Transforming Olefins into γ,δ-Unsaturated Nitriles through Copper Catalysis

Article abstract of DOI:10.1002/anie.201705859

We have developed a strategy to transform olefins into homoallylic nitriles through a mechanism that combines copper catalysis with alkyl nitrile radicals. The radicals are easily generated from alkyl nitriles in the presence of the mild oxidant di-tert-butyl peroxide. This cross-dehydrogenative coupling between simple olefins and alkylnitriles bears advantages over the conventional use of halides and toxic cyanide reagents. With this method, we showcase the facile synthesis of a flavoring agent, a natural product, and a polymer precursor from simple olefins.

Full text of DOI:10.1002/anie.201705859

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International Edition: DOI: 10.1002/anie.201705859
German Edition: DOI: 10.1002/ange.201705859
Radical Reactions
Transforming Olefins into g,d-Unsaturated Nitriles through Copper
Catalysis
Xuesong Wu, Jan Riedel, and Vy M. Dong*
Abstract: We have developed a strategy to transform olefins
into homoallylic nitriles through a mechanism that combines
copper catalysis with alkyl nitrile radicals. The radicals are
easily generated from alkyl nitriles in the presence of the mild
oxidant di-tert-butyl peroxide. This cross-dehydrogenative
coupling between simple olefins and alkylnitriles bears advan-
tages over the conventional use of halides and toxic cyanide
reagents. With this method, we showcase the facile synthesis of
a flavoring agent, a natural product, and a polymer precursor
from simple olefins.
W
hile radicals play a key role in biochemistry,[1] their
potential for use in organic synthesis remains vast, with new
concepts continually emerging,[2] including applications in
cross-coupling.[3] By combining Cu catalysis with radicals,
Heck-type transformations have been achieved, including
allylic trifluoromethylation,[4] arylation,[5] and alkylation.[6]
These radical transformations enable bond construction
patterns that were previously impossible and provide an
attractive approach for olefin synthesis (Figure 1). Inspired by
the versatility of nitriles,[7] we designed a strategy for trans-
forming simple olefins into g,d-unsaturated nitriles by taming
the reactivity of the cyanoalkyl radical. Rather than requiring
functionalized halides and toxic cyanide reagents, this trans-
formation enables olefin feedstocks to be coupled with alkyl
nitriles to generate homoallylic nitriles in a single step, using
an earth-abundant metal catalyst (Figure 1).[8]
Figure 1. Allylic cyanoalkylation using alkylnitrile.
The nitrile functional group is common in both materials[9]
and medicines,[10] and is also a useful handle for elaboration.[7]
As shown in Figure 1, we proposed a cross-dehydrogenative
coupling (CDC)[11] between an olefin and acetonitrile.[12]
Initial oxidation of an alkylnitrile forms the corresponding
cyanoalkyl radical, which can add to an olefin to give the alkyl
radical A.[13–16] Radicals such as A have been implicated in
olefin hydrocyanoalkylations[13] and bifunctionalizations.[14–16]
In the presence of a copper(II) catalyst, Koichi showed that
radicals can be trapped to generate the alkylcopper(III)
intermediate B with rate constants in excess of 106 mÀ1 sÀ1.[17]
Theoretical studies on the CF3 allylic functionalization invoke
a triflate-counterion-assisted elimination.[4b] On the basis of
these studies, we reasoned that the appropriate counterion
would be critical for controlling regio- and stereochemistry in
the final elimination.[18]
With this mechanistic hypothesis in mind, we focused on
the copper-catalyzed allylic cyanoalkylation of 1-dodecene in
acetonitrile, using di-tert-butyl peroxide (DTBP) as the
oxidant. DTBP is a convenient and inexpensive radical
initiator in synthetic and polymer chemistry, and is commonly
used for generating radicals from acetonitrile.[13–16] Zhu and
co-workers demonstrated that Cu/peroxide can generate
cyanoalkyl radicals from alkylnitriles, which can then add to
alkenes through an intermolecular process.[14a,b,d,e,16] In Zhuꢀs
work, the generated alkyl radicals are typically trapped to
afford bifunctionalizations, such as oxycyanoalkylation-
s[14a,b,d,e] and arylcyanoalkylation.[16] Rather than addition
reactions across the olefin, we envisaged diverting A to
achieve dehydrogenative olefin functionalization.
In the absence of copper, treatment of 1-dodecene with
DTBP afforded the known hydrocyanoalkylation product 4a
in 25% yield, with no desired cyanoalkene 3a. Copper(I) and
copper(II) complexes bearing weak counterions provided 4a
as the major product (28–70% yields; Table 1), in accordance
with reported studies on hydrocyanoalkylation.[13] The cata-
[*] Dr. X. Wu, J. Riedel, Prof. V. M. Dong
Department of Chemistry, University of California, Irvine
4403 Natural Sciences 1, Irvine, CA 92697 (USA)
E-mail: dongv@uci.edu
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
https://doi.org/10.1002/anie.201705859.
