Pd-Catalyzed Direct C-H Alkenylation and Allylation of Azine N -Oxides

Article abstract of DOI:10.1021/acs.orglett.8b00689

A Pd-catalyzed direct C₂-alkenylation of azine N-oxides with allyl acetate is disclosed. The products are formed through an allylation/isomerization cascade process. The use of a tri-tert-butylphosphonium salt as the ligand precursor and KF is mandatory for optimal yields. When cinnamyl acetate is used, the same catalytic system promotes C₂-cinnamylation of the azine N-oxide without subsequent isomerization. A mechanism is proposed on the basis of experimental studies and DFT calculations.

Full text of DOI:10.1021/acs.orglett.8b00689

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Pd-Catalyzed Direct C−H Alkenylation and Allylation of Azine
N‑Oxides
Fares Roudesly,† Luis F. Veiros,§ Julie Oble,*,† and Giovanni Poli*,†
†Sorbonne Universite,
75005 Paris, France
§Centro de Química Estrutural, Instituto Superior Tec
́
Faculte
́
des Sciences et Ingen
́
ierie, CNRS, Institut Parisien de Chimie Molec
́
ulaire, IPCM, 4 place Jussieu,
́
nico, Universidade de Lisboa, Av Rovisco Pais 1, 1049-001 Lisbon, Portugal
S
* Supporting Information
ABSTRACT: A Pd-catalyzed direct C2-alkenylation of azine
N-oxides with allyl acetate is disclosed. The products are
formed through an allylation/isomerization cascade process.
The use of a tri-tert-butylphosphonium salt as the ligand
precursor and KF is mandatory for optimal yields. When
cinnamyl acetate is used, the same catalytic system promotes
C2-cinnamylation of the azine N-oxide without subsequent
isomerization. A mechanism is proposed on the basis of experimental studies and DFT calculations.
zines constitute a prominent family of six-membered
best of our knowledge, thus far unknown transformations. Such
1
Anitrogen-containing heteroaromatics,
reactions could represent an important asset, as these
unsaturated substituents, once installed onto the heteroar-
omatic nucleus, can serve as a handle for a variety of
synthetically relevant manipulations. Following from our
ongoing interest in η3-allylpalladium chemistry,11 as well as
C−H activation reactions,12 we describe here the Pd-catalyzed
C2-alkenylation and allylation of azine N-oxides in the presence
of allyl and cinnamyl acetates, respectively (Scheme 1b). In
particular, we anticipated that the allylpalladium(II) inter-
mediates initially generated through the oxidative addition of an
allylic ester to a Pd(0) complex13,14 could activate the C2−H
bond of a PNO, thereby allowing its functionalization. This
expectation proved to be correct.
and pyridine, the
simplest member of this class of compounds, is found in a great
number of natural products, pharmaceutical agents, supra-
molecular assemblies, and molecular materials.2 Given the
ubiquity of this substructure, it is of no surprise that the
functionalization of this motif has garnered much interest
within the synthetic community, and significant efforts have
been devoted to this objective.2 However, despite remarkable
progress in the field of catalytic C−H activation,3 the direct
functionalization of azines remains a difficult task.2c To
overcome the intrinsic low reactivity of the pyridine nucleus
and the undesirable Lewis basicity of the pyridine nitrogen
atom, several research groups have implemented direct
functionalization strategies through the corresponding N-
oxides4 or N-iminopyridinium ylide5 derivatives. In particular,
Fagnou reported the first example of Pd-catalyzed direct C2-
arylation of pyridine N-oxides (PNOs) using aryl bromides as
arylating agents (Scheme 1a),6 which revealed the potential of
the PNO unit to undergo a C−H activation process. The
following studies were devoted mainly to arylation of azine N-
oxides.7 The focus on other PNO C−H functionalizations such
as alkylations8 and alkenylations has only been sporadic.7c,9 In
