/min; »
834, 652.
= 220 nm; er 93:7 (tR major = 12.313 min, tR minor = 11.662 min).
The enantiomeric ratio was determined by HPLC using a chiral (R)-2-Chloro-1-phenylethanol (3k)33 Colorless oil (86% yield, 80 mg)
column ADH [hexane/i-PrOH (90:10)]; flow 1 mL/min; » = 220 nm; er 1H NMR (CDCl3, 500 MHz): ´ 7.39-7.33 (m, 5H), 4.90 (dd, 1H, J = 3.4 e
94:6 (tR major = 11.173 min, tR minor = 10.553 min).
8.7 Hz), 3.75 (dd, 1H, J = 3.4 e 11.4 Hz), 3.65 (dd, 1H, J = 8.7 e 11.4
(S)-3-Chloro-1-(4-methylphenyl)propan-1-ol (3f)30 White solid, m.p. Hz), 2.61-2.39 (bs, 1H, exchange with D2O). [±]20D = -49° (c = 1, CHCl3).
42-43°C (66% yield, 73 mg) 1H NMR (CDCl3, 500 MHz): ´ 7.27 (d, 2H, J (Literature data: [±]22D = -53.1°, c = 1, CHCl3). 13C NMR (CDCl3, 100
= 7.8 Hz), 7.19 (d, 2H, J = 7.8 Hz), 4.92 (dd, 1H, J = 4.6 e 8.3 Hz), 3.76- MHz): ´ 139.86, 128.65, 128.43, 126.02, 74.03, 50.88. FT IR (NaCl, cm-
3.71 (m, 1H), 3.59-3.54 (m, 1H), 2.36 (S, 3H), 2.28-2.21 (m, 1H), 2.12- 1): ½ 3400, 3050, 2960, 1455, 1070, 705.
2.05 (m, 1H), 1.90-1.83 (bs, 1H, exchange with D2O). [±]20D = -13.2° (c The enantiomeric ratio was determined by HPLC using a chiral
= 1, CHCl3). 13C NMR (CDCl3, 125 MHz): d 140.85, 137.81, 129.46, column Lux- 1 Cellulose [hexane/i-PrOH (95:5)]; flow 0.5 mL/min; » =
125.87, 71.34, 41.92, 41.54, 21.26. FT IR (KBr, cm-1): ½ 3306, 2917, 220 nm; er 96:4 (tR major = 31.869 min, tR minor = 25.876 min).
1416, 1286, 1049, 817.
(S)-2,3-diHydro-1H-inden-1-ol (3l)34 White solid, m.p. 60-63 °C (40%
The enantiomeric ratio was determined by HPLC using a chiral yield, 32 mg) 1H NMR (CDCl3, 500 MHz): ´ 7.43 (m, 1H), 7.24 (m, 3H),
column Lux- 1 Cellulose [hexane/i-PrOH (90:10)]; flow 0.5 mL/min; » 5.26 (t, 1H, J = 6.07 Hz), 3.10-3.04 (m, 1H), 2.86-2.80 (m, 1H), 2.54-
= 220 nm; er 93:7 (tR major = 13.908 min, tR minor = 15.995 min).
2.47 (m, 1H), 1.99-1.92 (m, 1H), 1.64-1.53 (bs, 1H, exchange with
(S)-3-chloro-1-(3,4-dichlorophenyl)propan-1-ol (3g) White solid, D2O). [±]20D = +20° (c = 1, CHCl3). 13C NMR (CDCl3, 75 MHz, 35ÚC): ´
m.p. 44-47 °C (66% yield, 94 mg) 1H NMR (CDCl3, 500 MHz): ´ 7.49 (d, 145.02, 143.30, 143.29, 128.30, 126.69, 124.87, 124.16, 76.44, 35.94,
1H, J = 2.0 Hz), 7.44 (d,1H, J = 8.2 Hz), 7.21 (dd, 1H, J = 2.0 e 8.2 Hz), 29.77. FT IR (KBr, cmꢂ1): ½ 3336, 2939, 1607, 1478, 1459, 1329, 1213,
4.96 (dd, 1H, J = 4.2 e 8.6 Hz), 3.78-3.73 (m, 1H), 3.59-3.54 (m, 1H), 1096, 1056, 958, 742.
