Continuous Flow Sodiation of Substituted Acrylonitriles, Alkenyl Sulfides and Acrylates

Article abstract of DOI:10.1002/anie.202012085

The sodiation of substituted acrylonitriles and alkenyl sulfides in a continuous flow set-up using NaDA (sodium diisopropylamide) in EtNMe₂ or NaTMP (sodium 2,2,6,6-tetramethylpiperidide)?TMEDA in n-hexane provides sodiated acrylonitriles and alkenyl sulfides, which are subsequently trapped in batch with various electrophiles such as aldehydes, ketones, disulfides and allylic bromides affording functionalized acrylonitriles and alkenyl sulfides. This flow-procedure was successfully extended to other acrylates by using Barbier-type conditions.

Full text of DOI:10.1002/anie.202012085

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Accepted Article
Title: Continuous Flow Sodiation of Substituted Acrylonitriles, Alkenyl
Sulfides and Acrylates
Authors: Johannes H. Harenberg, Niels Weidmann, Konstantin
Karaghiosoff, and Paul Knochel
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Continuous Flow Sodiation of Substituted Acrylonitriles, Alkenyl
Sulfides and Acrylates
Johannes H. Harenberg,+,[a] Niels Weidmann,+,[a] Konstantin Karaghiosoff,[a] and Paul Knochel*[a]
Dedication
[a]
N. Weidmann, J. H. Harenberg,
Prof. Dr. K. Karaghiosoff, Prof. Dr. P. Knochel,
Department Chemie
Ludwig-Maximilians-Universität München
Butenandtstrasse 5-13, Haus F, 81377 München (Germany)
paul.knochel@cup.uni-muenchen.de
These authors contributed equally.
+
Supporting information for this article is given via a link at the end of the document.
Abstract: The sodiation of substituted acrylonitriles and alkenyl
sulfides in continuous flow set-up using NaDA (sodium
Table 1. Sodiation of cinnamonitrile (1a) using a microflow reactor and
subsequent batch quench of the intermediate sodium organometallic 2a with
various electrophiles of type 3 leading to functionalized cinnamonitriles of type 4.
a
diisopropylamide) in EtNMe2 or NaTMP (sodium 2,2,6,6-
tetramethylpiperidide)∙TMEDA in n-hexane provides sodiated
acrylonitriles and alkenyl sulfides, which are subsequently trapped in
batch with various electrophiles such as aldehydes, ketones,
disulfides and allylic bromides affording functionalized acrylonitriles
and alkenyl sulfides. This flow-procedure was successfully extended
to other acrylates by using Barbier-type conditions.
The metalation of unsaturated nitriles and sulfides is an
important synthetic procedure.[1] After quenching with various
electrophiles, highly functionalized unsaturated products are
obtained, which may be useful building blocks for biologically
active heterocycles and natural products.[2] The batch-metalation
of alkenyl nitriles or sulfides with lithium bases is often
complicated due to competitive allylic lithiations.[3] The use of
stronger, more polar bases like sodium or potassium amides may
avoid such limitations. However, the sodiation of such
unsaturated compounds is much less explored.[4] Moreover, the
use of sodium organometallics is of high interest due to the low
price, high abundancy and low toxicity of sodium salts.[5] Recently,
arylsodium compounds have been prepared by Collum using
NaDA (sodium diisopropylamide) as deprotonating agent[6] and by
Asako and Takai, who have investigated the utility of arylsodiums
in catalytic cross-couplings.[7] Yoshida, Ley, Organ and others
have demonstrated a high functional group tolerance performing
challenging metalations in a continuous flow set-up.[8] Based on
these studies, we have extended the Collum procedure to the
preparation of sodiated aryl and heteroaryl derivatives which are
difficult to generate otherwise and decompose upon batch-
entry electrophile
product[a]
entry electrophile
product[a]
nBu2S2
1
2
3a
3b
4aa: 95%, Z/E>99/1[b]
6
7
3f
4af: 93%, Z/E=54/46
4ab: 92%, Z/E>99/1[b]
3g
4ag: 82%, E/Z>99/1[c]
4ac: 74%,
4ah: 82%, E/Z>99/1
d.r.>99/1[c]
3
3c
3d
8
9
3h
Z/E=89/11[b]
4
5
4ad: 93%, Z/E>99/1[c]
3i
3j
4ai: 78%, E/Z>99/1[b]
4aj: 87%, E/Z>99/1[b]
sodiation.[9]
KDA ∙ TMEDA
(potassium diisopropylamide ∙
3e[d]
4ae: 93%, E/Z=9/1[b] 10
N,N,N′,N′- tetramethylethylenediamine) in n-hexane was used in
continuous flow for similar metalations.[10] Herein, we wish to
[a]
[b]
Yield of analytically pure product.
