Continuous flow multistep synthesis of α-functionalized esters via lithium enolate intermediates

Article abstract of DOI:10.1016/j.tet.2017.11.063

This manuscript describes a continuous flow protocol for the α-alkylation of esters. The method is based on the generation of lithium enolate intermediates from the esters and in situ delivered LDA. The process is then integrated with the electrophilic addition step and a quench in line. A series of α-functionalized ester have been prepared using this procedure with moderate to good yields. Key reaction parameters such as temperature and residence time and their influence on the reaction outcome are discussed in detail.

Full text of DOI:10.1016/j.tet.2017.11.063

Tetrahedron xxx (2017) 1e5
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Continuous flow multistep synthesis of a-functionalized esters via
lithium enolate intermediates
,
,
b
,
, b, *
Timo von Keutz a b, Franz J. Strauss b, David Cantillo a **, C. Oliver Kappe a
a Center for Continuous Flow Synthesis and Processing (CC FLOW), Research Center Pharmaceutical Engineering GmbH (RCPE), Inffeldgasse 13, 8010 Graz,
Austria
b Institute of Chemistry, NAWI Graz, University of Graz, Heinrichstrasse 28, 8010 Graz, Austria
a r t i c l e i n f o
a b s t r a c t
Article history:
This manuscript describes a continuous flow protocol for the a-alkylation of esters. The method is based
Received 26 September 2017
Received in revised form
17 November 2017
Accepted 21 November 2017
Available online xxx
on the generation of lithium enolate intermediates from the esters and in situ delivered LDA. The process
is then integrated with the electrophilic addition step and a quench in line. A series of -functionalized
a
ester have been prepared using this procedure with moderate to good yields. Key reaction parameters
such as temperature and residence time and their influence on the reaction outcome are discussed in
detail.
© 2017 Elsevier Ltd. All rights reserved.
Keywords:
Enolates
LDA
Continuous flow
1. Introduction
from nBuLi is more cost effective, reliable, and nBuLi solutions are
typically more stable over prolonged periods. In rare instances,
Lithium enolates are among the most important and commonly
significant differences in reactivity between commercial and in situ
generated LDA have been reported e and ascribed to the presence
of LiCl in the commercial reagent.5e7 The reaction between nBuLi
and diisopropylamine is very exothermic, and cryogenic conditions
(ꢀ78 ꢁC) are usually employed.1,2,4 On large scale production this is
an important drawback. To control the exotherm produced during
the LDA generation and potentially enable its safe production and
in situ utilization on large scale, several research groups have
developed continuous flow strategies.8e12 Thus, solutions of nBuLi
and diisopropylamine are pumped and mixed using a micromixer.
The enhanced mass transfer characteristic of a microreactor allows
used intermediates for the
a-functionalization of carbonyl com-
pounds.1 The construction of C-C bonds adjacent to carbonyl groups
via enolate intermediates has attracted particular attention over
the past decades (Fig. 1).2 A plethora of methods for the
a-alkyl-
ation and arylation of ketones, esters, and carboxylic acids,
including asymmetric C-C bond formation methods have been
developed and are nowadays fundamental techniques in organic
synthesis.1,2
Lithium diisopropylamide (LDA) is arguably the most commonly
used base for the quantitative formation of enolates. Since the
publication of the seminal work of Hamell and Levine over 6 de-
cades ago,3 organic chemists have benefited from its high regio-
selectivity and fast and complete enolate formation. Although LDA
is commercially available as solution in THF/hexanes or other non-
polar organic solvents, it is commonly prepared in situ from dii-
sopropylamine and n-butyl lithium (nBuLi).4 Generation of LDA
safe generation of LDA at much higher temperatures (ꢀ10 ꢁC, 0 ꢁ
C
or even room temperature10).
Certain enolate transformations are very difficult or impossible
to perform due to the high reactivity of the carbonyl moiety to-
wards the ensuing carbanion or the instability of the enolate itself.
Undesired self-condensations or polyalkylations often occur,
especially in the case of enolates derived from ketones and alde-
hydes. In this context, continuous flow and microreactor technol-
ogy offers unique opportunities to improve the efficiency and
selectivity of enolate-based alkylations. The exquisite mixing and
residence time control achieved in a microreactor enables very
accurate reaction times, if required in the order of second or even
milliseconds.12,13 Thus, a continuous flow LDA generator can be
* Corresponding author. Institute of Chemistry, NAWI Graz, University of Graz,
Heinrichstrasse 28, 8010 Graz, Austria.
