Sequential Palladium-Catalyzed Allylic Alkylation/retro-Dieckmann Fragmentation Strategy for the Synthesis of α-Substituted Acrylonitriles

Article abstract of DOI:10.1021/acs.orglett.9b03522

A straightforward synthesis of α-substituted acrylonitriles is described using 4-cyano-3-oxotetrahydro-thiophene (c-THT) as an acrylonitrile surrogate. This unprecedented two-step sequence featuring a palladium-catalyzed allylic alkylation (Pd-AA) and a retro-Dieckmann fragmentation provides a general entry into diversely substituted 1,4-dienes.

Full text of DOI:10.1021/acs.orglett.9b03522

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Sequential Palladium-Catalyzed Allylic Alkylation/retro-Dieckmann
Fragmentation Strategy for the Synthesis of α‑Substituted
Acrylonitriles
Tania Katsina,† Sachi Prem Sharma,† Roberto Buccafusca,† Derek J. Quinn,‡ Thomas S. Moody,‡,§
and Stellios Arseniyadis*,†
†Queen Mary University of London, School of Biological and Chemical Sciences, Mile End Road, London E1 4NS, U.K.
‡Almac Sciences, Department of Biocatalysis and Isotope Chemistry, Almac House, 20 Seagoe Industrial Estate, Craigavon BT63
5QD, Northern Ireland, U.K.
§Arran Chemical Company Limited, Unit 1 Monksland Industrial Estate, Athlone, Co. Roscommon, Ireland
S
* Supporting Information
ABSTRACT: A straightforward synthesis of α-substituted
acrylonitriles is described using 4-cyano-3-oxotetrahydro-thio-
phene (c-THT) as an acrylonitrile surrogate. This unprece-
dented two-step sequence featuring a palladium-catalyzed allylic
alkylation (Pd-AA) and a retro-Dieckmann fragmentation
provides a general entry into diversely substituted 1,4-dienes.
ubstituted acrylonitriles are valuable building blocks in
Ssynthetic organic chemistry. These double-headed war-
heads can indeed be engaged in a number of synthetic
transformations; the nitrile moiety being a well-known
precursor for other functional groups such as amines, acids,
aldehydes, and alcohols,1 while the alkene moiety can be
involved in a variety of transformations including 1,4-
additions,2−5 Diels−Alder cycloadditions,6 the Stetter reac-
tion,7 cross-couplings,8−10 and cross-metatheses11−13 just to
name a few. Their use in material sciences and polymer
chemistry is also unique; acrylonitrile remains one of the most
useful monomers in the synthesis of plastics, acrylic fibers, and
polyacrylonitrile.14 Finally, the acrylonitrile motif can be found
Figure 1. Use of 4-cyano-3-oxotetrahydrothiophene (c-THT, 1) as an
acrylonitrile surrogate for the synthesis of α-substituted acrylonitriles.
in a number of biologically active and structurally intriguing
natural products such as calyculin A, benthocyanin C,
ambiguinine G, cyanopuupehenone, or the tannins aleurinin
scalable route to α-substituted acrylonitriles imbedded within a
A and B.15,16 Interestingly, however, despite the plethora of
1,4-diene scaffold.
applications, the methods allowing direct access to substituted
We initiated our study by optimizing the Pd-catalyzed allylic
acrylonitriles, particularly α-substituted acrylonitriles, remain
alkylation of 4-cyano-3-oxotetrahydrothiophene 1 using
rather scarce. Indeed, apart from the traditional syntheses
cinnamyl acetate 2a as a model electrophilic allyl donor. The
results are depicted in Table 1. A rapid screening of the
reaction conditions (solvent and base) showed that running
the reaction in THF at rt using 5 mol % of Pd(PPh4)3 and 1
equiv of K2CO3 led to a very satisfying 87% yield (Table 1,
entries 1−10). Interestingly, the yield could be further
improved by simply running the reaction in the absence of
base under otherwise identical conditions (90%, Table 1, entry
11).
