Nickel-catalysed novel β,γ-unsaturated nitrile synthesis

Article abstract of DOI:10.1039/c3cc00029j

Through a nickel-catalysed Heck-type reaction, a direct coupling of alkenes with α-cyano alkyl bromides was achieved. This procedure provides a novel way for the synthesis of β,γ-unsaturated nitriles.

Full text of DOI:10.1039/c3cc00029j

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Nickel-catalysed novel b,c-unsaturated nitrile
synthesis†
Cite this: DOI: 10.1039/c3cc00029j
a
a
Shan Tang,z Chao Liuz and Aiwen Lei*ab
Received 2nd January 2013,
Accepted 1st February 2013
DOI: 10.1039/c3cc00029j
www.rsc.org/chemcomm
Through a nickel-catalysed Heck-type reaction, a direct coupling of and quite easy to obtain. Herein, we report the first novel
alkenes with a-cyano alkyl bromides was achieved. This procedure b,g-unsaturated nitrile synthesis via Ni-catalysed Heck-type alkenyla-
provides a novel way for the synthesis of b,c-unsaturated nitriles.
tion of a-cyano alkyl bromides with olefins (Scheme 1, path c).
To our knowledge, scarce reports exist on the alkenylation of
b,g-Unsaturated nitrile moieties are important constituents in some a-carbonyl alkyl halides with olefins, which were however based on
potential drugs and natural products.1 However, quite limited intramolecular reactions.5 Until recently, our group has achieved
methods have been reported for their synthesis up to now.2 the first intermolecular coupling of secondary and tertiary
Generally, the synthesis of b,g-unsaturated nitriles was achieved a-carbonyl alkyl bromides with olefins to achieve a-alkenylation
from the cyanation process of allylic substituted compounds of carbonyls in the presence of a nickel catalyst.6 As an extension,
(Scheme 1, path a).3 Nevertheless, most of these methods require employing a-cyano alkyl halides as the alkyl electrophiles may open
either toxic reagents or materials that are not easily available. From a door for the general synthesis of b,g-unsaturated nitriles.
the disconnection of the designed products, an alternative approach
However, the reaction between olefins and a-cyano alkyl
also has high potential, which is the direct alkenylation of a-cyano bromides has limitations when conducted under the optimized
alkyl halides. However, it remained nearly unstudied until now. To conditions for non-electron-rich olefins.6 For example, only a trace
our knowledge, only one example has been demonstrated by Fu and amount of the desired product could be observed with p-fluoro-
co-workers by using alkenylzinc reagents to couple with a-cyano styrene, while no alkenylation product formed for simple styrene
alkyl bromides (Scheme 1, path b).4 Obviously, the direct utilization (Scheme 2). This result clearly showed the distinction of reactivity
of alkenes as coupling partners with a-cyano alkyl halides to among activated alkyl electrophiles. a-Cyano alkyl bromides might
construct b,g-unsaturated nitriles would be a much more appealing achieve alkenylation with more difficulty compared to a-carbonyl
approach, as both alkenes and a-halide nitriles are readily available alkyl bromides. During investigation into the efficient alkenylation
of a-cyano alkyl bromides, a tendency should be noted. When the
reaction was conducted under 60 1C without the addition of any
additive, no alkenylation product was observed. In contrast, the
alkenylation product was observed in a yield of 34% when the
reaction was conducted at 120 1C (determined by NMR) (Scheme 3).
From this point of view, it could be seen that the generation of the
alkenylation product was solely promoted by the increase in
reaction temperature. In other words, temperature may play a key
role in promoting the formation of the alkenylation product.
Scheme 1 Synthesis of b,g-unsaturated nitriles.
a College of Chemistry and Molecular Sciences, Wuhan University, P. R. China.