** Corresponding author. Center for Continuous Flow Synthesis and Processing
(CC FLOW), Research Center Pharmaceutical Engineering GmbH (RCPE), Inffeldg-
asse 13, 8010 Graz, Austria.
E-mail address: oliver.kappe@uni-graz.at (C.O. Kappe).
https://doi.org/10.1016/j.tet.2017.11.063
0040-4020/© 2017 Elsevier Ltd. All rights reserved.
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2
T. von Keutz et al. / Tetrahedron xxx (2017) 1e5
mass transfer in biphasic reaction systems.18,19 The reaction
mixture was quenched in-line with a feed of distilled water at room
temperature, usually producing a biphasic mixture which sepa-
rated by gravity in the collection flask. The system was pressurized
using a back-pressure regulator at 5 bar. Due to the high reactivity
of the reagents and intermediates generated, strictly anhydrous
conditions were required for all experiments. Owing to the unde-
sired presence of moisture in some reagents, the amount of LDA
generated and utilized, with respect to the ester, was set to ca. 2
equivalents to ensure reproducible results. Higher amounts of LDA
did not lead to significantly improved results.
As generation of LDA for its direct use in continuous flow is a
well-known procedure,8e12 we focused our study on the conditions
for the generation of the lithium enolate intermediate and its re-
action with electrophiles. Evaluation of the reaction kinetics of the
enolate formation after addition of t-butyl propionate to a freshly
prepared solution of LDA was initially attempted in batch. The re-
action was monitored by FTIR using a ReactIR probe (Mettler-
Toledo), which was immersed into the reaction mixture. Notably,
the deprotonation of the ester by LDA proved to be very fast, faster
than the typical instrument measuring time (15 s) even at ꢀ78 ꢁC.
We then decided to directly optimize the residence time in the
continuous flow reactor. By using tubular reactors of different in-
ternal volumes for the enolate formation reaction zone (and
keeping all other reaction parameters constant) a set of reactions
with variable residence time was obtained (Table 1). For each
experiment the reactor was run for several minutes until steady-
state conditions were assured. Then, aliquots of the crude reac-
tion mixture from the reactor output were collected and analyzed
by GC-FID after acidification to pH 2 and separation of the organic
phase. A comparatively long residence time of 5 min for the elec-
trophilic addition step was used in all cases. The GC yield achieved
increased from 1 s reaction time to 5 s (entries 1e3).
Fig. 1. Typical a-functionalization reactions of carbonyl compounds via lithium enolate
intermediates.
coupled with a stream containing the carbonyl substrate to
generate the enolate intermediate. After an optimal contact time,
the generated enolate can be mixed with a suitable electrophile
minimizing side reactions.
In this manuscript, we present our results on the development
of a continuous flow multistep a-alkylation of esters. The sequential
process includes in situ generation of LDA, its reaction with the
ester to form an unstable lithium enolate intermediate, and sub-
sequent reaction with a suitable electrophile. Effect of temperature,
residence time, and other parameters on the yield and selectivity
for the key reaction steps are described in detail.
2. Results and discussion
Further improvement in the GC yield was not observed when
the reaction time was increased to 10 s (entry 4). Cryogenic con-
ditions were not needed for this reaction in continuous flow. Thus,
analogous results were achieved at ꢀ78 ꢁC and 0 ꢁC, including
comparable isolated yields (entries 5e7). Variable amounts of the
undesired homo-Claisen condensation product were observed in
all cases, reducing the yield of the reaction. It should be noted,
however, that similar results were also obtained in batch on small
scale for this substrate (ca. 1 mmol). The small volumes involved
likely allow good heat transfer to the cooling medium thus keeping
the selectivity high (this would most probably not be the case for
larger scale experiments, where temperature overshoots are diffi-
cult to control).
