Mechanistic study of the selectivity of olefin versus cyclobutene formation by palladium(0)-catalyzed intramolecular C(sp3)-H activation

Article abstract of DOI:10.1021/jo501610x

(Chemical Equation Presented) This study describes the mechanism and selectivity pattern of the Pd⁰-catalyzed C(sp³)-H activation of a prototypical substrate bearing two linear alkyl groups. Experimentally, the use of the Pd/P(t-Bu)₃ catalytic system leads to a ca. 7:3 mixture of olefin and benzocyclobutene (BCB) products. The C-H activation step was computed to be favored for the secondary position α to the benzylic carbon over the primary position β to the benzylic carbon by more than 4 kcal mol^-1, in line with previous selectivity trends on analogous substrates. The five-membered palladacycle obtained through this activation step may then follow two different pathways, which were computationally characterized: (1) decoordination of the protonated base and reductive elimination to give the BCB product and (2) proton transfer to the aryl ligand and base-mediated β-H elimination to give the olefin product. Experiments conducted with deuterated substrates were in accordance with this mechanism. The difference between the highest activation barriers in the two pathways was computed to be 1.2 kcal mol^-1 in favor of BCB formation. However, the use of a kinetic model revealed the critical influence of the kinetics of dissociation of HCO₃^- formed after the C-H activation step in actually directing the reaction toward either of the two pathways.

Full text of DOI:10.1021/jo501610x

Article
pubs.acs.org/joc
Mechanistic Study of the Selectivity of Olefin versus Cyclobutene
Formation by Palladium(0)-Catalyzed Intramolecular C(sp3)−H
Activation
Christos E. Kefalidis,† Michael Davi,‡ Philipp M. Holstein,‡ Eric Clot,*,† and Olivier Baudoin*,‡
̈
†Institut Charles Gerhardt, CNRS UMR 5253, Universite
Montpellier, France
́
Montpellier 2, case courrier 1501, Place Eugen
̀
e Bataillon, 34095
‡Universite
́
Claude Bernard Lyon 1, CNRS UMR 5246 - Institut de Chimie et Biochimie Molec
́
ulaires et Supramolec
́
ulaires, CPE
Lyon, 43 Boulevard du 11 Novembre 1918, 69622 Villeurbanne, France
S
* Supporting Information
ABSTRACT: This study describes the mechanism and
selectivity pattern of the Pd0-catalyzed C(sp3)−H activation
of a prototypical substrate bearing two linear alkyl groups.
Experimentally, the use of the Pd/P(t-Bu)3 catalytic system
leads to a ca. 7:3 mixture of olefin and benzocyclobutene
(BCB) products. The C−H activation step was computed to
be favored for the secondary position α to the benzylic carbon
over the primary position β to the benzylic carbon by more
than 4 kcal mol−1, in line with previous selectivity trends on
analogous substrates. The five-membered palladacycle ob-
tained through this activation step may then follow two different pathways, which were computationally characterized: (1)
decoordination of the protonated base and reductive elimination to give the BCB product and (2) proton transfer to the aryl
ligand and base-mediated β-H elimination to give the olefin product. Experiments conducted with deuterated substrates were in
accordance with this mechanism. The difference between the highest activation barriers in the two pathways was computed to be
1.2 kcal mol−1 in favor of BCB formation. However, the use of a kinetic model revealed the critical influence of the kinetics of
dissociation of HCO3− formed after the C−H activation step in actually directing the reaction toward either of the two pathways.
starting with oxidative addition to an active palladium(0)
species, followed by substitution of the halide with the
carbonate base, base-assisted intramolecular C(sp3)−H activa-
tion giving rise to a five- or six-membered palladacycle (6−7),
decoordination of the protonated base, and reductive
elimination. The formation of olefins 4 through C−H
activation of linear alkyl groups, reported initially by us5a−c
and subsequently by other groups,6g,q constitutes the missing
link in this global mechanistic picture. The aim of the current
mechanistic study is to fill this gap.
INTRODUCTION
■
Transition-metal-catalyzed C−H bond functionalization has
recently emerged as a powerful tool to transform otherwise
unreactive C−H bonds into carbon−carbon or carbon−
heteroatom bonds.1,2 This area is gradually changing the way
chemists functionalize organic molecules by providing atom-
and step-economical alternatives to more traditional methods
and facilitating the access to valuable and original compounds.