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Table 1: Counterion effects on Cu-catalyzed allylic cyanoalkylation.[a,b]
[a] Reaction conditions: 1a (0.20 mmol), CuXn (20 mol%) and DTBP
(0.80 mmol) in acetonitrile 2a (1.5 mL), 1108C, 6 h. The transformation
was performed in a 1 dram vial (diameter 1.4 cm/height 4.3 cm) which
was sealed using a screw cap with a Teflon septum. [b] Yields were
determined by NMR analysis of the unpurified reaction mixture using
1,3,5-trimethoxybenzene as an internal standard. Yield of isolated
product is shown within parentheses. [c] (CuOTf)2·PhMe (10 mol%).
[d] With veratronitrile (0.20 mmol). A 4:1 E/Z ratio was determined by
NMR analysis of the unpurified reaction mixture.
lysts used by Zhu and co-workers were not effective in our
proposed allylic cyanoalkylation.[14a,b,d,e,16] In contrast, (thio-
phene-2-carbonyloxy)copper(I) (CuTc, previously used as
a catalyst in allylic trifluoromethylation[4b]) provided cyanoal-
kene 3a as the major product in 30% yield. In comparison to
copper(I) acetate, we found that copper(II) acetate showed
higher efficiency and chemoselectivity, providing 3a in 47%
yield with > 20:1 regioselectivity. By replacing acetate with
the more basic pivalate, the desired alkene was obtained in
65% yield, > 20:1 regioselectivity. Other oxidants such as tert-
butyl hydroperoxide (TBHP) and dicumyl peroxide (DCP)
were ineffective. Using an electron-rich benzonitrile deriva-
tive as an additive further improved efficiency, presumably by
improving catalyst solubility. In the presence of one equiv-
alent of veratronitrile, 3a was obtained in 90% yield, greater
than 20:1 rr, and 4:1 E/Z. Only trace amounts of 4a were
observed (< 5% yield). These results support the notion that
a carboxylate counterion facilitates the elimination and
enables > 20:1 regioselectivity to provide the g,d-unsaturated
nitrile. A syn elimination affords the E isomer as the major
product.[19]
With this method, we elaborated a wide-range of terminal
olefins (Scheme 1). Unactivated linear terminal olefins gave
the corresponding g,d-unsaturated nitriles (3a–c) in 80–86%
yields with > 20:1 rr and 4:1 E/Z. For the substrates bearing
ester (3d, 3e), amide (3 f), cyano (3g), and ether (3h) groups,
regioselective CDC reactions with acetonitrile provided the
corresponding products in 75–82% yields. Increasing the
steric hindrance at the 4-position of the olefins slightly
decreased the yields but increased the E/Z ratios of the
products (3i 7:1 E/Z; 3j 11:1 E/Z; 3k > 20:1 E/Z). With a tert-
butyl group at the 3-position, we observed > 20:1 regioselec-
tivity and > 20:1 E/Z selectivity (3k). The regioselectivity was
unaffected by increased steric hindrance at the 4-position of
the olefins. 3-Aryl-substituted substrates gave the corre-
Scheme 1. Allylic cyanoalkylation of terminal olefins. Reaction condi-
tions: 1 (0.20 mmol), Cu(OPiv)2 (20 mol%), DTBP (0.80 mmol). and
veratronitrile (0.20 mmol) in alkylnitrile 2 (1.5 mL), 1108C, 6 h. E/Z
ratios determined by NMR analysis of the unpurified reaction mixture
are shown in parentheses. [a] 3t1 and 3t2 were isolated as a mixture.
[b] 24 h.
sponding nitriles (3l–n) in 40–46% yields with > 20:1 E/Z
selectivity. A substrate with an electron-withdrawing group
on the phenyl ring (3n) showed slightly higher reactivity than
one with an electron-donating group (3m). Trisubstituted
alkenyl nitriles were synthesized in 50–77% yields from 3,3-
and 1,1-disubstituted olefins (3o–r and 3t). A series of nitriles
were also tested as coupling partners and solvent. Propioni-
trile and butyronitrile showed decreased reactivity compared
to acetonitrile, most likely due to steric effects and the lower
solubility of the copper catalyst in these nitriles (3v, 3w).
À
Transformation with styrene, which has no allylic C H bond,
gave b,g-unsaturated nitrile 3x in 10% yield. Only trace
amounts of the hydrocyanoalkylation product
4 were
observed with the olefins shown in Scheme 1. Having
established facile access to various nitriles, we next focused
on applying them as building blocks.
Owing to the versatility of the cyano group, we were able
to use simple olefins to access a range of motifs, including an
industrial flavor agent, a natural product, and a polymer
precursor (Scheme 2). For example, treatment of 3b with
TMSCl in ethanol provided the pear flavoring ethyl 4-
2
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potential allylic radical F or p-allylcopper intermediate G
À
through allylic C H bond activation (Scheme 3c). We
observed no carbocation-rearrangement-type products (10),
which would arise from the carbocation intermediate H
(Scheme 3d).[25] Nor were these 1,2-hydride shift products
detected in experiments yielding compounds 3o–q
(Scheme 1). These observations suggest that allylic radicals
or carbocations are most likely not key intermediates in our
cross-coupling.