The residence time for the electrophilic addition of the lithium
enolate to methyl formate was evaluated in a second set of exper-
iments (Table 2). These experiments, executed using a small scale
batch procedure, showed the high reactivity of the lithium enolate
towards methyl formate. After 30 s the reaction was essentially
completed with a GC yield of 90% (Table 2, entry 1). Increased re-
action times, up to 30 min (entries 2e5) provided identical results,
The reaction conditions for the continuous flow multistep LDA
generation, lithium enolate formation and reaction with an elec-
trophile were optimized using the coupling of t-butyl propionate
with methyl formate, providing a-formyl ester 1, as model reaction
(Scheme 1). This reaction is typically performed in batch
at ꢀ78 ꢁC.14 The ester is mixed with an LDA solution and reacted for
30 min before adding the methyl formate. The ensuing a-formyl
esters are useful scaffolds for the preparation of thymine de-
rivatives,15,16 or coumarins,17 among other compounds.
The continuous flow setup consisted of 4 reaction zones (i.e. LDA
generation, enolate formation, electrophilic addition and quench)
(Fig. 2) and a total of 5 separate feeds, one for each of the reactants
involved and a quench feed. All reagents solutions were introduced
using commercially available peristaltic pumps (Vapourtec V-3 and
SF-10 pumps). The reactors were made of PFA tubing (i.d. 0.8 mL for
the LDA generation and 1.6 mm for all other reaction zones) and the
reagents were sequentially mixed using Teflon T-mixers (1.6 mm
i.d.). Clogging of the system occurred in some cases after enolate
formation during the reaction with the electrophile. To avoid
clogging the electrophilic addition reaction zone, including the T-
mixers, was immersed in an ultrasound bath. Sonication of tubing
and chips is often used in continuous flow chemistry to avoid
clogging when formation of solids is expected, as well as to enhance
indicating that the resulting a-formyl ester is stable under the re-
action conditions and side reactions do not occur (i.e. multiple
alkylation). Unfortunately the observed reaction times could not be
reproduced in a fully continuous setup with pre-cooling of the
methyl formate solution stream. A residence time of 1e2 min was
required. We ascribe this variation to the effect of adding a room
temperature reagent solution vs a precooled stream.
As mentioned above, the water stream used to quench the re-
action in-line produced a biphasic mixture that separated by
gravity in the collection flask. Acidification of the aqueous layer
with 2 M HCl to pH 2 under stirring permitted a simple workup
procedure by extraction of the product to the organic phase.
Scheme 1. LDA mediated coupling of t-butyl propionate with methyl formate.
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T. von Keutz et al. / Tetrahedron xxx (2017) 1e5
3
Fig. 2. Schematic view of the continuous flow setup utilized for the sequential LDA generation, enolate intermediate formation, and electrophilic addition.
Table 1
Effect of residence time for enolate formation in the LDA mediated
t-butyl propionate.
a
-formylation of
Entry
Temp (ꢁC)
equiv. LDAa
Time
Conversionb
Isolated Yield
1
2
3
4
5
6
7
0
0
0
0
ꢀ78
ꢀ78
0
2
2
2
2
2
2
2
1 s
2 s
5 s
10 s
10 s
5 s
58%
85%
91%
90%
94%
e
e
e
e
e
e
79%
77%
5 s
e
a
Calculated from the flow rates of the diisopropylamine and t-butyl propionate
solutions.
b
Determined GC-FID peak area integration.
Table 2
Effect of reaction time for electrophilic addition in the LDA mediated
a-formylation
of t-butyl propionate.a
Entry
Timeb
Temp.
0 ꢁ
equiv. LDA
Conversionc
1
2
3
4
5
30 s
C
2
2
2
2
2
90%
89%
85%
88%
89%
1 min
2 min
5 min
30 min
0
0
0
0
ꢁC
ꢁC
ꢁC
ꢁC
a
Conditions: 1 mmol scale. The substrate was added to the LDA solution under
vigorous stirring.
b
Time elapsed from the addition of methyl orthoformate until the quench with
water.
c
Fig. 3. Influence of temperature on the performance of the LDA mediated
a
-for-
Determined by GC-FID peak area integration.
mylation of methyl propionate under continuous flow conditions (a), homo-Claisen
condensation observed as side reaction (b), and nucleophilic addition of LDA to
methyl formate observed when the reactants were pre-mixed (c).
