Continuous Flow Magnesiation or Zincation of Acrylonitriles, Acrylates, and Nitroolefins. Application to the Synthesis of Butenolides

Article abstract of DOI:10.1021/acs.orglett.6b00086

Scalable continuous flow procedures are reported for the metalation and downstream functionalization of β-substituted acrylates. The flow conditions allow the metalation of acrylonitriles, acrylates, and nitroolefins at 0.25-2.50 mmol/min conversion rates. Magnesiations can be performed with short residence times (1-20 min) and near-ambient temperature using TMPMgCl·LiCl. Further, high temperature zincation (≤90°C) using TMPZnCl·LiCl is possible. This method allows a simple entry to 2(5H)-furanones by flow generation of magnesiated acrylates and a subsequent reaction with aldehydes. (Chemical Equation Presented).

Full text of DOI:10.1021/acs.orglett.6b00086

Letter
pubs.acs.org/OrgLett
Continuous Flow Magnesiation or Zincation of Acrylonitriles,
Acrylates, and Nitroolefins. Application to the Synthesis of
Butenolides
Maximilian A. Ganiek, Matthias R. Becker, Marthe Ketels, and Paul Knochel*
Department of Chemistry, Ludwig-Maximilians-Universitat, Butenandtstr. 5-13, 81377 Munich, Germany
̈
S
* Supporting Information
ABSTRACT: Scalable continuous flow procedures are reported
for the metalation and downstream functionalization of β-
substituted acrylates. The flow conditions allow the metalation
of acrylonitriles, acrylates, and nitroolefins at 0.25−2.50 mmol/
min conversion rates. Magnesiations can be performed with
short residence times (1−20 min) and near-ambient temper-
ature using TMPMgCl·LiCl. Further, high temperature
zincation (≤90 °C) using TMPZnCl·LiCl is possible. This
method allows a simple entry to 2(5H)-furanones by flow
generation of magnesiated acrylates and a subsequent reaction
with aldehydes.
Scheme 1. Zincation and Allylation of 3-Ethoxy-acrylonitrile
(3a) in Continuous Flow
he directed metalation of α,β-unsaturated carbonyl
Tderivatives is an important reaction since, after quenching
with various electrophiles, highly functionalized unsaturated
products are obtained.1 These compounds are useful building
blocks for the synthesis of natural products and heterocycles,2
many of which are biologically relevant, such as tetronic acids.3
The lithiation of acrylate derivatives and nitroolefins is often
complicated by polymerization and side reactions.4 Hence, such
lithiations are usually carried out at low reaction temperatures
(−78 or −110 °C).1a,4 The use of kinetically highly active bases
such as TMPZnCl·LiCl5 (1, TMPH = 2,2,6,6-tetramethyl-
piperidine), TMP2Zn·2MgCl2·2LiCl,6 or zincate bases7 im-
proves the stability of the organometallic intermediates but still
requires low metalation temperatures.8 The conduction of
reactions under flow conditions often improves yields and
selectivities.9 Previously we have shown that continuous flow
technology also dramatically improves metalation reactions.10
Herein, we wish to report the use of TMPZnCl·LiCl5 (1) and
TMPMgCl·LiCl (2)11 for the flow metalation and functional-
ization of various acrylates, acrylonitriles, and nitroolefins
leading to, after quenching with various electrophiles, polyfunc-
tional unsaturated products.
Our initial studies focused on the flow metalation of
acrylonitriles and nitroolefins, which are notoriously known
to polymerize under basic conditions. For instance, we found
that 3-ethoxy-acrylonitrile (3a, E:Z = 2:1) was smoothly
zincated at the α-position with TMPZnCl·LiCl (1) at 40 °C
within 10 min in a flow apparatus12 (Scheme 1). After an in-line
quench with allyl bromide in the presence of a copper catalyst
(10% CuCN·2LiCl),13 the expected product 4a (E:Z = 2:1) is
obtained in 78% isolated yield. In contrast, a reported batch
synthesis of 4a using LDA for the metalation requires a −110
°C temperature for the lithiation and −110 to −50 °C for the
subsequent allylation.14
This zincation procedure has a broad scope (Table 1). Thus,
allylation of zincated 3a with 3-bromo-1-cyclohexene or Pd(0)-
catalyzed Negishi cross-coupling15−17 with 4-iodoanisole gave
the expected products (4b−c) in 92−96% yield (entries 1−2).