The E- or Z- diastereoselectivity was
assigned in analogy to related products, for which X-ray data were obtained. [c] The
diastereoselectivity was determined by crystal structure analyses, see SI.
[d] 10 mol% CuCN∙2LiCl.
report that NaDA and NaTMP (TMPH
=
2,2,6,6-
tetramethylpiperidine) were efficient bases for the regioselective
flow-metalation of various substituted acrylonitriles and alkenyl
sulfides.[11] In first experiments, we have optimized the sodiation
of cinnamonitrile (1a) and have found that metalation with NaDA
(0.24 M in DMEA (dimethylethylamine), 1.2 equiv) at −78 °C using
a combined flow-rate of 10 mL/min and a 0.02 mL reactor
proceeded best with a residence time of 0.12 s affording organo-
sodium 2a. Subsequent trapping with electrophiles of type 3 such
as aldehydes, ketones, disulfides and allylic bromides afforded 2-
substituted cinnamonitriles of type 4 with usually high E/Z ratios
(Table 1, entries 1-10). Thus, for a quenching with aromatic
aldehydes, we obtained the Z-product of type 4 as major product,
1
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whereas for more sterically hindered ketones the E-product was
formed.
Table 2. Sodiation of substituted acrylonitriles and alkenyl sulfides of type 5
using a microflow reactor and subsequent batch quench of the intermediate
sodium organometallics of type 6 with various electrophiles of type 3 leading to
functionalized phenylacrylonitriles and alkenyl sulfides of type 7.
The diastereoselectivity of products of type 4 obtained after the
addition to a carbonyl electrophile was tentatively explained by
assuming that the sodiated nitrile 2a reacted fast with an aldehyde
(RCHO) according to pathway A leading to the allylic alcohol Z-4.
In contrast, by using ketones, an equilibration to the cummulene
form 2a’ may occur and the cyclic transition state A would be
disfavoured due to steric hindrance. E/Z isomerization of the
cummulene structure 2a’ occurred affording the E-4 product via
transition state B (Scheme 1).
entry
SM
product[a]
entry
SM
product[a]
1
5a
7ak: 97%[b]
Z/E=89/11
5f
7fn: 93%[c]
Z/E>99/1
7
8
E/Z=76/24
E/Z=83/17
2
5b
7bk: 84%[c]
Z/E=90/10
5f
7fd: 98%[c]
Z/E>99/1
E/Z=79/21
E/Z=83/17
Scheme 1. Tentative mechanism for the stereoselective addition of sodiated
phenylacrylonitrile 2a’ to aldehydes or ketones.
We have then extended this flow procedure to various
functionalized arylacrylonitriles of type 5.
Electron-rich
3
5c
7cl: 74%[b]
Z/E>99/1
5g
7gc: 95%[c]
Z/E>99/1
cinnamonitrile derivatives (5a-5d) were selectively metalated in 2-
position using NaDA in a continuous flow set-up within 0.12 s at
−78 °C. The resulting organosodiums (6a-d) were trapped in
batch with various carbonyl electrophiles, such as m-
anisaldehyde (3k), cyclohexanecarboxaldehyde (3l) or
cyclohexanone (3m), and with 3-bromocyclohexene (3e) using
10 mol% CuCN·2LiCl as catalyst, affording the desired alcohols
(7ak, 7bk, 7cl and 7dm) and an allylated cinnamonitrile derivative
(7de) in 57-97% yield with diastereomeric ratios up to >99/1
(Table 2, entries 1-5). Similarly, regioselective sodiation of
electron-deficient 3-(4-(trifluoromethyl)phenyl)acrylonitrile (5e)
followed by copper-catalyzed allylation with 3-bromocyclohexene
(3e) led to the functionalized phenylacrylonitrile (7ee) in 66% yield
with an E/Z ratio >99/1. Furthermore, an extension to methoxy-
and ethoxyacrylonitriles 5f and 5g was possible resulting in
secondary alcohols (7fn, 7fd, 7gc and 7gl) after batch-quench
with aromatic aldehydes (3c, 3d and 3n), and aliphatic aldehyde
(3l) in 91-98% and Z/E ratios >99/1 (entries 7-10). An alkenyl
sulfide such as phenyl(styryl)sulfane (5h) provided the sodium
derivative (6h) upon metalation with NaDA, which after trapping
with sterically demanding ketones such as adamantanone (3o)
and benzophenone (3g) gave tertiary alcohols (7ho and 7hg) in
85-95% yield and comparable E/Z ratios to the starting material
5h (entries 11-12).