Evaporation after drying over magnesium sulfate yielded in the
pure a-formyl ester (77%, >99% purity by GC-FID).
increase the temperature to ꢀ40 ꢁC or 0 ꢁC drastically reduced the
isolated yield (Fig. 3a). Improved mixing of the LDA and ester so-
lutions using different types of mixers did not improve the results.
Alternative pre-mixing of the ester and the methyl formate elec-
trophile was not possible due to the partial reaction of LDA with
methyl orthoformate to form N,N-diisopropylformamide (Fig. 3c).
This compound is usually prepared by reaction of diisopropylamine
with CO2 or formic acid.20 It should be pointed out that in this case
the same reaction in batch, in which the methyl formate was added
to the enolate solution under stirring, gave analogous results at the
same temperatures. This means that this reaction most likely is not
We next turned our attention to a more problematic substrate.
Methyl propionate, not bearing the bulky tert-butyl group, was
expected to exhibit more selectivity problems, in particular due to
homo-Claisen condensation during the deprotonation step
(Fig. 3b). The reaction was performed using the same setup as for t-
butyl propionate (cf. Fig. 2). The continuous flow reactor was run
and the temperature was modified allowing the system to stabilize
for several minutes before collecting aliquots from the reactor
output for GC FID analysis. In this case, an important temperature
dependence on reaction yield was observed. The reaction in this
case required ꢀ78 ꢁC during the enolate formation. Attempts to
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4
T. von Keutz et al. / Tetrahedron xxx (2017) 1e5
mass transfer limited, and the poor selectivity is derived from
similar reaction rates for the deprotonation of the ester and the
homo-Claisen condensation.
(>2 h), indicating that the reaction can be readily scaled out by
simply collecting the crude reaction mixture from the output for
longer periods.
Using t-butyl propionate as substrate for the enolate generation,
various electrophiles were successively fed into the reactor to
3. Conclusion
generate a series of a-functionalized esters (Table 3). The contin-
uous flow reactor was run for several minutes until steady state
conditions were achieved. Then, an aliquot of the crude reaction
mixture was collected from the reactor output for 5 min (2.5 mmol
scale) and processed. In the case of the reaction of t-butyl propio-
nate with methyl formate, the reaction mixture was collected for an
extended period of 17 min. Apart from methyl formate, used as
model for the optimization study (entry 1), alkyl and allyl bromides
We have developed a continuous flow procedure for the
multistep synthesis of
a-functionalized esters. The synthetic
sequence consists of generation of LDA from diisopropylamine and
a commercial nBuLi solution, its reaction with the ester to generate
an unstable lithium enolate, a final addition of the enolate inter-
mediate to an electrophile. Careful control of the temperature for
the key reaction steps has proven to be essential to achieve suitable
conversions and selectivities. Moderate to good isolated product
could be also added to the a-position of the carbonyl group with
good results, yielding derivatives 2 and 3 (entries 2 and 3). Allyl
bromide performed better and a higher conversion was achieved.
Benzyl bromide and chloride were also utilized to generate the
yields were obtained for several a-alkyl esters, after a simple
workup procedure that in some cases consisted of extraction under
acidic conditions.
corresponding a-benzyl ester 4. As expected, the bromide showed a
higher reactivity and full conversion of the substrate was achieved.
Only 46% conversion was obtained with benzyl chloride under the
same reaction conditions (entry 5). Benzophenone (entry 6) ensued
4. Experimental section
4.1. General procedures
the expected b-hydroxy derivative 5 with excellent conversion and
good isolated yield. The workup procedure included acidification of
the aqueous phase in the biphasic mixture obtained from the
output of flow reactor in all cases. The organic phase contained the
product, and the remaining substrate when full conversion was not
achieved. In the latter case purification by column chromatography
was required.
1H NMR spectra were recorded with a Bruker 300 MHz spec-
trometer. 13C NMR spectra were recorded with the same instru-
ment at 75 MHz. Chemical shifts (d) are expressed in ppm
downfield from TMS as internal standard. The letters s, d, t, q, and m
are used to indicate singlet, doublet, triplet, quadruplet, and
multiplet. GC-FID analysis was performed using a HP5 column
Notably, the reactor performed stable for long periods of time
(30 m ꢂ 0.250 mm ꢂ 0.025
m
m). GCeMS spectra were recorded
using a HP5-MS column (30 m ꢂ 0.250 mm ꢂ 0.25
mm) with helium
as a carrier gas (1 mL/min constant flow) coupled with a mass
spectrometer (EI, 70 eV). Sonication was performed using a stan-
dard laboratory ultrasound and the sonication (35 kHz, ultrasonic
peak output ¼ 160 W).