particular, the direct PNO allylation and vinylation10 are, to the
We started our investigation using PNO 1a and allyl
acetate.15 In line with the typical conditions used by Fagnou
in the PNO C2-arylations,6 we carried out our first reaction
using Pd(OAc)2 (10 mol %), P(t-Bu)3·HBF4 (30 mol %), and
K2CO3 (2.0 equiv) in toluene at 100 °C (Table 1, entry 1) but
using 2.0 equiv of PNO instead of 4.0 equiv. These conditions
generated C2-propenylated PNO 2a as the major compound
(56% NMR yield), along with small amounts of the C2-allylated
product 2a′ and the diallylated product 2a″. Scrutiny of the
16
base needed to release free P(t-Bu)3 was undertaken next. A
switch to Na2CO3 or i-Pr2NH (entries 2 and 3) led to a yield
drop, while the use of CsF and KF gave 66% and 70% NMR
yields, respectively, with a quasi-total selectivity for 2a (entries
4 and 5). Variation of the solvent was next addressed. While
xylene led to an NMR yield similar to that of toluene, CH3CN
was inefficient (entries 6 and 7) and THF increased the yield
and eased the workup (entry 8). The use of phosphines other
than P(t-Bu3) (mono- or bidentated, see the Supporting
Scheme 1. C−H Functionalizations of Pyridine N-Oxides
Received: February 28, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b00689
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 1. Optimization of the Pd-Catalyzed PNO
Alkenylation
Scheme 2. Scope with Allyl Acetate
a
ratio (2a/
c
2a, NMR yield
c
b
entry ligand
base
solvent
2a′/2a″)
(%) (E/Z)
1
2
3
4
5
6
7
8
9
P(t-Bu3)
P(t-Bu3)
P(t-Bu3)
P(t-Bu3)
P(t-Bu3)
P(t-Bu3)
P(t-Bu3)
K2CO3
Na2CO3
i-Pr2NH
CsF
Tol
78:4:13
74:16:10
100:0:0
56 (75/25)
36 (47/53)
11 (91/9)
66 (95/5)
70 (86/14)
74 (92/8)
3
Tol
Tol
Tol
100:0:traces
100:traces:0
100:0:traces
100:0:traces
100:0:0
KF
Tol
KF
xylene
MeCN
THF
THF
KF
P(t-Bu3) KF
80 (84/16)
PMe(t-
Bu2)
KF
0:0:0
10
11
12
PCy3
KF
KF
KF
THF
THF
THF
0:0:0
0:0:0
PMe3
P(t-Bu3)
100:0:0
31 (50:50)
a
Reaction conditions: 1a (2 equiv), allyl acetate (1 equiv), solvent
b
(0.25 M). Except for entry 12, the phosphines used were as the HBF4
salts. Determined by H NMR analysis of the crude mixture using
dimethyl sulfone as internal standard.
c
1
Information, SI) as well as other trialkylphosphonium salts did
not allow further improvements (entries 9−11). These results
confirmed that this transformation needs a bulky, monodentate,
electron-rich phosphine, and the tetrafluoroborate salt of the
phosphine is preferred to the corresponding air-sensitive free
phosphine (compare entries 7 and 12). Finally, separated
control experiments carried out by omitting the Pd source, the
ligand, or the base resulted in exclusive recovery of the starting
materials, which confirmed that each of the above three
components were necessary for the catalytic process (see the
SI).
positions 1, 2, or 3 completely inhibited the reaction (see the
SI). However, the use of cinnamyl acetate as a coupling partner
proved to be effective, giving PNOs 1a and 1c and pyridazine
N-oxide 1i and leading to the corresponding cinnamylated
adducts 3a (31% yield), 3c (22% yield), and 3i (48% yield) as
major products, together with minor amounts of the
corresponding isomerized adducts 4a, 4c, and 4i (Scheme 3).
With the optimal conditions in hand, several azine N-oxides
were coupled with allyl acetate to give 2-propenylazine N-
oxides (2a−l) in moderate to good isolated yields, with a
selectivity in favor of the E olefin (Scheme 2). The presence of
the electron-donating methoxy group at C4 (1b) gave a similar
yield as obtained for 1a (1a: 71% or 66% yield, from 0.5 or 5
mmol of allyl acetate, respectively; 1b: 67%). An aryl moiety at
C4 (1c) or C2 (1d, 1f) as well as a methyl group at C2 (1g) led
to the corresponding internal E olefins as major products, along
with minor amounts of the allylated compounds (2c′, 2d′, 2f′).