9
E/Z=83/17
E/Z=68/32
4
5
5d
7dm: 67%[c]
E/Z>99/1
5g
7gl: 91%[b]
Z/E>99/1
10
11
12
E/Z=79/21
E/Z=68/32
5d[d]
E/Z=79/21
7de: 57%[b]
E/Z>99/1
5h
7ho: 95%[c]
E/Z=77/23
E/Z=71/29
6
5e[d]
E/Z=78/22
Yield of analytically pure product.
assigned in analogy to related products, for which X-ray data were obtained. [c] The
diastereoselectivity was determined by crystal structure analyses, see SI.
[d] 10 mol% CuCN·2LiCl.
7ee: 66%[c]
E/Z>99/1
5h
7hg: 85%[b]
E/Z=68/32
E/Z=71/29
The E- or Z- diastereoselectivity was
[a]
[b]
Extension to alkyl-substituted acrylonitriles such as geranylnitrile
(8a, E/Z=50/50) and the related nitrile 8b (E/Z=65/35) was
possible under the standard sodiation conditions providing after
electrophilic quench the desired functionalized nitriles (10ap, 10al,
10aq, 10br) in 60-98% yield as E/Z mixtures (Table 3, entries 1-
4). Interestingly, starting from the diastereomerically pure
2
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acrylonitrile 8c (E/Z>99/1) the desired product 10cq was obtained
in 67% yield (Z/E=58/42) after quench with α-tetralone (3q) (entry
5) showing the prevalence of the cumulene structure of the
sodiated nitriles (see 2a in Table 1). However, the methoxy-
substituted acrylonitrile 8d (E/Z=80/20) afforded after continuous
flow sodiation and quenching with o-anisaldehyde (3k) the allylic
alcohol 10dk as single diastereoisomer in 58% yield (Z/E>99/1)
showing the importance of the methoxy group for controlling the
stereochemistry of the intermediate sodiated nitrile (entry 6). Also,
the dienylnitrile 8e was sodiated in flow and trapping with an allylic
bromide (3e) or an aldehyde (3k) furnished the functionalized
dienylnitriles (10ee and 10ek) in 74-82% yield (entries 7-8).
method more practical. Using the Takai procedure, we have
prepared hexane-soluble NaTMP∙TMEDA[13] and have performed
an efficient continuous flow sodiation of cinnamonitrile (1a)
selectively in 2-position within 0.12 s at −78 °C. A subsequent
batch trapping of 2a’ with various ketones of type 3 afforded the
desired tertiary alcohols of type 4 in 58-83% yield as single
regioisomers (Scheme 2). Similarly, ethoxyacrylonitrile 5g gave,
after batch quench with o-anisaldehyde (3k) and benzophenone
(3g), the allylic alcohols (7gk and 7gg) in 65-78% yield (Z/E>99/1).
Further, geranylnitrile (8a) provided the organosodium 9a upon
metalation with NaTMP∙TMEDA, which after a copper-catalyzed
allylation using 3-bromocyclohexene (3e) led to the desired
product (10ae) in 54% yield with a E/Z ratio of 52/48.
Table 3. Sodiation of alkyl- and alkenyl-substituted acrylonitriles of type 8 using
a microflow reactor and subsequent batch quench of the intermediate sodium
organometallics of type 9 with various electrophiles of type 3 leading to
functionalized alkyl- and alkenyl-substituted acrylonitriles of type 10.