Furthermore, E-cinnamonitrile (3b) reacts smoothly with
TMPZnCl·LiCl (1) at 90 °C18 within 10 min, and after
allylation the cinnamonitrile 4d is obtained in 75% yield (entry
3). Repeating the allylation reaction on a 10 mmol scale does
not require any reaction condition changes19 and furnishes 4d
in an improved yield of 83% after a ca. 35 min reaction time
and purification. Negishi cross-coupling15,17 of α-zincated 3b
with 4-iodoanisole proceeds in flow within 25 min at 60 °C
leading to the cinnamonitrile 4e (99%, E:Z = 8:1, entry 4).
Furthermore, quenching of zincated 3b with benzaldehyde (10
min, 70 °C) produces the allylic alcohol in 63% as the single E-
Received: January 13, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b00086
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Organic Letters
Letter
Table 1. Flow Zincation of Acrylonitriles and Nitroolefins
(3) with TMPZnCl·LiCl (1) and in-Line Quenching with
Electrophiles Leading to α-Functionalized Products (4)
Table 2. Flow Magnesiation of Acrylate Substrates (5) with
TMPMgCl·LiCl (2) Followed by in-Line Allylation and
Acylation Leading to β-Functionalized Products (6)
a
Yield of isolated product after column chromatographical purification.
b
c
Obtained by a Cu-catalyzed allylation.13 Obtained by a Cu-catalyzed
or Cu-mediated acylation.13 15 mmol scale. Yield based on the
d
e
amount of electrophile used.
Scheme 2. Flow Synthesis of Furan-5H-one (7a) from
Acrylate (5e)
a
Yield of isolated product after column chromatographical purification.
b
c
Obtained by a Cu-catalyzed allylation.13 Obtained using 2 mol %
[Pd(dba)2] and 4 mol % P(2-furyl)3.15 Obtained by adding 10 mol %
d
TMSCl to PhCHO. Obtained by a Cu-catalyzed acylation.13 Yield on
e
f
g
a 10 mmol scale. Yield based on the amount of electrophile used.
stereoisomer (entry 5). The α-zincation of nitroolefins typically
required temperatures from −50 to 0 °C under batch
conditions.8 We found that the zincation of nitroolefins 3c−d
proceeds under continuous flow conditions at 0−25 °C and
leads to new α-functionalized nitroolefins (4g−i) after in-line
allylation or acylation (entries 6−8).
Acrylic esters require stronger bases such as TMPMgCl·LiCl
(2) in order to undergo efficient metalation.8 Thus, β-
magnesiation occurs readily without notable isomerization,
polymerization, or attack of the ester if short flow residence
times and temperatures between 10 and 50 °C (Table 2, entries
1−5) were used. For instance, β-(2-furyl) acrylate (5a) is
cleanly β-magnesiated at 10 °C within 5 min despite the
presence of several acidic protons (on the furan ring11a). The
thiophene analog (5d) in contrast required lower temperatures
(≤20 °C) to suppress metalation of the heteroaromatic moiety.
The resulting low conversion of 5d at such low temperatures
could not be increased with longer residence times (5 or 15
min). However, increased flow rates20 (5 mL/min during
mixing and metalation) triggered high conversion of 5d and the
desired allylated product 6f was obtained in 72% yield in the
presence of 5% CuCN·2LiCl13 (entry 6).
