Unactivated C(sp3)-H Bond Functionalization of Alkyl Nitriles with Vinylarenes and Mechanistic Studies

Article abstract of DOI:10.1021/acs.orglett.6b02692

The first example of a metal-free unactivated C(sp³)-H bond functionalization of alkyl nitriles with terminal vinylarenes to provide γ-ketonitrile derivatives is described. This protocol features simple operations, a broad substrate scope, and atom and step economy. In addition, Cu-catalyzed C(sp³)-H bond functionalization of azodiisobutyronitrile (AIBN) and analogues with terminal vinylarenes to generate γ-ketonitriles was also studied. A preliminary free-radical pathway was confirmed by capturing an alkyl radical, and a conjugate system was found that can stabilize radical intermediates and be in favor of this transformation. Density functional theory (DFT) calculations also provide important evidence of the free-radical pathway.

Full text of DOI:10.1021/acs.orglett.6b02692

Letter
pubs.acs.org/OrgLett
Unactivated C(sp3)−H Bond Functionalization of Alkyl Nitriles with
Vinylarenes and Mechanistic Studies
Xing-Wang Lan,† Nai-Xing Wang,*,† Cui-Bing Bai,† Cui-Lan Lan,‡ Tong Zhang,† Shi-Lu Chen,*,‡
and Yalan Xing*,§
†Technical Institute of Physics and Chemistry & University of Chinese Academy of Sciences, Chinese Academy of Sciences, Beijing,
100190, China
‡School of Chemistry, Beijing Institute of Technology, Beijing 100081, China
§Department of Chemistry, William Paterson University of New Jersey, 300 Pompton Road, Wayne, New Jersey 07470, United States
S
* Supporting Information
ABSTRACT: The first example of a metal-free unactivated C(sp3)−H
bond functionalization of alkyl nitriles with terminal vinylarenes to
provide γ-ketonitrile derivatives is described. This protocol features
simple operations, a broad substrate scope, and atom and step economy.
In addition, Cu-catalyzed C(sp3)−H bond functionalization of azodi-
isobutyronitrile (AIBN) and analogues with terminal vinylarenes to
generate γ-ketonitriles was also studied. A preliminary free-radical pathway was confirmed by capturing an alkyl radical, and a
conjugate system was found that can stabilize radical intermediates and be in favor of this transformation. Density functional
theory (DFT) calculations also provide important evidence of the free-radical pathway.
he direct oxidative coupling methodology involving the C−
In order to realize the high-value transformation of styrenes,
our group developed C(sp3)−H bond functionalization of
alcohols with terminal vinylarenes to provide complex products
in one step (Scheme 1a).2i The reaction features use of simple
reagents, mildconditions, andgoodfunctionalgrouptolerance.In
the same year, we also developed a copper/manganese dual
catalyst whichcocatalyzed the direct unactivated C(sp3)−H bond
functionalization of ketones with terminal vinylarenes to
T
H bond functionalization has attracted much attention due
to its step economy and energy efficiency.1 In this context, using
simple alkenes containing ubiquitous functional groups to
introduce both a carbonyl group and another functional group
has been extensively studied recently.2 Despite the impressive
achievements in this field, direct functionalization of molecules
containingC(sp3)−Hbondsismuchmorechallengingbecauseof
itshighbond-dissociationenergy(BDE).3 Greateffortshavebeen
made on terminal alkenes efficiently transferring into complex
organic molecules through C(sp3)−H bond functionalization.
For example, Zhang and co-workers2a reported the C(sp3)−H
bond functionalization of cyclic ethers with terminal alkenes by
copper catalysis. Li and co-workers2d reported an example of
C(sp3)−H bond functionalization of amides with terminal
alkenes for selective synthesis of β-amino ketones and α,β-
unsaturated amides. Certainly, there are still tremendous research
opportunities to develop new methods using unactivated alkenes
with simple reagents.