2.21-2.14 (m, 1H), 2.09-2.02 (m, 1H), 1.64-1.55 (bs, 1H, exchange The enantiomeric ratio was determined by HPLC using a chiral
with D2O). [±]20D = -2.9° (c = 1, CHCl3). 13C NMR (CDCl3, 125 MHz): d column Lux- 1 Cellulose [hexane/i-PrOH (95:5)]; flow 0.5 mL/min; » =
144.0, 132.8, 131.7, 130.6, 127.8, 125.1, 70.1, 41.3. FT IR (KBr, cm-1): 220 nm; er 84:16 (tR major = 19.522 min, tR minor = 22.149 min).
½ 3391, 2917, 1564, 1468, 1396, 1285, 1201, 1131, 1030, 885, 824, (S)-1-(2-Naphthyl)-ethanol (3m)35 White solid, m.p. 73-74 °C (85%
1
666.
yield, 88 mg) H NMR (CDCl3, 500 MHz): ´ 7.85-7.82 (m, 4H), 7.53-
The enantiomeric ratio was determined by HPLC using a chiral 7.46 (m, 3H), 5.08 (q, 1H, J = 6.5), 1.68 (bs, 1H, exchange with D2O),
column Lux- 1 Cellulose [hexane/i-PrOH (90:10)]; flow 0.5 mL/min; » 1.59 (d, 3H, J = 6.5). [±]20D = -34° (c = 1, CHCl3). 13C-NMR (CDCl3, 75
= 220 nm; er 80:20 (tR major = 14.728 min, tR minor = 15.375 min).
MHz) ´ 143.3, 133.3, 132.9, 128.3, 127.9, 127.7, 126.1, 125.8, 123.9,
(S)-3-chloro-1(2-naphtyl)propan-1-ol (3h) Colorless oil (95% yield, 123.8, 70.4, 25.1. FT IR (KBr, cm-1): ½ 3347, 3052, 2970, 2924, 1598,
126 mg) 1H NMR (CDCl3, 500 MHz): ´ 7.87-7.83 (m, 4H), 7.50-7.46 (m, 1505, 1408, 1362, 1273, 1123, 1072, 1024, 899, 861, 823, 740.
3H), 5.14 (m, 1H, J = 4 e 8 Hz), 3.81-3.76 (m, 1H), 3.61-3.57 (m, 1H), The enantiomeric ratio was determined by HPLC using a chiral
2.37-2.30 (m, 1H), 2.23-2.19 (m, 1H), 2.07-2.05 (bs, 1H, exchange column Lux- 1 Cellulose [hexane/i-PrOH (95:5)]; flow 0.5 mL/min; » =
220 nm; er 90:10 (tR major = 11.179 min, tR minor = 12.040 min).
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ARTICLE
Journal Name
(S)-1-(2,4,6-triMethyl-phenyl)-ethanol (3n)36 Colorless oil (75%
Boca Raron, FL, 2011. d) T. Wirth, Microeactors in Organic
Chemistry and Catalysis, Wiley-VHC, Weinheim, 2013. e) J.-I.
Yoshida, Basics of Flow Microeactors Synthesis, Springer,
Japan, Kyoto, 2015.
1
yield, 74 mg) H NMR (CDCl3, 500 MHz): ´ 6.82 (s, 2H), 5.37 (q, 1H, J
= 6.7), 2.42 (s, 6H), 2.25 (s, 3H), 1.52 (d, 3H, J = 6.7). [±]20D = -21.8° (c
= 1, CHCl3). 13C-NMR (CDCl3, 75 MHz): ´ 137.6, 136.3, 135.6, 130.0,
67.4, 21.5, 20.6, 20.4. FT IR (NaCl, cm-1): 3209, 2925, 1611, 1449,
1365, 1076, 893, 850.
2
3
4
a) J. Wegner, S. Ceylan, A. Kirschninga, Adv. Synth. Catal.
2012, 354, 17 ꢂ 57. b) M. Brzozowski, M. OꢃBrien, S. V. Ley, A.
