Divergent Synthesis of CF3-Substituted Allenyl Nitriles by Ligand-Controlled Radical 1,2- and 1,4-Addition to 1,3-Enynes

Article abstract of DOI:10.1002/anie.201803668

A ligand-controlled system that enables regioselective trifluoromethylcyanation of 1,3-enynes has been identified, which provides access to a variety of CF₃-containing tri- and tetrasubstituted allenyl nitriles. We disclose that the involved propargylic radicals can be selectively trapped by (Box)Cu^II cyanide, while the tautomerized allenyl radicals are trapped by (phen)Cu^II cyanide (Box= bisoxazoline, phen=phenanthroline). In addition, the reaction features broad substrate scope and excellent functional group compatibility. Moreover, this protocol represents a novel regioselectivity-tunable functionalization of 1,3-enynes via radicals, which we believe will have great implications for the development of catalytic systems for selectivity control in radical and organometallic chemistry.

Full text of DOI:10.1002/anie.201803668

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Accepted Article
Title: Divergent Synthesis of CF3-Substituted Allenyl Nitriles by Ligand-
Controlled Radical 1,2- and 1,4-Addition of 1,3-Enynes
Authors: Guosheng Liu, Fei Wang, Dinghai Wang, ling Liang, Ronghua
Lu, Pinhong Chen, Zhenyang Lin, and Yu Zhou
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10.1002/anie.201803668
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COMMUNICATION
Divergent Synthesis of CF3-Substituted Allenyl Nitriles by
Ligand-Controlled Radical 1,2- and 1,4-Addition of 1,3-Enynes
Fei Wang,§[a] Dinghai Wang,§[a] Yu Zhou,[b] Ling Liang,[a] Ronghua Lu,[a] Pinhong Chen,[a] Zhenyang
Lin,*[b] and Guosheng Liu*[a]
Dedicated to Prof. Xiyan Lu on the occasion of his 90th birthday
Abstract: A ligand-controlled system that enables regioselective
selectively, has never been documented to date (Scheme 1a).
trifluoromethylcyanation of 1,3-enynes has been identified, which
Recently, our group developed a series of copper-catalyzed
asymmetric radical transformations (ARTs).[7,8] As a key step in
cyanation,[7] a benzylic radical intermediate was trapped by
reactive (Box)Cu(CN)2 species to generate the corresponding
Cu(III) species; then reductive elimination at a Cu(III) center led
to the formation of C-CN bonds.[7a-b] Notably, the electronic and
steric properties of ligands had a significant effect on the
reductive elimination step. Based on our previous studies, we
envisaged that, owing to the tautomerization between propargylic
radicals and allenylic radicals, two different Cu(III) intermediates,
propargyl-Cu(III) species int-III and allenyl-Cu(III) species int-IV,
formed by trapping the propargylic radicals and allenylic radicals
with copper(II) cyanide, would undergo reductive elimination,
yielding the 1,2-addition product 2 and 1,4-addition product 4,
respectively (Scheme 1b). In addition, we hypothesized that, if
the formation of the intermediates int-III and int-IV and their
reactivities toward reductive elimination could be controlled by
ligands, the products 2 and 4 might be divergently synthesized
by simply switching reaction conditions. Herein, we communicate
this ligand-controlled 1,2- and 1,4- radical addition of
1,3-enynes.[8] Notably, we found that the 1,2-addition cyanation
product 2 could be isomerized to the allenyl product 3 upon
treatment with a base. Our ligand-controlled copper-catalyzed
radical cyanation reaction provides an easy and straightforward
provides an access to
a variety of CF3-containing tri- and
tetra-substituted allenyl nitriles. We disclose that the involved
propargylic radicals can be selectively trapped by (Box)Cu(II) cyanide,
while the tautomerized allenyl radicals are trapped by (phen)Cu(II)
cyanide. In addition, the reaction features broad substrate scope and
excellent functional group compatibility. Moreover, this protocol
represents
a novel regioselectivity-tunable functionalization of
1,3-enynes via radicals, which we believe will have great potential
implications for the development of catalytic systems for selectivity
control in radical and organometallic chemistry.