E-mail: aiwenlei@whu.edu.cn; Fax: +86-27-68754067; Tel: +86-27-68754672
b Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology,
Peking University Shenzhen Graduate School, Shenzhen 518055, China
Scheme 2 Attempts for the alkenylation of a-cyano alkyl bromide with non-
† Electronic supplementary information (ESI) available. See DOI: 10.1039/c3cc00029j
‡ Shan Tang and Chao Liu contributed equally to this work.
electron-rich olefins.
c
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nickel(II) intermediate B. Consequently, higher temperature may
promote the oxidation of radical 3I by B to generate 3II.
(1)
Keeping this assumption in mind, we tried to conduct the reac-
tion at a much higher temperature. By changing the solvent to mesi-
tylene which has a higher boiling point, the reaction was conducted
at a temperature of 160 1C. To our delight, the desired product was
selectively obtained with an isolated yield of 82% (eqn (1)), which
supported our viewpoint on efficient oxidation of radical 3I.
After we obtained this exciting result, we tried to apply the
conditions to other substrates in the Ni-catalysed direct synthesis
of b,g-unsaturated nitriles. First of all, various non-electron-rich
olefins were employed to couple with 2-bromopentanenitrile
(Table 1). In the optimized catalysis system for the alkenylation
reaction, 2-bromopentanenitrile was applied to couple with a
range of non-electron rich olefins in good to excellent yields
(entries 1–6). Simple styrene afforded the desired product in
67% yield (entry 3). tert-Butyl, para- and ortho-methyl substituted
styrenes afforded the coupling products in good yields (entries 4,
5 and 7). The C–Cl bond was well tolerated in this transformation
Scheme 3 Effect of temperature on the reactivity towards alkenylation.
As we know, temperature has always been regarded as an
indispensable factor in organic reactions. However, attention
has mainly been paid to its ability to accelerate reaction rates.
While it has been revealed that temperature could affect the
selectivity of multiple reactions, some examples of successfully
controlling the selectivity to obtain certain products by just
changing the reaction temperature have been reported.7 Based
on the clues we found in the nickel-catalysed alkenylation of
a-cyano alkyl bromides, we decided to further investigate the
reaction by changing the reaction temperature.
Moreover, alkyl halides have been proposed to undergo a
single electron transfer (SET) process to generate free radicals
with a nickel catalyst.6,8 As it has been shown that the b-hydride
elimination from the nickel species and the reductive elimination
of nickel hydride are not as facile as for palladium,9 we first
outlined the following radical pathway shown in Scheme 4 for the
alkenylation of a-cyano alkyl bromides. The reaction of a-cyano
alkyl bromides with Ni0 generates the active NiI species A (this
step was proved by EPR detection, see ESI†), which then donates
an additional electron to a-cyano alkyl bromides to generate the
radical species 2I and a NiII species B through a SET reduction
step (step 1). Afterwards, the radical addition of 2I to olefin 1
generates benzylic radical 3I (step 2), which is followed by the SET
oxidation of radical 3I by B to generate 3II (step 3). Ultimately,
benzylic cation 3II was deprotonated by base to release the final
product 3 (step 4). During the whole process, step 3 was believed
to be the key step for the generation of the final product. This
viewpoint was supported by the fact that an electron-donating
substituent, which is in favor of cation formation, is beneficial for
the product formation. Accordingly, it is easy to understand that
non-electron-rich olefins are not in favor of cation formation so
that the alkenylation product is not easily obtained. We believe
that increasing the temperature can raise the redox potential of
Table 1 Scope of alkenes to construct b,g-unsaturated nitriles through nickel catalysis
Entry
Alkene 1
Product 3
Yielda (%)
1b
2b
3b
4b
5b
6c
1a: R = F
1b: R = Cl
1c: R = H
1d: R = Bu
1e: R = Me
3a: R = F
3b: R = Cl
3c: R = H
3d: R = Bu
3e: R = Me
82
56
67
83
87
90
t
t
1f: R = OMe
3f: R = OMe
7b
80
71
8c
9c
1i: R = H
1j: R = CF3
1k: R = OMe
3i: R = H
3j: R = CF3
3k: R = OMe
90
54
98
10c
11c
a
b
Isolated yields. Method A: the reactions were carried out with 1
(0.50 mmol), 2 (0.75 mmol), Ni(PPh3)4 (5 mol%), dppp (6 mol%), K3PO4
c
(1.0 mmol), mesitylene (2 mL), 160 1C, 3 h. Method B: the reactions
were carried out with 1 (0.50 mmol), 2 (0.75 mmol), Ni(PPh3)4 (5 mol%),
dppp (6 mol%), K3PO4 (1.0 mmol), toluene (2 mL), 100 1C, 10 h.