In contrast to the wealth of methods recently developed for the
functionalization of arene and heteroarene C(sp2)−H bonds,3
relatively little work has focused on the functionalization of
unreactive, nonacidic C(sp3)−H bonds of alkyl groups.4 In this
context, our group5 as well as others6 have developed a series of
palladium(0)-catalyzed reactions from aryl halides or pseudo-
halides for the construction of C(sp3)−C(sp2) bonds or the
dehydrogenation of C(sp3)−C(sp3) bonds based on C(sp3)−H
activation. These methods allow for the rapid and efficient
synthesis of original structural motifs such as olefins, fused
carbocycles and heterocycles, and polyarylated molecules.
In previous papers, we have computationally characterized
the mechanism of the palladium(0)-catalyzed intramolecular
C(sp3)−H arylation of aryl halides 1 to give benzocyclobutenes
(BCBs) 25d,7 and indanes 35f (Scheme 1). These fused
carbocycles arise from a sequence of five elementary steps
RESULTS AND DISCUSSION
■
Experimental Observations. We first analyzed the
reaction of model substrate 1a under standard conditions
involving Pd(OAc)2/P(t-Bu)3 as the catalyst (10 mol % Pd),
K2CO3 as the base (1.3 equiv), and DMF as the solvent
(Scheme 2a). GC−MS analysis of the crude mixture revealed
the formation of two sets of products in a 7:3 ratio, i.e., olefin
4a, the identity of which was proven after chromatographic
purification, and two other products of the same molecular
Special Issue: Mechanisms in Metal-Based Organic Chemistry
Received: July 17, 2014
© XXXX American Chemical Society
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Scheme 1. Overall Mechanism for the Palladium(0)-Catalyzed C(sp3)−H Activation of Aryl Halides
Scheme 2. C−H Activation of Protiated and Deuterated Substrates
a
GC ratio.
weight as 4a (m/z 171 for [M+•]), tentatively assigned as BCB
diastereoisomers 2a and 2b (d.r. = 1.5:1), which could not be
isolated and unambiguously identified.8 A similar product
distribution was obtained with Pd2dba3 as the Pd source (10
mol % Pd) instead of Pd(OAc)2, again with K2CO3 as the base.
In contrast, with Pd2dba3 as the Pd source and KOAc instead of
K2CO3, olefin 4a was the only observed product. These results
indicate that carbonate and not acetate is the active base when
Pd(OAc)2 is employed as the Pd source, in line with previous
cases where a polar solvent such as DMF was employed.5 Of
note, the formation of 2a and 2b was not observed under
previously reported conditions using P(o-tol)3 or analogues5a,b
and is currently favored by the use of P(t-Bu)3, an optimal
ligand for BCB formation.5d Although the formation of 2a and
B
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2b clearly arises from activation at one of the α C−H bonds of
1a, it was not possible to conclude at this point whether the
same initial bond cleavage is also responsible for the formation
of olefin 4a. To lift this ambiguity, the reactions of deuterated
substrates 1b−d were analyzed. First, the reaction of compound
1b bearing fully deuterated ethyl groups was studied (Scheme
2b). Major albeit incomplete (71%) deuterium incorporation
C−H bond > secondary α C−H bond > primary β C−H bond
> tertiary α C−H bond.5b−f,6e
The C−H bond activated in TSCHα presents an interaction
with Pd in the reactant RCH prior to its cleavage (Pd···H =
2.116 Å, C−H = 1.112 Å, Pd···Cα = 3.073 Å; Figure 2). In the
2
on the aromatic ring was observed by H NMR spectroscopy
(Figure S2 in the Supporting Information). This incomplete
deuterium transfer can be assigned to an external proton source
(presumably traces of water) exchanging with the migrating
deuterium atom, consistent with previous observations on
related Pd migrations.9 Indeed, when nondeuterated substrate
1a was reacted in the presence of 10 equiv of D2O, partial
deuterium incorporation on the aromatic ring was observed by
2H NMR spectroscopy. The reaction of partially deuterated
substrates 1c and 1d was next examined (Scheme 2c,d). Only
product 4d (but not 4c) displayed deuterium incorporation on
the aromatic ring as a result of H/D atom transfer from the α
methylene carbon to the ortho sp2 carbon. This observation is
consistent with previous deuterium-labeling experiments5a and
with the revised mechanism described in the next paragraph.