Scheme 1. Direct C(sp3)−H Bond Functionalization ofSimple
Reagents with Vinylarenes
Nitriles are among the most versatile scaffolds and can serve as
precursors for aldehydes, amides, nitrogen-containing hetero-
cycles and carboxylic acids, etc.4 In particular, ketonitriles have
servedasakeyunitinthesynthesisofvariouspharmaceuticals and
bioactive compounds.5 Directly C−H activation to incorporate
nitriles groups represents one of the most efficient and economic
strategies for the synthesis of substituted nitrile compounds. In
fact, the addition of nitriles, especially simple alkyl nitriles, to
alkenes via a radical process has been rarely investigated due to its
enolate formation. Only a few examples have been reported by
Liu,6 You,7 Liu,8 Ji,9,10 Tang,11 Zhu,12 etc. involving direct
oxidative cyanomethylation reactions by incorporating the alkyl
nitriles with alkenes.
Received: September 7, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b02692
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Letter
construct dicarbonyl compounds with good regioselectivity and
functional group tolerance (Scheme 1b).2j This protocol afforded
an excellent strategy for the synthesis of complex dicarbonyl
compounds only using simple reagents and mild conditions. As
part of our efforts on the development of direct unactivated
C(sp3)−H bond functionalization, we envisage whether unac-
tivated C(sp3)−H bond functionalization of alkyl nitriles with
terminal vinylarenes to synthesize high-value γ-ketonitriles can be
realized. Herein, we describe a metal-free catalyzed unactivated
C(sp3)−H bond functionalization of alkyl nitriles with terminal
vinylarenes to construct γ-ketonitriles (Scheme 1c), which is
convenient and economical, shows a broad substrate scope, and
exhibits good functional group tolerance. To the best of our
knowledge, this is the first report of γ-ketonitrile preparation
through direct unactivated C(sp3)−H bond functionalization of
alkylnitriles inone pot. Bothofthe twoprevious reactions involve
the free-radical pathway, but a preliminary mechanism was just
proposed. Inthis paper, bymeans ofradical trapping experiments,
nonconjugate substrates, and a competing kinetic isotope effect, a
free radical mechanism of this transformation is confirmed.
Finally, density functional theory (DFT) calculations were
performed to further verify the mechanism.
the result, a series of bases were examined, but DBU was found to
be the most efficient base (entry 3 vs entries 5−9). Subsequently,
we screened the peroxides, finding that TBHP exhibited the best
effect,whileotherperoxideshadpoorornoactivityatall(entries3
and 10 vs entries 11−13). After varying the amount of base and
peroxide, the yield was not further improved (entries 14−16).
Prolonging the reaction time to 48 h improved the yield to only
72%. Notably, when the reaction was performed without DBU or
TBHP, no desired product was obtained, revealing that using a
base and peroxide is critical for this transformation.
With the optimal conditions in hand, the substrate scope of the
oxidative coupling reaction was investigated (Scheme 2). As
Scheme 2. Substrate Scope for Reaction of Vinylarenes with
a
Nitriles
We commenced our investigations with styrene (1a) and
acetonitrile (2a) (both as reactant and solvent) as model
substrates in the presence of base and peroxide, with the results
shown in Table 1. Initially, we explored the cage effect8 of solvent
(Table 1, entries 1−4). It was found that 6 mL of acetonitrile were
optimal and a 70% yield of the γ-ketonitrile 3a was achieved in the
presence of 1 equiv of DBU and 4 equiv of TBHP. Encouraged by
a
Table 1. Modification of the Reaction Conditions
b
a
entry
base (equiv)
peroxide (equiv)
solvent (mL)
yield (%)
Reaction conditions: vinylarenes (1 equiv, 0.2 mmol), alkyl nitriles (6
mL) as solvent, DBU (1 equiv), TBHP (5.5 M in decane, 4 equiv) in
sealed tube at 110 °C for 24 h, unless otherwise noted; yields of the
isolated products.