In contrast, a 4-(trifluoromethyl)phenyl substituent at C2 gave
solely the corresponding propenylated adduct 2e without any
detectable amount of the allylated precursor. In general, the
presence of a substituent at the C2 position renders the
transformation more sluggish, and 24 h is necessary to obtain
an optimal result. 3-Acetylpyridine N-oxide (1h) gave 56%
yield of the expected propenylated pyridine N-oxide 2h,
confirming that this C−H functionalization is directed by the
N-oxide and not by the acetyl moiety and that keto functions
are tolerated. Finally, pyridazine (1i), pyrazine (1j), quinoline
(1k), and isoquinoline (1l) N-oxides also reacted satisfactorily.
It is worth noting that, in the case of isoquinoline, the
propenylation reaction took place exclusively at position 2.
Then the scope of the reaction was studied with other allyl
acetates. Unfortunately, the introduction of substituents at
Scheme 3. Scope with Cinnamyl Acetate
The synthetic applications of alkenylated PNOs were then
evaluated (Scheme 4). First, compounds 2a and 2b could be
deoxygenated by treatment with PCl3 in toluene to give
pyridines 5a and 5b.7b Furthermore, treatment of 2a with
OsCl3 cat./NMO smoothly gave the diol 6a, while ozonolysis
led to 2-formylpyridine N-oxide 7a.17
Then, to gain insight into the mechanism, and particularly
the C−H bond activation step, deuterium labeling experiments
were carried out (Scheme 5). The intermolecular competition
reaction between PNO and PNO-d5 gave a primary kinetic
isotopic effect (KIE) value of 4, while the parallel reactions
B
DOI: 10.1021/acs.orglett.8b00689
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 4. Synthetic Applications
Scheme 6. Proposed Mechanism of the Catalytic Cycle
Scheme 5. Mechanistic Studies
requires a high energy barrier (22 kcal/mol) and is in full
accordance with the experimental reaction conditions (16 h,
100 °C).20 The subsequent reductive elimination affords the
allylated PNO E (ΔG = −17 kcal/mol) coordinated to
Pd(0)P(t-Bu3). Finally, substrate-to-product ligand exchange
releases 2a′ and regenerates complex A. As for the diallylated
product 2a″, sometimes observed (in particular in the presence
of carbonate as the base), it is expected to derive from a
subsequent C−H activation of the allylic position of 2a.23
The isomerization step was next studied (Scheme 6,
bottom).24 Starting from the C2-allylated PNO (Me3P)-
(AcOH)Pd(0) complex G, a regioselective oxidative hydro-
palladation25 leads to intermediate H (ΔG = −6 kcal/mol) with
an energy barrier of 11 kcal/mol. The subsequent reductive
dehydropalladation involving an internal H atom generates the
more stable C2-coordinated alkene isomer I (ΔG = −11 kcal/
mol), which finally undergoes ligand exchange with a new
molecule of 2a′ (ΔG = 6 kcal/mol), providing 2a.
experiment resulted in a KIE value of 3 (see the SI). These
results suggest that C−H bond breaking is involved in the
turnover-limiting step of the catalytic cycle. The isomerization
step was studied next. Accordingly, 2-allyl PNO 2a′ was
prepared via an independent synthesis18 and tested for
isomerization. While heating of 2a′ in a sealed tube at 100
°C for 16 h in THF gave only 10% of isomerization, its
treatment under the classical reaction conditions for 16 h
brought about 79% of isomerized product 2a.
Finally, a DFT study of the full transformation19 was
accomplished, which led to the following mechanistic proposal
(Scheme 6). First, the allyl acetate coordinates complex
Pd(0)P(t-Bu3) was generated from the in situ reduction of
Pd(OAc)2 by the phosphine, affording intermediate A. Then,
oxidative addition led to the η3-allylpalladium(II) complex B
with an energy barrier of 21 kcal/mol.20 In keeping with the
observation of the cyclic intermediate κ2(AcO)Pdκ2((t-Bu3)-
PCMe2CH2) by the Hartwig group21 in the Pd(OAc)2/P(t-
Bu)3-catalyzed arylation of PNOs, we checked at this stage the
viability of a mechanism involving cyclometalation of B.