Difunctionalizations of alkenes have emerged as a powerful
and efficient tool for significantly increasing the complexity of
organic molecules in organic synthesis.[1] Owing to the high
reactivity of radical species, difunctionalizations of terminal
alkenes through a radical process have recently received much
attention.[2] As a special class of alkenes, the substituted
1,3-enynes 1 can also undergo radical addition to the double
bond, yielding two mesomeres of propargylic radical species int-I
and allenyl radical species int-II. However, the radical is mostly
located at the propargylic position (int-I).[3] Thus, the subsequent
radical interception exclusively occurs at the propargylic position
to yield functionalized propargylic products (1,2-addition).[4,5] For
instance, Loh and coworkers reported an elegant
copper-/cobalt-catalyzed radical dioxygenation of 1,3-enynes to
provide 1,2-addition products exclusively, in which a propargylic
radical was trapped by peroxide radicals.[5a] Later on, similar
radical dioxygenation reactions were developed by Woerpel and
coworkers, where the dioxygen was used to trap propargylic
radicals.[5b] However, only few cases were demonstrated about
the 1,4-radical addition of 1,3-enynes.[6] To the best of our
knowledge, the tuneable 1,2-/1,4- radical addition of 1,3-enynes
1, yielding the corresponding propargyl and allenyl products
access to the CF3-substutited allenyl cyanides
respectively (Scheme 1b).
3 and 4
[a] F. Wang, D. Wang, L. Liang, R. Lu, Dr. P. Chen, Prof. Dr. G. Liu,
State Key Laboratory of Organometallic Chemistry, Center for Excellence
in Molecular Synthesis, Shanghai Institute of Organic Chemistry,
University of Chinese Academy of Sciences, Chinese Academy of
Sciences .
345 Lingling Road, Shanghai, China, 200032
E-mail: gliu@mail.sioc.ac.cn
Homepage: http://guoshengliu.sioc.ac.cn/
[b] Y. Zhou, Prof. Dr. Z. Lin
Scheme 1. Regioselective cyanation of propargylic radicals by copper
catalysis.
Department of Chemistry, The Hong Kong University of Science and
Technology, Clear Water Bay, Kowloon, Hong Kong, China
E-mail: chzlin@ust.hk
§
These authors contributed equally to this work.
Supporting information for this article is given via a link at the end of the
document.
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10.1002/anie.201803668
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COMMUNICATION
To test the above hypothesis, we started to examine the
reaction of 1,3-enyne 1a using the copper-catalyzed system
developed in our group with phenanthroline-type ligands.[10a] As
shown in Table 1, to our delight, when Cu(CH3CN)4PF6/phen
were used as catalyst, the reaction in CH3CN proceeded well to
afford the major1,4-addition product (allenyl cyanide 4a) as well
as the minor 1,2-addition product (2a and 3a) in total 70% yield
with 10:1 ratio. Ligands L1 and L2 provided good results, but the
L2 gave a better selectivity (the ratio of 1,4/1,2-addition = 16:1,
Conditions A). Meanwhile, bipyridine is also a suitable ligand for
the reaction, giving an excellent yield, albeit with slightly lower
selectivity (11:1). Notably, the reaction gave the products in only
20% yield with 6:1 ratio in the absence of ligands, and poor mass
balance was observed. Interestingly, further ligand screening
revealed that, compared to less bulky ligands, the bulky ligands
L3-L5 gave the major 1,2-addition products 2a and 3a with an
opposite selectivity. In addition, increasing the steric hindrance of
the ligands (from L3 to L5) could improve the selectivity (from
2.3:1 to 7:1), but resulted in a decreased yield (from 65% to 24%).
Gratifyingly, when bisoxazoline ligands (L6-L8) were employed,
the reaction gave the preferred 1,2-addition products (2a+3a)
with excellent selectivities, especially for L8. Notably, when the
crude mixture was treated with Et3N, the propargylic cyanide 2a
was completely converted into the allenylcyanide 3a in 86%
isolated yield (Conditions B: one-pot procedures for radical
cyanation and isomerization).[11]
could be tolerated under the current reaction conditions (entries
1-15, 19). Interestingly, for the substrate 1g bearing the reactive
styrenyl and enynyl moieties, the reaction exclusively occurred
on the C-C double bond in 1,3-enynes, furnishing the desired
products 4g and 3g respectively in good yields and
regioselectivities (entry 7). The substrate 1h with a good leaving
group (OTs) was also suitable to give the desired products 4h
Table 2. Substrate Scope.a,b
Table 1. Ligand Screening.a,b
With the optimized reaction conditions in hand, we turned our
attention to explore the substrate scope. As shown in Table 2,
when a series of 1,3-enynes were treated under the reaction
conditions A (with L2) or B (with L8), the reactions proceeded
smoothly to deliver the corresponding 1,4/1,2-addition
allenylcyanides 4 and 3 respectively, with good to excellent
yields and regioselectivities. In addition, various functional
groups, such as imide (1a-1b), carbazole (1c), esters (1d-1h, 1s),
ether (1i, 1o), alkyl (1j-1l), sulfonylamide (1m) and halide (1n),
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10.1002/anie.201803668
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COMMUNICATION
and 3h in good yields, with the OTs group remained intact (entry
8). Furthermore, substrates bearing heteroaryls, such as furan
(1p), thiophen (1q) and pyridine (1r), were also suitable for the
reaction to give CF3-substituted allenyl cyanides in moderate to
good yields with good regioselectivities (entries 16-18).