1
2
3
4
5
6
7
8
9
DBU(1)
DBU (1)
DBU (1)
DBU (1)
DABCO (1)
Et3N (1)
t-BuOK (1)
K2CO3 (1)
NaOH(1)
DBU (1)
DBU (1)
DBU (1)
DBU (1)
DBU (0.5)
DBU (2)
DBU (1)
DBU (1)
DBU (1)
DBU (1)
−
TBHP (4)
TBHP (4)
TBHP (4)
TBHP (4)
TBHP (4)
TBHP (4)
TBHP (4)
TBHP (4)
TBHP (4)
TBHP (4)
K2S2O8 (4)
DTBP (4)
BPO (4)
2
4
6
8
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
23
57
70
61
32
29
53
24
trace
63
13
0
shown in Scheme 2, not only electron-donating groups, such as
tertiary butyl (3b), methyl (3c), and methoxyl (3d), but also
electron-withdrawing groups, such as halogen (F, Cl, Br) (3e−g)
and cyano (3h) on the phenyl ring of the styrene at the para-
position, could smoothly undergo the reaction, achieving
moderate to good yields, which indicated the electronic effect
was not an important factor. Exceptionally, only a trace amount of
product (3i) was generated using p-nitryl styrene as th esubstrate;
we speculated the strong electron-withdrawing group on the
phenyl ring inhibited this transformation. In addition, substituted
groups on the phenyl ring of styrene at the meta- and ortho-
position gave less or no yield of the corresponding products (3j−
3o). The reactivity of para-, meta-, and ortho-cholor-substituted
styrenes was as follows: para > meta > ortho, suggesting the
positionofthesubstituentsimpactedthereaction. Thus, thesteric
effect was thought to be a more crucial factor to this reaction. In
addition, the p-chloromethyl substituted styrene and 2-vinyl
naphthalene were tolerated in this transformation, forming the
corresponding products in 24% (3p) and 60% (3q) yield,
respectively. Afterward, valeronitrile and ethyl 2-cyanoacetate as
substrates (also as solvent) with styrene werealso tested, but poor
c
10
11
12
13
14
15
16
20
42
65
45
70
18
72
0
TBHP (4)
TBHP (4)
TBHP (2)
TBHP (4)
TBHP (4)
TBHP (4)
TBHP (4)
−
d
17
e
18
f
19
20
21
DBU (1)
0
a
Reaction condition: styrene 1a (1 equiv, 0.2 mmol), acetonitrile 2a as
solvent, base, TBHP (5.5 M in decane) in sealed tube at 110 °C for 24
h, unless otherwise noted. Isolated yields. TBHP (70% in water). 3
b
c
d
e
f
Å MS, 300 mg. 80 °C. 48 h.
B
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Letter
or no yield was afforded; we speculated that the solvent and cage
effects inhibited this transformation.
Scheme 4. Mechanistic Studies
Considering that azodiisobutyronitrile (AIBN) and its
analogues, which are commercially available, can easily form a
tertiary radical containing a cyano group, we turned our attention
to the coupling of terminal vinylarenes with AIBN and its
analogues to construct γ-ketonitriles via a radical process. Initial
studies on reaction conditions revealed that this transformation
differed from the reaction of vinylarenes with acetonitrile. Thus,
we further explored the reaction conditions by employing a
transition metal to promote this transformation. After screening a
series of catalytic systems, we found that Cu(OTf)2/1,10-phen/
DBU inDCE under air was the optimal condition for this reaction
(see Supporting Information (SI), Table S1). Under the optimal
reaction conditions, the substrate scope of this reaction was
investigated (Scheme 3). Styrene with an electron-donating (p-
Scheme 3. Substrate Scope for Reaction of Vinylarenes with
a
AIBN and Analogues
theC(sp3)−Hbondcleavageofacetonitrileisinvolvedintherate-
determining step.
On the basis of our experimental results and previous
literature,2i,j a plausible mechanism was proposed for the reaction
(Scheme 5). First, highly activated t-BuO· and HO· could be
Scheme 5. Plausible Reaction Mechanism
a
Reaction conditions: vinylarenes (0.3 mmol, 1 equiv), AIBN or
analogues (0.6 mmol, 2 equiv), Cu(OTf)2 (0.5 equiv), 1,10-phen (1
equiv), DBU (1 equiv) and DCE (3 mL) at 80 °C under air for 24 h;
yields of the isolated products.
methyl, m-methyl, p-tertiary butyl) and electron-withdrawing (p-
halide) substituents provided the corresponding products in
moderate yields, but p-nitryl styrene still afforded no correspond-
ing product. Similarly, the diazo analogues with styrene also
smoothly formed the corresponding product 5i and 5j,
respectively.