Computational Studies. Previous DFT calculations on the
mechanism of the formation of BCB 2 from aryl halides
Figure 2. Geometries of the extrema along the pathway for the
formation of BCB 2a from 1a. Most of the H atoms have been omitted
for clarity.
transition-state geometry, the C−H bond is significantly
elongated (1.428 Å), while the formation of the O−H bond
is well-advanced (1.276 Å). This is accompanied by a significant
reduction of the Pd···Cα bond distance (2.462 Å) and by the
creation of an agostic interaction with the geminal C−H bond
(C−H = 1.105 Å, Pd−C−H = 74.2°). Overall, this pattern of
interactions leads to a relatively low activation barrier of ΔG⧧ =
19.8 kcal mol−1 for the C−H activation from RCH through
TSCHα. This transformation is computed to be exoergic by ΔG
= −19.2 kcal mol−1. The product of the C−H activation step,
2−
(Scheme 1) catalyzed by Pd[P(t-Bu)3] and mediated by CO3
have already outlined the important features of this trans-
formation.5d,7 In particular, the crucial transition state (TS)
associated with C−H activation presents a geometry where P(t-
Bu)32−is coordinated trans to the metalated aromatic ring and
CO3 is coordinated opposite to the cleaved C−H bond
according to a concerted metalation−deprotonation (CMD)10
mechanism. Other geometries were considered and already
discussed in detail, such as proton abstraction by a cis-
coordinated carbonate6e,i,p and intermolecular proton abstrac-
tion.7,11 For the current study, only the geometry with the
pseudo-trans relationship between CO32− and the cleaved C−H
bond was considered, in line with these previous results. To
characterize the lowest TS for the C−H activation of substrate
1a at the α and β positions, various conformations of this
substrate were examined (Figure S3 in the Supporting
Information). Only the geometry of each lowest-energy TS is
displayed in Figure 1.12 The lowest TS associated with the
activation of a primary β C−H bond, TSCHβ was computed to
lie 4.2 kcal mol−1 above TSCHα. Thus, the current calculations
show that the preferred site for the C−H activation of substrate
1a is the secondary α position through TSCHα. This result is
consistent with the selectivity trend observed experimentally for
analogous substrates bearing different alkyl groups: primary α
P
CH, features a five-membered palladacycle coordinated to the
protonated base HCO3− (Figure 2, top right). The formation of
−
BCB 2a through C−C coupling requires dissociation of HCO3
to generate the ML3 intermediate RCC. This transformation is
computed to be exoergic by ΔG = −12.8 kcal mol−1. A large
part of this value is due to entropic effects, as the dissociation
enthalpy is computed to be positive (ΔH = 4.1 kcal mol−1).
From RCC, the reductive C−C coupling through TSCC was
computed to have an activation barrier of ΔG⧧ = 27.4 kcal
mol−1 and leads to the exoergic formation (ΔG = −1.9 kcal
mol−1) of PCC, i.e., the BCB product 2a (presumed major
diastereoisomer) coordinated to Pd[P(t-Bu)3]. This high
kinetic barrier reflects the significant ring strain that must be
overcome to form the BCB system. Overall, the highest Gibbs
energy barrier to overcome in the formation of 2a from 1a is
thus ΔG⧧ = 27.4 kcal mol−1 associated with C−C bond
formation.
Another possibility from PCH is to use the proton on the
coordinated HCO3− to break the Pd−C(sp2) bond between the
aromatic ring and the metal.5d The corresponding TS, TStransf
(Figure 3), was located at ΔG⧧ = 24.3 kcal mol−1 above PCH. In
the TS, the Pd−C(sp2) bond distance has increased to 2.251 Å
(vs 1.989 Å in PCH) and the O−H bond has lengthened to
1.338 Å (vs 0.975 Å in PCH). The forming C(sp2)−H bond has
a similar length in the TS (1.332 Å) as the breaking O−H
bond. From PCH, the protonation of the aromatic ring is
significantly easier than the protonation of the Pd−C(sp3)
bond to revert to RCH, with the latter having an associated
activation energy barrier of ΔG⧧ = 39.0 kcal mol−1. The
Figure 1. Geometries and relative energy (kcal mol−1) of the
transition-state structures computed for the C−H activation of 1a at
(left) Cα and (right) Cβ.
product of the protonation of the Pd−C(sp2) bond, Ptransf
,
C
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elimination. Instead, the carbonate is once again used as an
internal base to deprotonate the C−H bond. In TSβ‑elim, the
C−H bond has lengthened to 1.254 Å, whereas the O···H bond
distance is 1.573 Å. The activation barrier for the process from
Ptransf to TSβ‑elim is computed to be ΔG⧧ = 28.6 kcal mol−1. The
product of the transformation, Pβ‑elim, features, after dissocia-
−
tion of HCO3 , olefin 4a coordinated through the alkene CC
bond. This product is ΔG = −14.9 kcal mol−1 more stable than
Ptransf, and the overall transformation from PCH to Pβ‑elim is thus
composed of two consecutive exoergic steps. Pβ‑elim is
computed to be more stable than PCC by ΔG = −7.9 kcal
mol−1. The olefin complex is thus the thermodynamic product.