However, generation of such a 4-membered palladacycle via
propene expulsion was energetically much too costly (see
Figure S7). Formation of the related palladacycle η3(allyl)-
Pdκ2((t-Bu3)PCMe2CH2) via AcOH expulsion was instead
found to be energetically accessible, with a barrier of 33 kcal/
mol, but again, its subsequent evolution was energetically
implausible, as C−H activation of the PNO by the palladacycle
has a prohibitive barrier of over 60 kcal/mol (see Figure S8).
On the other hand, PNO/acetate ligand exchange to afford
intermediate [η3(allyl)Pd(P(t-Bu3))(PNO)]+/AcO− C is only
moderately exergonic (ΔG = 10 kcal/mol)22 and sets the stage
for the turnover-limiting outer-sphere deprotonation/pallada-
tion at C2 of the coordinated PNO ligand to provide complex
D (ΔG = 7 kcal/mol). This crucial C−H activation step
In summary, we have developed a method for the direct Pd-
catalyzed C2 alkenylation and cinnamylation of azine N-oxides
with allyl acetate and cinnamyl acetate, respectively. This
straightforward C−H functionalization method requires the use
of a P(t-Bu)3·HBF4/KF system as the ligand precursor. On the
basis of our experimental results in combination with DFT
calculations a mechanism involving a turnover limiting outer
sphere deprotonation/palladation as the key C−H activation
step is proposed.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b00689.
Further optimizations, DFT study details, atomic
coordinates of all optimized species, experimental
procedures, compound characterization (PDF)
C
DOI: 10.1021/acs.orglett.8b00689
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Hoof, S.; Svensson, E.; Tzschucke, C. C. Chem. - Eur. J. 2013, 19,
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AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: julie.oble@sorbonne-universite.fr.
*E-mail: giovanni.poli@sorbonne-universite.fr.
ORCID
Giovanni Poli: 0000-0002-7356-1568
Notes
́
Eur. J. Org. Chem. 2016, 2016, 3509. (r) Theveau, L.; Schneider, C.;
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We acknowledge Horizon 2020 ERANet-LAC project
CelluloseSynThech for financial support as well as CNRS,
■
Sorbonne Universite,
d’Avenir programme, ref ANR-11-IDEX-0004-02). L.F.V.
acknowledges Fundacao para a Ciencia e Tecnologia, UID/
́
and Labex Michem (Investissements
̧
̂
̃
QUI/00100/2013. Support through CMST COST Action,
CA15106 (CHAOS) is also gratefully acknowledged.
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D
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calculations at the M06/[SDD* (Pd), 6-311++G(d,p)]//PBE0/
[SDD* (Pd), 6-31G(d,p)] level were performed using the Gaussian
09 package. Solvent effects (THF) were considered by means of the
PCM model with SMD radii. A complete account of the computa-
tional details and the corresponding list of references are provided as
SI..
(20) This is a rather high barrier but not so for a reaction that occurs
at high temperature (100 °C) over a long period (16 h) and achieves
moderate yields. See, for example: Mastalir, M.; Glatz, M.; Gorgas, N.;
Stoger, B.; Pittenauer, E.; Allmaier, G.; Veiros, L. F.; Kirchner, K.
̈
Chem. - Eur. J. 2016, 22, 12316.
(21) Tan, Y.; Barrios-Landeros, B.; Hartwig, J. F. J. Am. Chem. Soc.
2012, 134, 3683.
(22) (a) Free energy values relative to A.. (b) From complex B, an
η3-η1-allyl equilibrium, followed by PNO coordination is feasible but
leads to a mechanistic dead end (see SI, Figure S4)..
(23) Campeau, L.-C.; Schipper, D. J.; Fagnou, K. J. Am. Chem. Soc.
2008, 130, 3266.
(24) As the computations showed identical mechanisms using PMe3
or P(t-Bu)3, the isomerization study was carried out with the former
phosphine for computational expediency.
(25) Mekareeya, A.; Walker, P. R.; Couce-Rios, A.; Campbell, C. D.;
Steven, A.; Paton, R. S.; Anderson, E. A. J. Am. Chem. Soc. 2017, 139,
10104.
E
DOI: 10.1021/acs.orglett.8b00689
Org. Lett. XXXX, XXX, XXX−XXX