To gain insight into the mechanism, some mechanistic studies
weredesigned and performed (Scheme 4). First, 5 equivof radical
scavenger 2,2,6,6-tetramethyl-1-piperidinyloxyl (TEMPO) were
respectively added into the two systems under standard
conditions, and it was found that the two transformations were
completely inhibited. Adducts of TEMPO and alkyl radical could
be detected by HRMS. Thus, these results suggested that the
present reactions should involve a free radical process (Scheme
4a). Then, we chose two typical nonconjugate alkenes as
substrates to verify the free-radical mechanism. No desired γ-
ketonitriles were formed when using allylbenzene or vinyl-
cyclohexane as the substrate, suggesting that nonconjugate
alkenes were not suitable for this transformation (Scheme 4b).
Thus, we believed that the phenyl group could disperse the
electron of the free radical to stabilize the nascent radical
intermediate due to the p-π conjugate effect. Finally, we studied
theintermolecular competing kinetic isotope effect (KIE)and the
value of KH/KD = 15.7 was delivered (Scheme 4c), indicating that
generatedfromTBHPunderheatingwiththeaidofbasesthrough
several procedures, which could activate the C(sp3)−H bond of
acetonitrile andabstract theα-Hatom ofacetonitrile togenerate a
primary alkyl radical. Addition of the alkyl radical to the double
bond of vinylarenes 1 afforded a transient intermediate radical A,
and then A and t-BuOO· form intermediate B. Finally,
intermediate B could be converted to the target product 3 in
the presence of DBU. Further studies regarding the detailed
mechanism are currently underway.
In order to verify the accuracy of these mechanisms, the
investigation used DFT calculations along with hybrid functional
B3LYP, as it is implemented in the Gaussian 09 package (Scheme
6; for details see SI).13 Initially, t-BuOOH was decomposed into
two activated radicals, requiring a free energy of 18.2 kcal/mol.
C
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Scheme 6. DFT-Computed Energy Profiles for C(sp3)−H
Bond Functionalization of Acetonitrile with Styrene
ACKNOWLEDGMENTS
Financial support for this research was provided by the Natural
Science Foundation of China (21572240).
■
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ASSOCIATED CONTENT
* Supporting Information
■
(8) Li, Z.; Xiao, Y.; Liu, Z.-Q. Chem. Commun. 2015, 51, 9969.
(9) Chu, X.-Q.; Meng, H.; Zi, Y.; Xu, X.-P.; Ji, S.-J. Org. Chem. Front.
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TheSupportingInformationisavailablefreeofchargeontheACS
Publications website at DOI: 10.1021/acs.orglett.6b02692.
(10) Chu, X.-Q.; Xing, Z.-H.; Meng, H.; Xu, X.-P.; Ji, S.-J. Org. Chem.
Front. 2016, 3, 165.
Segmental experimental results and procedures, character-
izationdata,andcopiesofspectraforallcompounds(PDF)
(11) Zhou, D.; Li, Z.-H.; Li, J.; Li, S.-H.; Wang, M.-W.; Luo, X.-L.; Ding,
G.-L.; Sheng, R.-L.; Fu, M.-J.; Tang, S. Eur. J. Org. Chem. 2015, 2015,
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AUTHOR INFORMATION
(12) Bunescu, A.; Wang, Q.; Zhu, J. Angew. Chem., Int. Ed. 2015, 54,
■
3132.
Corresponding Authors
(13) All of the energies discussed in the paper are Gibbs free energies in
the liquid phase. Computational details and references are givenin the SI.
*E-mail: nxwang@mail.ipc.ac.cn.
*E-mail: shlchen@bit.edu.cn.
*E-mail: xingy@wpunj.edu.
Notes
The authors declare no competing financial interest.
D
DOI: 10.1021/acs.orglett.6b02692
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