Figure 4 shows the energy diagram for the formation of BCB
2a and olefin 4a from the common palladacycle intermediate
PCH. The highest activation barrier to overcome along the
pathway associated with the formation of Pβ‑elim is 28.6 kcal
mol−1, which is slightly higher than the corresponding value for
the formation of the BCB product (27.4 kcal mol−1). This
would tend to indicate that the BCB product 2a should be the
major kinetic product of the reaction. However, a critical aspect
of the mechanism is the competition between dissociation of
−
HCO3 from PCH, opening the pathway toward BCB
formation, and protonation of the aryl ligand, opening the
pathway for olefin formation. Such dissociation processes are
very difficult to compute accurately.
Figure 3. Geometries of the extrema along the pathway for the
formation of olefin 4a from 1a. Most of the H atoms have been
omitted for clarity.
To address this issue, the reaction rate was simulated. The
kinetic model shown in Figure 5 was considered, in which the
rate constants ki were estimated at T = 413 K using the Eyring
equation with the computed ΔG⧧ values. The rate constant k−1
for the coordination of HCO3− to RCC was approximated using
the Gibbs free energy difference between RCC and PCH, i.e.,
features a κ2-CO3 ligand and is ΔG = −7.8 kcal mol−1 more
stable than PCH. Rotation around the Pd−C(sp3) bond in Ptransf
2−
and concomitant decoordination of one oxygen atom of CO3
allows the system to reach the transition-state structure TSβ‑elim
in which a β C−H bond is broken. However, the hydrogen
atom is not transferred to the metal as in a typical β-H
ΔG⧧−1 = G(PCH) − G(RCC) − G(HCO3 ) = 12.8 kcal mol−1.
−
Figure 4. Comparison of the energetics (Gibbs energies, kcal mol−1) associated with the pathways for C−C bond formation (right) and olefin
formation (left) for substrate 1a from palladacycle PCH
.
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favored because both transformations PCH → Ptransf and Ptransf
→ Pβ‑elim are strongly exoergic. The inverse reactions are
−
associated with high barriers, and if HCO3 dissociation from
PCH is slow enough, Ptransf starts to accumulate to finally yield
the olefin as the major product.
It is noteworthy that the above mechanism proposed for the
formation of olefin 4a contrasts with the mechanism usually
proposed for the Heck reaction, which involves β-hydride
elimination to form a Pd−H bond.14 From Ptransf, dissociation
2−
of CO3 would afford an intermediate, P′transf, that might be
prone to β-H elimination (Figure 7). However, in the present
Figure 5. Kinetic model used to model the competition between the
formation of benzocyclobutene 2a and olefin 4a.
Then the influence of different values of k1 on the overall
reaction kinetics was analyzed using this model.
The differential equations associated with the kinetic model
in Figure 5 were solved using the Copasi software for an initial
RCH concentration of 1 mmol mL−1.13 Three different
situations were considered, each associated with a different
Figure 7. Geometries of P′transf and PHeck
.
−
value of the activation barrier for the dissociation of HCO3
case, η2 coordination of the aromatic ring to the cationic metal
center is observed, and no transition state for β-H elimination
could be located. Nevertheless, the corresponding product
featuring a Pd−H bond, PHeck, was located on the potential
energy surface. This intermediate was computed to be less
stable than Pt′ransf by ΔG = 10.8 kcal mol−1, but more
importantly, the energy difference between PHeck and the κ2-
CO3 intermediate Ptransf is very high (ΔG = 58.7 kcal mol−1).
This rules out any Heck-type pathway in the formation of olefin
4a. The proposed pathway for the formation of 4a might also
be operative in Heck reactions mediated by carbonate or similar
bases. The base would substitute the X− anion in the
coordination sphere of the metal and would perform the β
C−H bond cleavage similar to the current mechanism.15
from PCH. Figure 6 shows a comparison of the evolutions of the
CONCLUSION
■
In this article, we have analyzed the mechanism as well as the
selectivity pattern for the Pd0-catalyzed C(sp3)−H activation of
a prototypical substrate (1a) bearing two ethyl groups. This
reaction mainly gives rise to an alkene product (4a) when Pd/
P(t-Bu)3 is used as the catalytic system, together with minor
amounts of BCB products (2a and 2b). The C−H activation
step was computed to be favored for the secondary position α
to the benzylic carbon over the primary position β to the
benzylic carbon by more than 4 kcal mol−1, in line with
previous selectivity trends on analogous substrates. The
corresponding five-membered palladacycle may then follow
two different pathways, which were computationally charac-
terized: (1) decoordination of the protonated base and
reductive elimination to give the BCB product (2a) and (2)
proton transfer to the aryl ligand and base-mediated β-H
elimination to give the olefin product (4a). The results of
experiments conducted using deuterated substrates were in
accordance with this mechanism. The computed activation
barriers would tend to suggest that BCBs 2a and 2b rather than
olefin 4a should be the main reaction products. However, a
kinetic model showed the critical influence of the kinetics of
dissociation of HCO3− formed after the C−H activation step in
actually directing the reaction toward either of the two
Figure 6. Comparison of the evolutions of the concentrations of PCC
,
Ptrans, and Pβ‑elim with time obtained with the kinetic model in Figure 5
using the Copasi software. The curves are associated with different
−
values of the activation barrier for HCO3 dissociation from PCH
(black, 6 kcal mol−1; blue, 9 kcal mol−1; red, 12 kcal mol−1).