employing hazardous hydrogen cyanide17 or cyanogen halide
as a cyanate source,18 only a few efficient methods have been
reported, and they usually rely on the cyanation of
alkynes.19−21
With the aim of developing an alternative approach, we
envisaged to tame the singular reactivity of 4-cyano-3-
oxotetrahydrothiophene (c-THT, 1) as an acrylonitrile
surrogate22 by subjecting it to a sequential palladium-catalyzed
allylic alkylation23/retro-Dieckmann fragmentation (Figure
1).22,24 Indeed, we envisioned that this two-step sequence
would allow a straightforward, highly versatile and potentially
Received: October 4, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b03522
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Letter
a
Table 1. Systematic study
Table 2. Scope of the Method with Various Linear Allyl
Acetates
a
b
Entry
Solvent
Base
Yield (%)
1
2
3
4
5
6
7
8
toluene
CH3CN
CH2Cl2
Et2O
DMF
THF
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
NEt3
80
80
83
76
70
87
82
-
THF
THF
DBU
9
10
11
THF
THF
THF
Li2CO3
NaOAc
-
76
86
90
a
All reactions were run on a 0.3 mmol scale using 1 equiv of
b
cynammyl acetate and 5 mol % of Pd(PPh3)4. Isolated yield.
With these optimal conditions in hand [Pd(PPh4)3 (5 mol
%), THF, rt], we rapidly aimed at evaluating the efficacy of this
palladium-catalyzed allylic alkylation on a broad range of linear
allyl acetates;25,26 the results are depicted in Table 2.
Overall, the reaction appeared to be quite general. Indeed,
with the exception of the para-nitro-substituted allyl acetate
(2j), which only afforded the desired product in a moderate
55% isolated yield, the use of para-substituted cinnamyl
acetates led to the corresponding allylated products 3d and
3g−k in good to excellent yields ranging from 64% to 90%
(Table 2, entries 1−7). In the case of the ortho- and meta-
substituted cinnamyl acetates 2b−c and 2e−f, good to
excellent yields were obtained; however, a slightly lower
reactivity was observed in the case of the ortho- and meta-
bromo substituted derivatives (66% and 57%, respectively).
Finally, the allylated products resulting from the naphthalene
(3l, 78%), the furan (3m, 85%), and the thiophene (3n, 69%)
precursors were obtained in good yields, whereas the use of cis-
1,4-diacetoxy-2-butene (2o) afforded the corresponding
allylated product 3o in only 33% isolated yield.
As the allylation step showed great promise, we next
evaluated the key retro-Dieckmann fragmentation, which
would ultimately unveil the α-substituted acrylonitrile moiety.
After screening various conditions, we rapidly discovered that
exposing the C-allylated products to a 10% aqueous solution of
NaOH at rt led to the best results. The retro-Dieckmann
conditions were therefore applied to all the allylated products
previously synthesized (3a−o). As a general trend, all the
reactions afforded the desired α-substituted acrylonitrile in
high yields independently of the substitution pattern on the
olefin. Hence, with the exception of the ortho- and para-methyl
substituted precursors 3b and 3c, which only afforded the
corresponding 1,4-dienes 4b and 4c in 28% and 35% yield,
respectively, all the other substrates were isolated in good to
excellent yields ranging from 60% to 91% (Table 2, entries 1−
7). This was also the case with the naphthalene (4l), the furan
(4m), and the thiophene (4n) derivatives, which were isolated
in 85%, 55%, and 83% yield, respectively. In the case of the
allyl acetate precursor 3o, the reaction logically provided the
corresponding 1,4-diene 4o with concomitant hydrolysis of the
acetate (Table 2, entry 11). Most importantly, the entire
sequence could be run on a gram scale without any noticeable
a
All reactions were run on a 0.3 mmol scale using 1 equiv of allyl
acetate 2a−o and 5 mol % of Pd(PPh3)4. All retro-Dieckmann
reactions were run on a 0.12 mmol scale using 1:1 mixture of THF
and a 10% saturated aqueous solution of NaOH (2 mL). Isolated
yield.
b
B
DOI: 10.1021/acs.orglett.9b03522
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
loss in yield and without ever observing the formation of the
conjugated 1,3-diene (Table 2, entry 1).
allyl acetate 2v, which led to the corresponding allylated
product 3v in 89% yield despite the presence of the free OH
(Table 3, entry 7). All of the resulting α-allylated products
(3p−v) were eventually engaged in the retro-Dieckmann
fragmentation step; all afforded the corresponding α-
substituted acrylonitriles 4p−v in yields ranging from 10% to
80% depending on the inherent volatility of the products.
To extend the scope of the method, we applied the same Pd-
AA/retro-Dieckmann fragmentation sequence to methyl 4-
oxotetrahydrothiophene-3-carboxylate 5, used here as a methyl
acrylate surrogate (Scheme 1). To our delight, the desired α-
Mechanistically, the retro-Dieckmann fragmentation pro-
ceeds through a 1,2-addition of a hydroxide ion onto the
carbonyl moiety, which then rapidly undergoes elimination to
form the stable α-substituted acrylonitrile with subsequent
release of sodium thioglycolate. The reaction is fast
(approximately 10 min) and affords the corresponding α-
substituted α,β-unsaturated nitrile as a single E stereoisomer.