Table 3
Results obtained for reactions of various electrophiles with the in situ generated
lithium t-butyl propionate intermediate.a
Entry
1
Electrophile
Product
Conversionb
Yield
77%c
>99%
4.2. General procedures for the sequential continuous flow
generation of lithium enolates and their reactions with electrophiles
All solutions were prepared in round bottom flasks (RBFs) using
dry solvents and dry glassware. The RBFs were constantly flushed
with argon and sealed with a rubber seal. We used the flow setup
shown in Fig. 2. In the first step LDA was in-situ prepared from a
precooled solution of diisopropylamine (ꢃ99.5%) in THF (HPLC
grade, dried over molecular sieves) (0.50 mL/min, 2.50 M) and a
commercially available n-butyl lithium solution in hexanes
(0.40 mL/min, 2.50 M). The two solutions were combined and
reacted for 2.0 min at 0 ꢁC. A solution of methyl butyrate or tert-
butyl propionate in THF (2.50 mL/min, 0.20 M) was injected via a T-
piece. The deprotonation occurred at 0 ꢁC within 5 s residence time.
The resulting mixture was combined with a cooled feed of the
electrophile dissolved in THF (1.13 mL/min, 1.50 mol/L) and reacted
at ambient temperature for 2.2 min. In case of using methyl formate
as electrophile the reactor was immersed in an ultrasound bath.
The reaction was finally quenched by injecting water (1.50 mL/
min). After the system achieved steady state conditions, the
biphasic mixture was collected from the reactor output for 5 min
(17 min for 1 and 1b) and the workup was performed in batch. Ethyl
acetate (half amount of the collected solution) was added to afford
an efficient phase separation. The separated aqueous layer was
acidified to pH ¼ 2 with aqueous 2.0 M HCl and extracted with
diethyl ether (2 ꢂ ). The combined ether layers were dried over
Na2SO4 and the solvents were removed under reduced pressure.
2
3
71%
55%
65%
>99%
4
5
6
>99%
46%
Br 72%
Cl 29%
80%
>99%
a
Conditions: continuous flow setup and conditions as depicted in Fig. 2 were
used. The reaction mixture was collected for 5 min (2.5 mmol scale).
b
4.2.1. 2-Methyl-3-oxopropanoate tert-butyl ester (1)
Determined by GC-FID peak area integration.
c
The reaction mixture was collected for 17 min.
1.04 g (17 min collection time, 79%) were obtained as a colorless
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T. von Keutz et al. / Tetrahedron xxx (2017) 1e5
5
oil without further purification. Rf ¼ 0.69 (hexane/EtOAc 5:1). 1H
Acknowledgements
NMR (300 MHz, CDCl3): (major ketone tautomer)
d
¼ 9.72 (1H, d,
3J ¼ 1.6 Hz, CHO), 3.28 (1H, qd, J ¼ 7.2, 1.5 Hz, CH), 1.46 (9H, s,
The CC FLOW project (Austrian Research Promotion Agency FFG
No. 862766) is funded through the Austrian COMET Program by the
Austrian Federal Ministry of Transport, Innovation and Technology
(BMVIT), the Austrian Federal Ministry of Science, Research and
Economy (BMWFW) and by the State of Styria (Styrian Funding
Agency SFG).
C(Me)3), 1.27 (3H, d, 3J ¼ 7.2 Hz, Me). 13C NMR (75 MHz, CDCl3):
(major ketone tautomer)
(C(Me)3), 53.5 (CH), 28.0 (C(Me)3), 10.1 (Me). MS-EI: m/z 85 (54%),
d
¼ 197.8 (CHO), 169.0 (COOtBu), 82.2
57 (100%).
4.2.2. 2-Formyl-butyric acid methyl ester (1b)
Appendix A. Supplementary data
311 mg (17 min collection time, 29%) were obtained as a color-
less oil without further purification. Rf ¼ 0.71 (hexane/EtOAc 5:1).