Interestingly, with the ligand L8, the reactions of substrates 1t-1u
bearing a tertiary substitutents proceeded smoothly to give the
1,2-addition products 3t-3u in excellent yields and
regioselectivities. However, the reactions of 1t-1u with the ligand
L2 afforded 1,4-additon products (4t-4u) in moderate yields with
poor regioselectivties (~1:1, entries 20-21). Finally, substrate 1v
with o-chlorophenyl group was suitable for the reactions to
deliver the corresponding 1,4/1,2-addition allenyl nitriles 4v and
3v in excellent regioselectivities, respectively (entry 22).
yields. Importantly, substituents at the 2-position were not only
limited to the methyl group, other substituents bearing ester and
alcohol in 1,3-enynes were also suitable for this transformation,
and the reactions provided the corresponding products 6p-6t in
good to excellent yields which could be further converted into
other CF3-modified high-value chemicals.[13] Notably, a substrate
bearing the free hydroxyl group could also be employed for the
reaction, giving the desired product 6s in 89% yield. In addition,
substrates 5u-5v with a phenyl group at the terminal of alkyne
were also good candidates for the reaction, and the desired
products 6u-6v were obtained in 93% and 59% yields,
respectively. To further evaluate the potential synthetic utility of
the present method, we performed a gram-scale reaction of 5a
and found that it worked very nicely to give the desired product
6a in an even better yield (96%).
Then, we paid our attention to the reaction of substituted
1,3-enynes 5, involving a tertiary propargylic radical intermediate
after radical addition (Table 3). Similar to our previous studies,[12]
the propargyl nitrile 7 bearing a quaternary carbon center was
not produced; instead, the reaction exclusively afforded the
tetra-substituted allenes 6 through a 1,4-addition process, which
might be attributed to the steric hindrance at the C2 position
preventing the tertiary propargyl radical interacting with reactive
Cu(II) cyanide species; however, the steric effect at the C4
position is not significant, which allows for the formation of the
allenyl nitriles 6 selectively. In addition, different reaction
parameters were examined (for details, see SI); pleasingly, upon
treatment of 5a with Cu(I)/Phen (condition C), the desired
product 6a was isolated in 89% yield. Furthermore, the reaction
exhibited excellent functional group compatibility, substrates
bearing imide (6a, 6r), sulfonamide (6g), carbazole (6h), ester
(6j-6m), ether (6f, 6i), halide (6e), alkyl (6b-6d) and heteroaryl
groups (6n-6o) can be employed under our current reaction
conditions, giving the desired products with good to excellent
To get insight into the plausible mechanism, radical clock
substrate 8 was synthesized and subjected to the condition B,
the ring-opening product 10 was obtained in 25% yield, along
with small amounts of the 1,4-addition product 9 in 10% yield;
while the reaction of 8 under the conditions C afforded the
product 9 in 71% yield, and trace amount of the ring-opening
product 10 was observed (eq. 1). We reasoned that, the
propargylic radical intermediate int-V generated by CF3 radical
addition would proceed through two pathways: (1)
tautomerization to the allenyl radical int-VI; (2) a cyclopropane
ring-opening reaction giving a terminal alkyl radical int-VII.