Polyzos, Acc. Chem. Res., 2015, 48, 349-362. c) D. Webb, T. F.
The enantiomeric ratio was determined by GC using a chiral column
Cyclodex B carrier gas: hydrogen; isothermal 180°C; flow 1.1 mL/min;
FID = 260° C; er 70:30 (tR major = 5.464 min, tR minor = 5.299 min).
Jamison, Chem. Sci., 2010, 1, 675-680. d) D. T. McQuade, P. H.
Seeberger, J. Org. Chem., 2013, 78, 6384-6389.
1
(S)-1-(2-Thienyl)ethanol (3o)35a Colorless oil (70% yield, 54 mg) H
a) P. Poechlauer, J. Colberg, E. Fisher, M. Jansen, M. D.
Johnson, S. G. Koenig, M. Lawler, T. Laporte, J. Manley, B.
Martin, A. OꢃKearney-McMullan, Org. Process Res. Dev., 2013,
17, 1472-1478. b) S. G. Newman, K. F. Jensen, Green Chem.,
2013, 15, 1456-1472.
NMR (CDCl3, 500 MHz): ´ 7.27-7.25 (m, 1H), 7.00-6.97 (m, 2H), 5.15
(q, 1H, J = 6.2 Hz), 2.05-1.83 (bs, 1H, exchange with D2O), 1.63 (d, 3H,
J = 6.2 Hz). [±]20D= -12° (c = 1, CHCl3) (Literature data: [±]20D = -15.7°,
c = 0.8, CHCl3). 13C NMR (75 MHz, CDCl3): ´ 150.0, 126.6, 124.3,
123.1, 66.1, 25.2. FT IR (NaCl, cmꢂ1): ½ 3336, 3104, 3072, 2973, 2927,
2873, 1720, 1537, 1445, 1435, 1370, 1310, 1287, 1232, 1185, 1150,
1065, 1037.
a) S. Mascia, P. L. Heider, H. Zhang, R. Lakerveld, B. Benyahia,
P. I. Barton, R. D. Braatz, C. L. Cooney, J. M. B. Evans, T. F.
Jamison, K. F. Jensen, A. S. Myerson, B. L. Trout, Angew. Chem.
Int. Ed., 2013, 52, 12359-12363. b) R. D. Mahale, S. P. Chaskar,
K. E. Patil, G. C. Maikap, M. K. Gurjar, Org. Process Res. Dev.,
2012, 16, 710-713.
The enantiomeric ratio was determined by HPLC using a chiral
column Lux- 1 Cellulose [hexane/i-PrOH (95:5)]; flow 0.5 mL/min; » =
220 nm; er 83:17 (tR major = 22.100 min, tR = minor 21.172 min).
1-(2-Pyridyl)ethanol (3p)35a,b Colorless oil (90% yield, 66 mg) 1H NMR
(CDCl3, 600 MHz): ´ 8.53 (d, 1H, J = 4.5 Hz ), 7.68 (t, 1H, J = 8 Hz), 7.28
(d, 1H, J = 8 Hz), 7.2 (m, 1H), 4.89 (q, 1H, J = 6.7 Hz), 4.47-4.16 (bs,
1H, exchange with D2O), 1.49 (d, 3H, J = 6.7 Hz). 13C NMR (CDCl3, 75
MHz): ´ 147.4, 146.6, 142.0, 133.5, 123.4, 66.9, 25.0. FT IR (NaCl, cmꢂ
1): ½ 3205, 2971, 2926, 2866, 2370, 1736, 1620, 1595, 1580, 1480,
1424, 1369, 1314, 1291, 1261, 1216, 1190, 1167, 1088, 1044, 1028,
1008.
5
6
L. Pellegatti, J. Sedelmeier, Org. Process Res. Dev., 2015, 19,
551-557.
a) B. Gutmann, D. Cantillo, C. O. Kappe, Angew. Chem. Int. Ed.,
2015, 54, 6688-6729. b) P. Porta, M. Benaglia, A. Puglisi, Org.
Process Res. Dev., 2016, 20, 2-25.
7
L. Malet-Sanz, F. Susanne, J. Med. Chem., 2012, 55, 4062-
4098.