Scheme 4 Proposed mechanism.
c
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and the reaction proceeded chemoselectively to afford the desired secondary a-cyano alkyl bromides are still suitable substrates
alkenylation product (entry 2). An electron-donating substituent under the present conditions (Table 2, entries 4, 5, 8 and 9).
like p-methoxystyrene afforded good results at a lower tempera- Tertiary a-cyano alkyl bromides were too reactive and they could
ture (100 1C, entry 6). Styrene bearing a methyl group at the not be tolerated at the moment. While under the conditions that
a-position also gave the desired product (entry 8). To our delight, developed with primary a-cyano alkyl bromides, we did get the
1,1-diaryl substituted ethylenes were also suitable substrates for cross-coupling product 2-bromo-2-methylpropanenitrile with
this alkenylation (entries 9–11). Both an electron-donating group 1,1-diphenylethylene in 14% yield (Table 2, entry 7). This result
(entry 11) and a strong electron-withdrawing trifluoromethyl showed the generality for the construction of b,g-unsaturated
group (entry 10) were introduced into the 1,1-diaryl substituted nitriles using this nickel catalysed alkenylation system.
ethylene, providing the alkenylation products in good yields.
In conclusion, we have demonstrated the first nickel catalysed
Since an excess of PPh3 ligand may cause the formation of Heck-type alkenylation of a-cyano alkyl bromides for the general
phosphonium salts,10 alkenylation did occur but with low conver- synthesis of b,g-unsaturated nitriles. Importantly, high temperature
sion for primary a-cyano alkyl bromides under the present condi- contributed to the selective alkenylation with non-electron-rich olefins,
tions.11 Thus we turned to further optimization of the reaction which provides an example of successfully controlling the oxidation of
systems. To our knowledge, Ni(PPh3)4 is usually prepared by the radicals. Further optimization to expand the substrate scope as well as
reduction of the mixture of Ni(acac)2 and PPh3 with Diisobutylalu- more mechanistic investigation is underway in our laboratory.
minium Hydride (DIBAL-H).12 Therefore, Ni(PPh3)4 was replaced by
This work was supported by the 973 Program (2012CB725302)
the combination of Ni(acac)2 and DIBAL-H for further optimization. and the National Natural Science Foundation of China
Subsequent ligand scanning showed that dppf was the most (21025206 and 21272180), the China Postdoctoral Science Foun-
efficient ligand for the alkenylation of primary a-cyano alkyl dation funded project (2012M521458). We are also grateful for
bromides (see ESI† for detailed condition optimization).
the support from the Program for Changjiang Scholars and
With our optimized method, primary a-cyano alkyl bromides Innovative Research Team in University (IRT1030).
could give the alkenylation product in good yields (Table 2, entries
1–3). Upon expanding the substrate scope, the temperature was
still important for the reaction with non-electron-rich styrenes, the
reaction of p-methylstyrene should be conducted at a higher
Notes and references
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Entry Alkene 1 bromide 2
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Yieldb (%)
1
1i
65
80
54
2c
3
1e
1g
2b
2b
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5
1i
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96
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˜
´
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9
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61
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a
Method C: the reactions were carried out with 1 (0.50 mmol), 2
(0.75 mmol), 5 mol% Ni(acac)2, dppf (6 mol%), DIBAL-H (12 mol%),
K3PO4 (1 mmol), toluene (2 mL), 100 1C, 10 h. Isolated yields. The
reaction was conducted at 120 1C. 48 h.
b
c
d
c
This journal is The Royal Society of Chemistry 2013
Chem. Commun.