Supplementary data related to this article can be found at
https://doi.org/10.1016/j.tet.2017.11.063.
1H NMR (300 MHz, CDCl3): (major ketone tautomer)
d
¼ 9.72 (1H,
d, 3J ¼ 2.4 Hz, CHO), 3.79 (3H, s, OMe), 3.23 (1H, dt, 3J ¼ 7.1, 2.4 Hz,
CH), 1.94 (2H, dq, 3J ¼ 7.4, 7.2 Hz, CH2), 0.99 (3H, t, 3J ¼ 6.2 Hz,
CH2Me). 13C NMR (75 MHz, CDCl3): (major ketone tautomer)
References
d
¼ 197.4 (CHO), 170.0 (COOMe), 60.0 (CH), 52.3 (OMe), 20.1 (CH2),
1. Braun M. Helv Chim Acta. 2015;98:1e31.
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4.2.3. Methyl-hexanoic acid tert-butyl ester (2)
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CDCl3):
d
¼ 2.34-2-27 (1H, m, CH), 1.68e1.58 (1H, m, CHCH2), 1.45
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€
ꢀ
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d
¼ 176.4 (COOtBu), 79.7 (C(Me)3), 40.4 (CH), 33.6
9. Bakonyi B, Furegati M, Kramer C, La VL, Ossola F.
J Org Chem. 2013;78:
(CHCH2), 29.4 (CH2), 28.1 (C(Me)3), 22.6 (CH2), 17.2 (CHMe), 14.0
9328e9339.
(CH2Me). MS-EI: m/z 131 (8%), 113 (14%), 85 (25%), 57 (100%).
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(a) . In: Darvas F, Hessel V, Dorman G, eds. Flow Chemistry. Berlin: De Gruyter;
2014;
4.2.4. tert-Butyl-2-methylpent-4-enoate (3)
The product was purified by flash column chromatography
(eluent petroleum ether/EtOAc 19:1) yielding 275.9 mg, (65%) as a
colorless oil. Rf ¼ 0.28 (hexane/EtOAc 19:1). 1H NMR (300 MHz,
(b) . In: Reschetilowski W, ed. Microreactors in Preparative Chemistry. Wein-
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(c) . In: Wirth T, ed. Microreactors in Organic Synthesis and Catalysis. second ed.
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(d) . In: Hessel V, Schouten JC, Renken A, Wang Y, Yoshida J-i, eds. Handbook of
Micro Reactors. Weinheim: Wiley-VCH; 2009.
CDCl3):
d
¼ 5.88e5.72 (1H, m, CH¼CH2), 5.09e5.00 (2H, m,
CH¼CH2.), 2.44e2.35 (2H, m, CH2), 2.18e2.14 (1H, m, CH), 1.44 (9H,
s, C(Me)3), 1.11 (3H, d, 3J ¼ 6.8 Hz, Me). 13C NMR (75 MHz, CDCl3):
d
¼ 174.5 (COOtBu),135.8 (CH¼CH2),116.5 (CH¼CH2), 80.0 (C(Me)3),
13. For general reviews on flow chemistry, see: (a) Jensen KF, Reizmana BJ,
Newman SG. Lab Chip. 2014;14:3206e3212;
40.0 (CH), 38.0 (CH2), 28.1 (C(Me)3),16.6 (Me). MS-EI: m/z 114 (27%),
97 (22%), 69 (53%), 57 (100%).
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7502e7519;
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(f) Gutmann B, Cantillo D, Kappe CO. Angew Chem Int Ed. 2015;54:6688e6728.
4.2.5. Methyl-3-phenyl-propionic acid tert-butyl ester (4)
The product was purified by flash column chromatography
(eluent petroleum ether/EtOAc 19:1) yielding 396.5 mg, 1.80 mmol
(72%) as a colorless oil. Rf ¼ 0.29 (hexane/EtOAc 19:1). 1H NMR
14. El-Mansy MF, Kang JY, Lingampally R, Carter RG. Eur
150e157.