F. Cavani, J. H. Teles, ChemSusChem, 2009, 2, 508-534.
8
9
The enantiomeric ratio was determined by HPLC using a chiral
column Lux- 1 Cellulose [hexane/i-PrOH (95:5)]; flow 0.5 mL/min; » =
220 nm; er 50:50.
a) A. Giovine, B. Musio, L. Degennaro, A. Falcicchio, A. Nagaki,
J.-I. Yoshida, R. Luisi, Chem.-Eur. J., 2013, 19, 1872-1876. b) L.
Carroccia, B. Musio, L. Degennaro, G. Romanazzi, R. Luisi, J.
1-(3-Pyridyl)-ethanol (3q)35c Colorless oil (>99% yield, 73 mg) 1H
Flow Chem., 2013,
3, 29-33. c) L. Degennaro, F. Fanelli, A.
NMR (CDCl3, 500 MHz): ´ 8.53 (s, 1H), 8.45 (d, 1H), 7.75-7.72 (m, 1H),
Giovine, R. Luisi, Adv. Synth. Catal., 2015, 357, 21-27.
7.29-7.26 (m, 1H), 4.93 (q, 1H, J = 6,4 ), 2.82 (bs, 1H, exchange with 10 a) A. Hirao, S. Itsuno, S. Nakahama, N. Yamazaki, J. Chem. Soc.,
D2O), 1.51 (d, 3H, J = 6.4 Hz). [±]20D = +12.9° (c = 1, CHCl3) (Literature
data: [±]20D (R) = +19.6° (c = 1g/100ml, CHCl3, er = 97.5 : 3.5). 13C NMR
(CDCl3, 75 MHz): ´ 147.4, 146.6 , 142.0, 133.5, 123.4, 66.9, 25.0. FT
IR (NaCl, cmꢂ1): ½ 3205, 2971, 2926, 2866, 2370, 1736, 1620, 1595,
1580, 1480, 1424, 1369, 1314, 1291, 1261, 1216, 1190, 1167, 1088,
1044, 1028, 1008. er 80:20 (estimated on the basis of ±]20D value).
Chem. Commun. 1981, 7, 315-317. b) E. J. Corey, R. K. Bakshi,
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Acknowledgements
We thank National Project ꢀFIRB - Futuro in Ricercaꢁ (code: CINECA
RBFR083M5N), Regional Project ꢀReti di Laboratori Pubblici di
Ricercaꢁ (Project. Code 20), ꢀLaboratorio SISTEMAꢁ code
Synth, Coll. 1990, 7, 402-406.
PONa300369 financed by Italian MIUR, and Interuniversity 11 E. J. Corey, C. J. Helal, Angew. Chem. Int. Ed., 1998, 37, 1986-
Consortium CINMPIS for financial support.
2012.
12 a) M. Periasamy, S. Anwar, Tetrahedron Asymmetry, 2006, 17
,
3244-3247. b) H. S. Kettouche, A. H. Djerourou, Open Catal. J.,
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Notes and references
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a) V. Hessel, H. Lowe, A. Muller, G. Kolb, Chemical Micro 13 A. M. Salunkhe, E. R. Burkhardt, Tetrahedron Lett., 1998, 38
Process Engineering: Processing and Plants, Wiley-VHC, 1523-1526.
Weinheim, 2005. b) V. Hessel, A. Renken, J. C. Schouten, J.-I. 14 R. E. Huertas, J. A. Corella, J. A. Soderquist, Tetrahedron Lett.,
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Handbook, Wiley-VHC, Weinheim, 2009. c) C. Wiles, P. Watts, 15 B. Ahmed-Omer, A. J. Sanderson, Org. Biomol. Chem., 2011,
,
A
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Micro Reaction Technology in Organic Synthesis, CRC Press,
3854-3862.
6 | J. Name., 2012, 00, 1-3
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DOI: 10.1039/C6OB00336B
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ARTICLE
16 A. D. Mamuye, S. Monticelli, L. Castoldi, W. Holzera, V. Pace, 29 M. M.-C. Lo, G. C. Fu, Tetrahedron 2001, 57, 2621-2634.
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,
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