Based on our previous studies, the alkyl radical int-VII is more
favored to react with (Box)Cu(II) cyanide species to give the
desired cyanation product 10; the allenyl radical int-VI is more
favored to react with (phen)Cu(II) cyanide to generate the allenyl
nitrile product 9 in a much better yield. Compared to secondary
alkyl carbon radicals, a primary alkyl carbon radical is less
sterically hindered, and the Cu(III) species int-VIII would suffer
from a higher energy barrier for reductive elimination, thus
resulting in a slightly lower yield.[14]
Table 3. Substrate Scope for tetra-Substituted allenes.a,b
On the basis of the proposed mechanism shown in Scheme
1b, further mechanistic investigation via DFT calculation was
surveyed (see SI for more details). The free energy profiles
(Figure 1) clearly shows that the ligand phen favors the
1,4-addition product (left) while L8 promotes the 1,2-addition
product (right). Due to that an allenyl radical is expected to be
more sterically demanding than an alkyl radical, in the case of
Phen (Fig 1a), the transition state TSAII_AIV (leading to the
allenyl-Cu intermediate AIV) lies slightly higher in energy than
TSAI_AIII (leading to the alkyl-Cu intermediate AIII). However, the
reductive elimination from the allenyl-Cu intermediate AIV (giving
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10.1002/anie.201803668
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COMMUNICATION
Figure 1. Free energy profiles calculated for the reaction pathways leading to 1,2- and 1,4-addition of 1,3-enyne under different ligand
conditions (a for phen and b for L8).
[1]
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reductive elimination from the alkyl-Cu intermediate AIII via
TSAIII_2 (giving 1,2-addition) shows an appreciable barrier. In
contrast, the strong steric hindrance of L8 makes the formation of
the allenyl-Cu intermediate BIV (giving 1,4-addition) kinetically
very unfavourable, as the relevant TS (TSBII_BIV) lies even higher
than the TS (TSBIII_2) for the reductive elimination from the
alkyl-Cu intermediate BIII leading to the 1,2-addition (Fig 1b).
DFT results clearly support that regioselectivity is tuned by
ligand.
In summary, we have developed a trifluoromethylcyanation
reaction of 1,3-enynes, which provides an efficient protocol for
allenyl nitriles with high regioselectivities. The current reaction
exhibits broad substrate scope and excellent functional group
compatibility. Moreover, distinct from traditional radical
processes, both 1,2- and 1,4-difunctionalization of 1,3-enynes
can be achieved. We believe the regioselectivity-tunable
functionalization of 1,3-enynes via radicals will have great
potential implications for the development of catalytic systems for
selectivity control in radical and organometallic chemistry.
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Acknowledgements
We thank the National Nature Science Foundation of China (Nos.
21523005, 21472219, 21790331 and 21761142010), National
Basic Research Program of China (973-2015CB856600), the
Science and Technology Commission of Shanghai Municipality
(Nos. 17QA1405200 and 17JC1401200), the strategic Priority
Research Program (No. XDB20000000) and the Key Research
Program of Frontier Science (QYZDJSSW-SLH055) of the
Chinese Academy of Sciences. Z.L. and Y. Z. thanks the
Research Grants Council of Hong Kong (HKUST16304416 and
HKUST-SBI16SC08). This research was partially supported by
CAS Interdisciplinary Innovation Team.
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Conflict of interest
The authors declare no conflict of interest.
Keywords: 1,3-enynes • copper • regioselective • allenyl nitriles
• radical reaction
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10.1002/anie.201803668
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COMMUNICATION
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investigation on the enantioselective reaction will be examined in our
laboratory. For details, see the supporting information.
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[14] The coordination between radical intermediates and Cu(II)cyanide is
reversible, and high barrier for reductive elimination will cause some
other side reactions. For DFT calculations, see: ref. 7a.
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10.1002/anie.201803668
Angewandte Chemie International Edition
COMMUNICATION
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COMMUNICATION
A ligand-controlled radical 1,2- and
1,4-addition of 1,3-enynes has been
developed, which provides an access
to a variety of CF3-containing tri- and
tetra-substituted allenyl nitriles. The
reaction features broad substrate
scope and excellent functional group
compatibility. Moreover, this protocol
represents a novel
F. Wang, § D. Wang,§ Y, Zhou, L. Liang,
R. Lu, P. Chen, Z. Lin, G. Liu*
Page No. – Page No.
Title
Divergent Synthesis of CF3-Substituted
Allenyl Nitriles by Ligand-Controlled
Radical 1,2- and 1,4-Addition of
1,3-Enynes
regioselectivity-tunable
functionalization of 1,3-enynes via
radicals.
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