concentrations of PCC, Ptransf, and Pβ‑elim as functions of time for
the three different situations considered. The curves in black
correspond to a barrier of 6 kcal mol−1 for HCO3− dissociation,
and in that case, only the BCB product 2a is formed. Increasing
the barrier for dissociation to 9 kcal mol−1 significantly alters
the final ratio between the different products, as illustrated by
the curves in blue, which show that olefin 4a is formed in a ratio
of ca. 1:4 with respect to BCB 2a. Finally, for a dissociation
barrier of 12 kcal mol−1 (curves in red), the olefin now
becomes the preferred product with a ratio qualitatively similar
to the one observed experimentally. For the three situations
−
described above, the dissociation of HCO3 is always much
faster than protonation of the aryl ring, as the ratio k1/k3 varies
from ca. 109 to 106. Thus, even when dissociation of HCO3− is
ca. 106 times faster than protonation, the olefin formation is
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MgSO4. Evaporation of the solvent and purification of the residue by
flash chromatography (cyclohexane/ethyl acetate 95:5) afforded the
title compound as a yellow oil (240 mg, 0.92 mmol, 90%). Rf 0.53
pathways. Overall, this study addressing the formation of olefin
versus carbocyclic products fills the gap of previous mechanistic
reports on Pd0-catalyzed C(sp3)−H activation. In addition, it
presents a new scenario for the β-hydrogen elimination
mechanism in Heck-type reactions.
1
(cyclohexane/ethyl acetate 9:1). H NMR (300 MHz, CDCl3) δ 7.69
(dd, J = 7.9, 1.6 Hz, 1H), 7.61 (dd, J = 7.9, 1.3 Hz, 1H), 7.36−7.30 (m,
1H), 7.19−7.14 (m, 1H). 13C{1H} NMR (75 MHz, CDCl3) δ 141.6,
140.3, 137.3, 134.9, 133.2, 128.1, 126.0, 57.4, 34.6 (quint, J = 19 Hz),
14.4 (sept, J = 19 Hz). IR (neat) ν 2970, 2224, 1564, 1469 cm−1.
HRMS (EI) calcd for C12H4D10BrN [M+•] 261.0937, found 261.0932.
2-(1,1,2,2,2-d5-Ethyl)-2-phenyl-3,4,4-d3-but-3-enenitrile (4b).
Compound 4b was obtained according to the general C−H activation
procedure from compound 1b (50 mg, 0.19 mmol), Pd(OAc)2 (4.4
mg, 0.02 mmol, 10 mol %), P(t-Bu)3·HBF4 (11.2 mg, 0.038 mmol, 20
mol %), and dry K2CO3 (34.8 mg, 0.25 mmol, 1.3 equiv). The residue
was purified by flash chromatography (cyclohexane/ethyl acetate 98:2)
to afford the title compound as a yellow oil (17 mg, 0.10 mmol, 53%).
Rf 0.50 (cyclohexane/ethyl acetate 9:1). Compound 4b was obtained
with 71% deuterium incorporation on the aromatic ring as determined
EXPERIMENTAL SECTION
■
General Information. Unless otherwise noted, all nonaqueous
reactions were performed under an oxygen-free atmosphere of argon
with rigid exclusion of moisture from reagents and glassware using
standard techniques for manipulating air-sensitive compounds. K2CO3
was dried under vacuum at 140 °C for 24 h and then stored under an
argon atmosphere in a glovebox. Other reagents were commercially
available and were used without further purification unless otherwise
stated. The solvents were dried by standard methods prior to use.
Anhydrous THF was obtained by distillation over sodium/
benzophenone. Analytical thin-layer chromatography (TLC) was
performed using 0.25 mm silica gel 60-F plates. Visualization of the
developed chromatograms was performed by UV absorbance (254
nm). Flash chromatography was performed using silica gel 60 (60−
200 mesh) with the indicated solvent system according to standard
techniques. GC analyses were performed with a GC−MS apparatus,
with injection on a DB-5 ms column lined with a mass (EI) detection
system. Infrared data are reported in reciprocal centimeters (cm−1).