J Org Chem. 2016:
15. Guo X, Shen J. Monatsh Chem. 2014;145:657e661.
(300 MHz, CDCl3):
d
¼ 7.18e7.29 (5H, m, Harom.), 2.98 (1H, m, CH),
16. Xin M, Zhang L, Jin Q, et al. Eur J Med Chem. 2016;110:115e125.
17. Harada K, Kubo H, Tomigahara Y, et al. Bioorg Med Chem Lett. 2010;20:
272e275.
18. For reviews on combination of microfluidics with ultrasounds, see: (a) Fer-
nandez Rivas D, Cintas P, Gardeniers HJGE. Chem Commun. 2012;48:
10935e10947;
(b) Fernandez Rivas D, Kuhn S. Top Curr Chem. 2016;374:70.
19. For selected examples on the use of ultrasounds to avoid clogging of contin-
uous flow reactors, see: (a) Noe€l T, Naber JR, Hartman RL, McMullen JP,
Jensen KF, Buchwald SL. Chem Sci. 2011;2:287e290;
2.65 (2H, m, CH2), 1.39 (9H, s, C(Me)3), 1.14 (3H, d, 3J ¼ 6.6 Hz, Me).
13C NMR (75 MHz, CDCl3):
(Carom.), 128.2 (Carom.), 126.1 (Carom.), 80.0 (C(Me)3), 42.3 (CH2), 40.0
(CH), 28.0 (C(Me)3), 17.0 (Me). MS-EI: m/z 164 (35%), 147 (10%), 119
(14%), 91 (100%), 57 (49%).
d
¼ 175.5 (COOtBu), 140.0 (Carom.), 120.0
4.2.6. tert-Butyl-3-hydroxy-2-methyl-3,3-diphenylpropanoate (5)
The crude product was recrystallized from hexane yielding
621.6 mg (80%) as a colorless solid. Mp: 89e91 ꢁC. Rf ¼ 0.44 (hex-
(b) Sedelmeier J, Ley SV, Baxendale IR, Baumann M. Org Lett. 2010;12:
3618e3621;
(c) Cantillo D, Damm M, Dallinger D, Bauser M, Berger M, Kappe CO. Org Process
Res Dev. 2014;18:1360e1366;
(d) Horie T, Sumino M, Tanaka T, Matsushita Y, Ichimura T, Yoshida J-I. Org
Process Res Dev. 2010;14:405e410.
ane/EtOAc 9:1). 1H NMR (300 MHz, CDCl3):
d
¼ 7.63 (2H, d, 3J ¼ 8.3
Hz, Harom.), 7.52 (2H, d, 3J ¼ 8.3 Hz, Harom.), 7.37e7.26 (4H, m,
H
arom.), 7.17e7.22 (2H, m, Harom.), 4.82 (1H, s, OH), 3.59 (1H, q,
20. (a) Das Neves Gomes C, Jacquet O, Villiers C, Thuery P, Ephritikhine M, Cantat T.
Angew Chem Int Ed. 2012;51:187e190;
3J ¼ 7.0 Hz, CH), 1.32 (9H, s, C(Me)3), 1.20 (3H, d, 3J ¼ 7.1 Hz, Me). 13
C
(b) Liu X-F, Ma R, Qiao C, Cao H, He L-N. Chem Eur J. 2016;22:16489e16493;
(c) Fang C, Lu C, Liu M, Zhu Y, Fu Y, Lin B-L. ACS Catal. 2016;6:7876e7881;
(d) Jens CM, Nowakowski K, Scheffczyk J, Leonhard K, Bardow A. Green Chem.
2016;18:5621e5629;
NMR (75 MHz, CDCl3):
d
¼ 176.7 (COOtBu), 147.7 (Carom.), 144.3
(Carom.), 128.1 (Carom.), 126.8 (Carom.), 126.5 (Carom.), 125.6 (Carom.),
125.4 (Carom.), 81.7 (COH), 78.1 (C(Me)3), 47.7 (CH), 27.8 (C(Me)3),
12.7 (Me). MS-EI: m/z 296 (28%), 295 (100%), 239 (58%).
(e) Frogneux X, Jacquet O, Cantat T. Catal Sci Technol. 2014;4:1529e1533.
Please cite this article in press as: von Keutz T, et al., Continuous flow multistep synthesis of a-functionalized esters via lithium enolate
intermediates, Tetrahedron (2017), https://doi.org/10.1016/j.tet.2017.11.063