To broaden the scope of the flow metalation/quenching
sequence, we have investigated acylations of magnesiated
acrylates with acid chlorides (entries 1−5). Remarkably, after
optimization of the flow reaction conditions (temperature, flow
rate, residence time, and catalyst loading) the preparation of
highly electrophilic Michael acceptors such as 6a−e was
performed without substantial polymerization. Thus, the flow
rates chosen for the benzoylation of 5c allow the production of
ca. 1 mmol of product (6d) per min (entry 4). Running the
benzoylation of 5c for 15 min gives 15 mmol of enone ester 6d
in 99% yield after isolation, confirming the good scalability19 of
this method. Interestingly, the acylation of magnesiated 5c with
methacrylol chloride allows the synthesis of the methyl ester of
B
DOI: 10.1021/acs.orglett.6b00086
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 3. Synthesis of Butenolides (7) by Magnesiation of
Acrylates (5) and Quenching with Aldehydes in Flow
Scheme 3. Synthesis of 3,4,5-substituted Butenolides (8) by
Continuous Flow Metalation of the 3-Position
example, E-ethyl 2-dimethylamino acrylate (5e) is quantita-
tively magnesiated with TMPMgCl·LiCl (2) at room temper-
ature within 10 min in continuous flow (Scheme 2).
In-line quenching with benzaldehyde leads to butenolide 7a
(85−91%) after lactonization (Scheme 2). This butenolide
synthesis has a broad scope, and a range of furan-2(5H)-ones
(7b−m) have been prepared in an analogous manner in 61−
98% yield (Table 3). Electron-poor and -rich aromatic
aldehydes (entries 1−2; 4−5), as well as α,β-unsaturated
(entry 8), benzylic (entry 9), or aliphatic aldehydes (entries 3,
10, 12) were used as electrophiles. Scaling up of the reactions
leading to 7h and 7l to 10 mmol (entries 7 and 11) proceeded
without loss of yield after reaction times of 4 min (7h) and 40
min (7l). Since furan-2(5H)-ones with substituents in the 3-
position are occurring in bioactive molecules,3 we have further
developed flow metalations of butenolides 7 (Scheme 3) in this
position. Thus, the high temperature zincation (70 °C, 5 min)
of butenolide 7h using TMPZnCl·LiCl (1) leads to bisarylic
tetronates 8a and 8c in 59−87% yield after cross-coupling15,16
with the corresponding aryl iodides (Scheme 3). Furthermore,
magnesiation (50 °C, 10 min) of 7a was achieved with
TMPMgCl·LiCl (2), leading to the corresponding 3,4,5-
substituted butenolide (8b) after Cu(I)-catalyzed allylation13
in 65% yield. This method offers novel substitution patterns
under mild and practical conditions and employs easily
accessible starting materials.
In summary, we have demonstrated a practical flow
magnesiation and zincation of acrylate derivatives allowing
the synthesis of highly substituted unsaturated molecules and
butenolides of potential biological relevance. Despite the
sensitive nature of some intermediates, flow technology enables
the use of high temperatures without the production of
extensive amounts of side products. The scale-up of these
reactions is achieved without any further optimization by
running the flow reactions for longer time periods. In some
cases, a beneficial effect of working at high flow rates (≥5 mL/
min)20 was noted. Further extensions to the flow metalation of
sensitive substrates are currently being investigated in our
laboratories.
a
Yield of isolated product after column chromatographical purification.
b
Quenching with the electrophile was performed at 25 °C. Yield on a
10 mmol scale. Yield based on the amount of electrophile used.
c
penicillic acid21 in 63% yield (entry 5). Applying fast flow rates
(5 mL/min) during the acylation suppressed in this case side
reactions to an acceptable extent.20
Many butenolides are biologically active,3 and their synthesis
by the addition of β-metalated acrylates to aldehydes is well-
known.1a,2a,4b−d Whereas β-lithiated acrylates often give low
yields upon addition to an aldehyde,4b,c their β-magnesiated
counterparts react smoothly to the desired products.8 For
C
DOI: 10.1021/acs.orglett.6b00086
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Organic Letters
Letter
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b00086.
■
S
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Detailed experimental procedures and characterization
data for new compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: paul.knochel@cup.uni-muenchen.de.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the DFG (SFB 749 and DIP) for financial support.
We thank Vapourtec Ltd. for helpful technical support and
Rockwood Lithium GmbH (Frankfurt), BASF AG (Ludwig-
shafen) for the generous gift of chemicals. M.K. would like to
thank the Foundation of the German Economy for financial
support.
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DOI: 10.1021/acs.orglett.6b00086
Org. Lett. XXXX, XXX, XXX−XXX