NMR spectra (1H, 2H, 13C, 19F, DEPT 135, COSY, HMQC, NOESY)
were recorded in deuterated chloroform (1H 7.26 ppm, 13C 77.0
ppm), unless otherwise noted. All spectra were obtained with
complete proton decoupling. Chemical shifts are reported in parts
per million (ppm). The data are reported as follows: chemical shift
(multiplicity, coupling constant in Hz, integration). Multiplicities are
abbreviated as follows: s = singlet, d = doublet, t = triplet, q = quartet,
quint = quintet, sept = septet, m = multiplet, and br = broad. When
ambiguous, proton and carbon assignments were established using
COSY, HMQC, and DEPT experiments. High-resolution mass
spectrometry (HRMS) was performed in electron impact (EI) mode
using a magnetic analyzer.
2
1
by H NMR spectroscopy (acetone/acetone-d6 95:5). H NMR (300
MHz, CDCl3) δ 7.45−7.29 (m, 5H). 13C{1H} NMR (75 MHz,
CDCl3) δ 138.7, 137.0 (t, J = 24.8 Hz), 129.0, 128.0, 126.2, 120.7,
115.8 (quint, J = 24.2 Hz), 50.9, 31.6−32.7 (m), 9.2−8.2 (m). IR
(neat) ν 2970, 2230, 1574, 1470 cm−1. HRMS (EI) calcd for
C12H5D8N [M+•] 179.1545, found 179.1543.
2-(2-Bromophenyl)-2-(2,2,2-d3-ethyl)-4,4,4-d3-butyronitrile
(1c). LiHMDS (1.06 M in THF, 2.89 mL, 3.06 mmol) was added
dropwise at 0 °C to a solution of (2-bromophenyl)acetonitrile (200
mg, 1.02 mmol) in THF (1 mL). The reaction mixture was stirred at 0
°C for 30 min, and then iodoethane-2,2,2-d3 (245 μL, 3.06 mmol) was
added dropwise. The reaction mixture was stirred at rt overnight. After
hydrolysis with a saturated aqueous solution of NH4Cl (10 mL), the
aqueous phase was extracted with Et2O (3 × 5 mL), and the combined
organic layers were washed with brine and dried over MgSO4.
Evaporation of the solvent and purification of the residue by flash
chromatography (cyclohexane/ethyl acetate 95:5) afforded the title
compound as a yellow oil (228 mg, 0.88 mmol, 86%). Rf 0.50
1
(cyclohexane/ethyl acetate 9:1). H NMR (300 MHz, CDCl3) δ 7.68
(dd, J = 7.9, 1.6 Hz, 1H), 7.60 (dd, J = 7.9, 1.3 Hz, 1H), 7.35−7.29 (m,
1H), 7.18−7.13 (m, 1H), 2.61 (d, J = 14.1 Hz, 1H), 2.04 (d, J = 14.1
Hz, 1H). 13C{1H} NMR (75 MHz, CDCl3) δ 135.9, 134.6, 131.6,
129.2, 127.5, 122.4, 120.2, 52.0, 29.7, 9.0 (sept, J = 19 Hz). IR (neat) ν
2228, 1560, 1471, 1018 cm−1. HRMS (EI) calcd for C12H8D6BrN
[M+•] 257.0686, found 257.0689.
General C−H Activation Procedure. A dry Schlenk tube
containing a magnetic rod was charged with the aryl bromide,
Pd(OAc)2 (10 mol %), P(t-Bu)3·HBF4 (20 mol %), and dry K2CO3
(1.3 equiv). The Schlenk tube was evacuated, backfilled with argon
twice, and then capped with a rubber septum. Dry DMF (c = 0.24 mol
L−1) was injected under argon, and then the septum was replaced by a
screwcap and the mixture was stirred at 140 °C (preheated oil bath)
until disappearance of the starting material as monitored by GC−MS
analysis. After cooling, the mixture was diluted with Et2O and filtered
through Celite. The organic solution was washed three times with
brine and dried over MgSO4. After filtration, the solvent was
evaporated under reduced pressure. The residue was purified by
flash chromatography (silica gel).
2-(2,2,2-d3-Ethyl)-2-phenyl-4,4-d2-but-3-enenitrile (4c). Com-
pound 4c was obtained according to the general C−H activation
procedure from compound 1c (50 mg, 0.19 mmol), Pd(OAc)2 (4.4
mg, 0.02 mmol, 10 mol %), P(t-Bu)3·HBF4 (11.2 mg, 0.038 mmol, 20
mol %), and dry K2CO3 (34.8 mg, 0.25 mmol, 1.3 equiv). The residue
was purified by flash chromatography (cyclohexane/ethyl acetate 98:2)
to afford the title compound as a yellow oil (20 mg, 0.11 mmol, 59%).