On the basis of further experiments and previous
reports,[14–16] we propose the mechanism shown in Scheme 4.
Scheme 2. Application of the g,d-unsaturated nitriles. TMS=trimethyl-
silyl.
decenoate (5) in 85% yield.[20] The 4-alkyl g-lactones are
members of a large family of natural flavors that are widely
used in food industry.[21] From the same compound 3b, g-
decalactone (6) was obtained in 73% yield through a one-pot,
hydrolysis and intramolecular hydroacyloxylation. Our strat-
egy provides an efficient route to fatty acids. For example,
lyngbic acid, which is isolated from the marine cyanophyte
Lyngbya majuscule,[22] exhibits antimicrobial activity.[23]
Through hydrolysis of the cyano group in compound 3h,
lyngbic acid (7) can be obtained in 87% yield. Ru-catalyzed
hydrogenation of 3d provided the nylon-9 precursor 8 in 75%
yield.[24]
Scheme 4. Proposed mechanism and rationale for the regioselectivity.
Next, we examined internal olefins (Scheme 3). With (E)-
5-decene, the transformation gave cyanoalkene 3y in 62%
yield with > 20:1 rr and 11:1 E/Z after 24 h (Scheme 3a). With
(Z)-5-decene, the E isomer 3y was obtained as the major
product in a similar yield and E/Z selectivity as the E-olefin
Pivalate-assisted deprotonation of alkylnitrile with copper(II)
pivalate produces the cyanoalkylcopper(II) species J (path-
way a). Homolytic cleavage of J gives the cyanoalkyl radical
and copper(I) species. Addition of the cyanoalkyl radical to
the olefin generates the radical intermediate A. Concerted
carboxylate elimination of A provides the g,d-unsaturated
nitrile product and a copper(I) species. To explain the
regioselectivity, we propose that p-bonding of the cyano
group to copper(III)[26] shields the H at the b position to direct
the pivalate to abstract the H at the d position. The copper(I)
species decomposes DTBP through a single-electron-transfer
redox reaction to regenerate copper(II) and a methyl radical.
The methyl radical could also abstract hydrogen from
alkylnitrile to produce the cyanoalkyl radical (pathway b).
The following radical-trapping and radical-clock experi-
ments support the proposed mechanism (Scheme 5). Forma-
tion of the allylic cyanoalkylation product was suppressed in
the presence of TEMPO, a known radical inhibitor. Instead,
the products of cyanomethyl radical trapping (11) and methyl
trapping (12) were both observed in 14% and 27% yields,
respectively. These results support the notion that cyano-
methyl radical and methyl radical intermediates are involved
in the transformation. In the absence of Cu(OPiv)2, the
products 11 and 12 were also observed (in 5% and 39%
yields, respectively). However, in the absence of DTBP, only
11 was observed (12% yield). These results support the idea
that pathways a and b are responsible for the activation of
acetonitrile. Next, we found that the compound 14 was
À
substrate (60% yield, 12:1 E/Z) (Scheme 3b). The C C
bonds were formed at the 5-position of the substrates. No 3-
propylnon-4-enenitrile (9) was observed from either the
Scheme 3. Allylic cyanoalkylation of internal olefins.
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Scheme 5. Intermediate-trapping and radical-clock experiments.
[a] Yields based on TEMPO.
obtained in 60% yield from (1-cyclopropylvinyl)benzene (13)
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In summary, we have developed a copper-catalyzed cross-
dehydrogenative coupling of unactivated olefins with alkylni-
3
À
triles through dual sp C H bond cleavage. High chemo- and
regioselectivity for E2-type elimination is conferred by 1) the
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By using a catalyst derived from earth-abundant salts, we can
access 4-alkenylnitriles from simple olefins. Both terminal
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Acknowledgements
Funding was provided by the National Science Foundation
(CHE-1465263) and UC Irvine.
Conflict of interest
The authors declare no conflict of interest.
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Manuscript received: June 8, 2017
Revised manuscript received: July 18, 2017
Version of record online: && &&, &&&&
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Radical Reactions
When two become one: A strategy was
developed for transforming olefins into
homoallylic nitriles through a mechanism
that combines copper catalysis with alkyl
nitrile radicals. The radicals are easily
generated from alkyl nitriles in the pres-
ence of the mild oxidant di-tert-butyl
peroxide. This cross-dehydrogenative
coupling between simple olefins and
alkylnitriles bears advantages over the
conventional use of halides and toxic
cyanide reagents.
X. Wu, J. Riedel,
V. M. Dong*
&&&& — &&&&
Transforming Olefins into g,d-
Unsaturated Nitriles through Copper
Catalysis
6
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Angew. Chem. Int. Ed. 2017, 56, 1 – 6
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