Scheme 2. General set-up for the sodiation of functionalized acrylonitriles with
NaTMP∙TMEDA in a microflow reactor and subsequent batch quench of the
intermediate sodium organometallics with various electrophiles leading to
functionalized acrylonitriles.
entry
substrate
electrophile
product[a]
I2
1
8a, E/Z=50/50
3p
10ap: 75%, Z/E=68/32
2
3
4
5
8a, E/Z=50/50
8a, E/Z=50/50
8b, E/Z=65/35
8c, E/Z>99/1
3l
3q
3r
10al: 60%, Z/E=64/36
10aq: 98%, Z/E=53/47
10br: 85%, Z/E=55/45
10cq: 67%, Z/E=58/42
However, the sodiation of other acrylates still remained
challenging. Applying our standard sodiation method to ethyl
cinnamate (11a) afforded solely the condensation product 13a
showing that the sodiation of 11a was possible, but difficult to
control. Thus, the intermediate organosodium 12a reacted
instantaneously with another molecule of 11a before the desired
electrophile quench proceeded (Scheme 3a). To prevent this self-
condensation reaction, sterically hindered tert-butyl cinnamate
(11b) was used affording organosodium 12b after continuous flow
3q
6
7
8d, E/Z=80/20
3k
10dk: 58%, Z/E>99/1
sodiation.
A
copper-catalyzed batch allylation with 3-
bromocyclohexene (3e) gave the desired product 13be in 61%
yield with an E/Z ratio >99/1 (Scheme 3b). To overcome the need
of sterically hindered esters, we envisioned a Barbier-type in situ
trapping[14] of the highly reactive organosodiums of type 12.
Interestingly, ethyl cinnamate (11a), which underwent self-
condensation side reactions applying our standard flow conditions
(Scheme 3a), was sodiated at −78 °C under Barbier-conditions
and afforded organosodium 12a, which was instantaneously
trapped by adamantanone (3o), outcompeting self-condensation
and resulting in the tertiary alcohol 13ao in 66% yield (E/Z >99/1).
Similarly, methyl-3-methoxyacrylate (11c) was sodiated in 3-
position in the presence of adamantanone (3o) using NaDA (1.2
equiv) affording the spirolactone 13co in 58% yield (Scheme 3c).
8e, 2E/2Z=69/31
3e[b]
10ee: 74%, 2E/2Z=77/23
8
8e, 2E/2Z=69/31
[a] Yield of analytically pure product. [b] 10 mol% CuCN·2LiCl.
3k
10ek: 82%. 2Z/2E=76/24
Recently, Takai and Asako published a straightforward
synthesis of lithium-free sodium 2,2,6,6-tetramethylpiperidide
(NaTMP) in n-hexane by using sodium dispersion, TMPH,
TMEDA and isoprene.[12] This method would allow us to avoid the
use of the amine DMEA as solvent and therefore making our
3
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Scheme 3. Sodiation of substituted acrylates of type 11 using a microflow
reactor under standard-flow conditions and Barbier conditions. In situ quench of
the intermediate sodium organometallics of type 12 with adamantanone (3o)
afforded functionalized acrylates of type 13.
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In summary, we have reported the sodiation of substituted
acrylonitriles and alkenyl sulfides in a continuous flow set-up
using NaDA (sodium diisopropylamide) in EtNMe2 (DMEA) and
NaTMP (sodium 2,2,6,6-tetramethylpiperidide) ∙ TMEDA in n-
hexane. The resulting sodiated acrylonitriles and alkenyl sulfides
were subsequently trapped in batch with various electrophiles
such as aldehydes, ketones, disulfides and allylic bromides
affording functionalized acrylonitriles and alkenyl sulfides. This
flow-procedure was successfully extended to other acrylates by
using Barbier-type conditions.
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Acknowledgements
[10] J. H. Harenberg, N. Weidmann, P. Knochel, Angew. Chem. Int. Ed. 2020,
59, 12321; Angew. Chem. 2020, 132, 12419.
N. Weidmann thanks the German Academic Scholarship
Foundation for a fellowship. We thank the DFG and LMU for
financial support. We further thank BASF (Ludwigshafen) and
Albemarle (Frankfurt) for the generous gift of chemicals and
Uniqsis for technical support.
[11] Commercially available equipment from Uniqsis was used. For a detailed
optimization, see SI.
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Keywords: flow chemistry • sodiation • acrylonitriles • alkenyl
sulfides • Barbier-type reactions
[13] For the synthesis of NaTMP∙TMEDA, see SI.
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4
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Entry for the Table of Contents
Sodium in Flow: A sodiation of substituted acrylonitriles and alkenyl sulfides with NaDA or NaTMP∙TMEDA was performed using a
commercial continuous flow set-up leading to the corresponding organosodiums. Trapping with various electrophiles afforded
functionalized acrylonitriles and alkenyl sulfides. This flow-procedure was successfully extended to other acrylates by using Barbier-
type conditions.
Institute and/or researcher Twitter usernames: @KnochelLab
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