Rf 0.48 (cyclohexane/ethyl acetate 9:1). Compound 4c showed no
2-Ethyl-2-phenylbut-3-enenitrile (4a).5b Compound 4a was
obtained according to the general C−H activation procedure from 2-
(2-bromophenyl)-2-ethylbutyronitrile (1a) (100 mg, 0.39 mmol),
Pd(OAc)2 (8.9 mg, 0.039 mmol, 10 mol %), P(t-Bu)3·HBF4 (23.0 mg,
0.079 mmol, 20 mol %), and dry K2CO3 (71.1 mg, 0.51 mmol, 1.3
equiv). The residue was purified by flash chromatography (cyclo-
hexane/ethyl acetate 99:1) to afford the title compound as a yellow oil
(43 mg, 0.25 mmol, 64%). Rf 0.48 (cyclohexane/ethyl acetate 9:1). 1H
NMR (300 MHz, CDCl3) δ 7.45−7.28 (m, 5H), 5.92 (dd, J = 17.1,
10.2 Hz, 1H), 5.54 (d, J = 17.1 Hz, 1H), 5.33 (d, J = 10.2 Hz, 1H),
2.17−1.98 (m, 2H), 1.02 (t, J = 7.3 Hz, 3H).
2-(2-Bromophenyl)-2-(1,1,2,2,2-d5-ethyl)-3,3,4,4,4-d5-butyr-
onitrile (1b). LiHMDS (1.06 M in THF, 2.89 mL, 3.06 mmol) was
added dropwise at 0 °C to a solution of (2-bromophenyl)acetonitrile
(200 mg, 1.02 mmol) in THF (1 mL). The reaction mixture was
stirred at 0 °C for 30 min, and then iodoethane-d5 (245 μL, 3.06
mmol) was added dropwise. The reaction was stirred at rt overnight.
After hydrolysis with a saturated aqueous solution of NH4Cl (10 mL),
the aqueous phase was extracted with Et2O (3 × 5 mL), and the
combined organic layers were washed with brine and dried over
2
deuterium incorporation on the aromatic ring as determined by H
1
NMR spectroscopy (acetone/acetone-d6 95:5). H NMR (400 MHz,
CDCl3) δ 7.44−7.42 (m, 2H), 7.40−7.37 (m, 2H), 7.32−7.30 (m,
1H), 5.90 (s, 1H), 2.09 (d, J = 14.0 Hz, 1H), 2.02 (d, J = 14.0 Hz, 1H).
13C{1H} NMR (125 MHz, CDCl3) δ 139.1, 137.7, 129.3, 128.3, 126.5,
121.0, 116.5, 51.4, 33.2, 9.1. IR (neat) ν 2227, 1590, 1493 cm−1.
HRMS (EI) calcd for C12H8D5N [M+•] 176.1356, found 176.1359.
2-(2-Bromophenyl)-2-(1,1-d2-ethyl)-3,3-d2-butyronitrile (1d).
LiHMDS (1.06 M in THF, 2.89 mL, 3.06 mmol) was added dropwise
at 0 °C to a solution of (2-bromophenyl)acetonitrile (200 mg, 1.02
mmol) in THF (1 mL). The reaction mixture was stirred at 0 °C for
30 min, and then iodoethane-1,1-d2 (245 μL, 3.06 mmol) was added
dropwise. The reaction mixture was stirred at rt overnight. After
hydrolysis with a saturated aqueous solution of NH4Cl (10 mL), the
aqueous phase was extracted with Et2O (3 × 5 mL), and the combined
organic layers were washed with brine and dried over MgSO4.
Evaporation of the solvent and purification of the residue by flash
chromatography (cyclohexane/ethyl acetate 95:5) afforded the title
compound as a yellow oil (239 mg, 0.93 mmol, 91%). Rf 0.48
F
dx.doi.org/10.1021/jo501610x | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
1
(cyclohexane/ethyl acetate 9:1). H NMR (300 MHz, CDCl3) δ 7.68
REFERENCES
■
(dd, J = 7.8, 1.5 Hz, 1H), 7.60 (dd, J = 7.8, 1.2 Hz, 1H), 7.35−7.29 (m,
1H), 7.19−7.13 (m, 1H), 0.89 (s, 6H). 13C{1H} NMR (75 MHz,
CDCl3) δ 136.3, 135.0, 132.1, 129.7, 128.0, 122.9, 120.7, 52.3, 29.6
(quint, J = 19 Hz), 10.0. IR (neat) ν 2968, 2232, 1565, 1470 cm−1.