This two-step sequence was eventually applied to branched
allyl acetates as well.23g,h,27 Interestingly, replacing the
hydrogen atom at the 2-position by a methyl (2q), a phenyl
(2r), or a methyl ester (2s) did not hamper the reactivity of
the Pd-AA and the yields remained satisfactory (Table 3,
entries 1−4). A slight decrease in reactivity was observed in the
case of the 2-chloro- and the 2-isopropyl-substituted allyl
acetates 2t and 2u (Table 3, entries 5−6); however, the
reactivity was regained with the 2-methyl carbinol substituted
a
Scheme 1. Implementation of the Method
Table 3. Scope of the Method with Various Branched Allyl
a
Acetates
a
All Pd-AA reactions were run using 1 equiv of allyl acetate 2a or
epoxides 8a and 8b and 5 mol % of Pd(PPh3)4. All retro-Dieckmann
reactions were run using a 1:1 mixture of THF and a 10% saturated
aqueous solution of NaOH (2 mL).
allylated product 7 was obtained in 64% yield over the two
steps with no hydrolysis of the ester moiety. In addition, we
also tested the method using vinyl epoxides instead of allyl
acetates. Interestingly, in the presence of 8a and 8b, the linear
products 9a and 9b were obtained thus confirming the known
trend regarding the opening of epoxides in the presence of
Pd(PPh3)4.28 The latter were then engaged in the retro-
Dieckmann fragmentation to form the corresponding 1,4-
dienes 4o and 10, albeit in lower yields than usual due to a
lower reactivity of the corresponding allylated intermediates.
To illustrate further the synthetic versatility of the method, a
series of post-functionalizations were conducted on 4a
(Scheme 2) including both biocatalytic and chemical trans-
formations. We first screened Almac’s ERESK-9600 ene-
reductase (ERED) enzyme kit for the stereoselective reduction
of the acrylonitrile moiety. All of the reactions were performed
utilizing the well-established coupled-enzyme approach,
employing a glucose/GDH system to regenerate the required
cofactor. Several hit enzymes were identified with ERED
ER304 generating the desired saturated nitrile 11 in 42% yield
and up to 92% ee at screening scale. We also screened a
focused library of nine nitrile hydratases and 15 nitrilases from
Almac’s NESK-2400 nitrile manipulating enzyme kit for the
mild and selective hydrolysis of the nitrile moiety. Among the
24 enzymes tested, enzyme NH103 led to the quasi-
quantitative conversion of nitrile 4a to amide 12 at screening
scale. Work is ongoing to further establish the biotransforma-
tion utility and scope.
Some more traditional chemical transformations were also
carried out. Hence, the selective reduction of the nitrile moiety
using DIBAL-H afforded the corresponding aldehyde 13 in
79% yield. The selective reduction of the cyano-olefin in the
presence of Stryker’s reagent provided the corresponding
saturated nitrile 11 in 57% yield. Meanwhile, the selective
a
All reactions were run on a 0.3 mmol scale using 1 equiv of allyl
acetate 2p−v and 5 mol % of Pd(PPh3)4. All retro-Dieckmann
reactions were run on a 0.12 mmol scale using a 1:1 mixture of THF
and a 10% saturated aqueous solution of NaOH (2 mL). Isolated
yield. Highly volatile.
b
c
C
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Scheme 2. Selective Post-functionalizations
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affording the corresponding epoxide 14 in 66% yield.
In summary, we have developed a highly straightforward and
scalable route to α-substituted acrylonitriles through a
sequential palladium-catalyzed allylic alkylation/retro-Die-
ckmann fragmentation of 4-cyano-3-oxotetrahydro-thiophene.
The resulting 1,4-dienes bearing an acrylonitrile moiety were
subsequently converted to various useful building blocks using
biocatalytic and chemical transformations.
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ASSOCIATED CONTENT
* Supporting Information
■
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The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b03522.
1
Details of experimental procedures, H and 13C NMR
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: s.arseniyadis@qmul.ac.uk.
ORCID
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2007, 129, 2428−2429.
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Am. Chem. Soc. 2009, 131, 10964−10973.
Thomas S. Moody: 0000-0002-8266-0269
Stellios Arseniyadis: 0000-0001-6831-2631
Notes
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The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
Queen Mary University of London is acknowledged for
financial support.
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