HRMS (EI) calcd for C12H10D4BrN [M+•] 255.0561, found 255.0555.
2-(1,1-d2-Ethyl)-2-phenyl-3-d-but-3-enenitrile (4d). Com-
pound 4d was obtained according to the general C−H activation
procedure from compound 1d (50 mg, 0.19 mmol), Pd(OAc)2 (4.4
mg, 0.02 mmol, 10 mol %), P(t-Bu)3·HBF4 (11.3 mg, 0.039 mmol, 20
mol %), and dry K2CO3 (35.0 mg, 0.25 mmol, 1.3 equiv). The residue
was purified by flash chromatography (cyclohexane/ethyl acetate 98:2)
to afford the title compound as a yellow oil (18 mg, 0.10 mmol, 54%).
Rf 0.50 (cyclohexane/ethyl acetate 9:1). Compound 4d was obtained
with 43% deuterium incorporation on the aromatic ring as determined
by H NMR spectroscopy (acetone/acetone-d6 95:5). H NMR (300
MHz, CDCl3) δ 7.45−7.28 (m, 5H), 5.54−5.52 (m, 1H), 5.33−5.32
(m, 1H), 1.01 (s, 3H). 13C{1H} NMR (75 MHz, CDCl3) δ 138.6,
137.0 (t, J = 24.9 Hz), 128.9, 127.9, 126.1, 120.6, 116.3, 50.9, 32.3, 9.5.
IR (neat) ν 2970, 2236, 1448 cm−1. HRMS (EI) calcd for C12H10D3N
[M+•] 174.1231, found 174.1231.
Computational Details. Geometry optimizations were performed
with the Gaussian 09 package at the B3PW91 level of hybrid density
functional theory.16−18 The palladium atom was represented by the
relativistic effective core potential (RECP) from the Stuttgart group
and the associated basis sets,19 augmented by an f polarization
function.20 The phosphorus atom was represented by the RECP from
the Stuttgart group and the associated basis set,21 augmented by a d
polarization function.22 The remaining atoms (C, H, N, O) were
represented by a 6-31G(d,p) basis set. The influence of the solvent
(N,N-dimethylformamide) was taken into consideration through
single-point calculations on the gas-phase optimized geometry by
COSMO calculations with the SMD model using the ORCA
software.23 For the COSMO calculations, the pseudopotential was
kept on Pd and all of the atoms were treated with def2-tzvp basis
sets.24 Influence of the dispersion forces was considered by adding to
the COSMO energy the D3(BJ) corrections as described by
Grimme.25 All of the energies reported in the present work are
Gibbs free energies obtained by summing the COSMO energy, the
gas-phase Gibbs contribution at 413 K, and the D3(BJ) correction. To
complement our DFT study, we computed the energies of the various
extrema using other DFT methods (Tables S1 and S2 in the
Supporting Information), and the results were very similar to those
obtained with B3PW91; therefore, our computational strategy seems
sound.
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ASSOCIATED CONTENT
■
S
* Supporting Information
Figures S1−S3, copies of NMR spectra for new compounds,
and Cartesian coordinates for computed structures. This
material is available free of charge via the Internet at http://
pubs.acs.org.
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AUTHOR INFORMATION
■
Corresponding Authors
*E-mail: clot@univ-montp2.fr.
*E-mail: olivier.baudoin@univ-lyon1.fr.
Kundig, E. P. Chem. Sci. 2013, 4, 1995. (q) Bheeter, C. B.; Jin, R.; Bera,
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J. K.; Dixneuf, P. H.; Doucet, H. Adv. Synth. Catal. 2014, 356, 119.
(r) Mao, J.; Zhang, S.-Q.; Shi, B.-F.; Bao, W. Chem. Commun. 2014, 50,
3692. (s) Yan, J.-X.; Li, H.; Shi, J.-L.; Wang, X.; Shi, Z.-J. Angew. Chem.,
Int. Ed. 2014, 53, 4945.
Notes
The authors declare no competing financial interest.
(7) Kefalidis, C. E.; Baudoin, O.; Clot, E. Dalton Trans. 2010, 39,
10528.
ACKNOWLEDGMENTS
■
This work was financially supported by Agence Nationale de la
Recherche (programme blanc “AlCaCHA”) and Institut
Universitaire de France.
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1
resonating at ca. 3.3 ppm (methine signal) in the H NMR spectrum
G
dx.doi.org/10.1021/jo501610x | J. Org. Chem. XXXX, XXX, XXX−XXX

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Article
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