Para-Selective C-H Olefination of Aniline Derivatives via Pd/S,O-Ligand Catalysis

Article abstract of DOI:10.1021/jacs.9b01908

Herein we report a highly para-selective C-H olefination of aniline derivatives by a Pd/S,O-ligand-based catalyst. The reaction proceeds under mild reaction conditions with high efficiency and broad substrate scope, including mono-, di-, and trisubstituted tertiary, secondary, and primary anilines. The S,O-ligand is responsible for the dramatic improvements in substrate scope and the high para-selectivity observed. This methodology is operationally simple, scalable, and can be performed under aerobic conditions.

Full text of DOI:10.1021/jacs.9b01908

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Article
para-Selective C-H Olefination of Aniline
Derivatives via Pd/S,O-Ligand Catalysis
Kananat Naksomboon, Jordi Poater, F. Matthias Bickelhaupt, and M. Ángeles Fernández-Ibáñez
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para-Selective CH Olefination of Aniline Derivatives via Pd/S,O-
Ligand Catalysis
Kananat Naksomboon,† Jordi Poater,‡,§ F. Matthias Bickelhaupt,,¶ and M. Ángeles Fernández-Ibáñez*,†
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† Van’t Hoff Institute for Molecular Sciences, University of Amsterdam, Science Park 904, 1098 XH Amsterdam, The Neth-
erlands
‡ Departament de Química Inorgànica i Orgànica & Institut de Química Teòrica i Computacional (IQTCUB), Universitat de
Barcelona, 08028 Barcelona, Spain.
§ ICREA, Pg. Lluís Companys 23, 08010 Barcelona, Spain.
 Department of Theoretical Chemistry and Amsterdam Center for Multiscale Modeling (ACMM), VU University Amster-
dam, The Netherlands.
¶ Institute for Molecules and Materials, Radboud University Nijmegen, The Netherlands
ABSTRACT: Herein we report a highly para-selective CH olefination of aniline derivatives by a Pd/S,O-ligand based catalyst.
The reaction proceeds under mild reaction conditions with high efficiency and broad substrate scope, including mono, di- and tri-
substituted tertiary, secondary and primary anilines. The S,O-ligand is responsible for the dramatic improvements in substrate scope
and the high para-selectivity observed. This methodology is operationally simple, scalable and can be performed under aerobic
conditions.
1. INTRODUCTION
the para-olefination of unsubstituted N,N-dialkylanilines using
Pd as catalyst, Cu as oxidant and a mixture of DCE/HOAc as
solvent is reported.7f Therefore, a general strategy for para-
selective CH olefination of aromatic amines is still elusive.
Herein, we report a highly efficient para-selective CH ole-
fination of aniline derivatives promoted by a Pd/S,O-ligand
based catalyst (Scheme 1 d). The reaction proceeds under mild
conditions with a broad range of mono-, di- and trisubstituted
tertiary, secondary and primary anilines. Remarkably, anilines
bearing several electron withdrawing groups are also compati-
ble, affording the para-olefinated products in good yields. In
addition, this para-selective CH olefination of anilines is also
easily scalable and is compatible with the use of oxygen as the
only oxidant, which are important features for industrial appli-
cations. The S,O-ligand is responsible for the dramatic im-
provements in substrate scope and the high para-selectivity
observed.
Aromatic amines are ubiquitous structural motifs in natural
products, pharmaceuticals, fluorescent dyes and organic func-
tional materials.1 As a consequence, the selective functionali-
zation of anilines is of great interest in organic chemistry. His-
torically, Friedel-Crafts reactions of aniline derivatives are
problematic, as has been stated in classical textbooks.2 Cross
couplings are effective reactions for the functionalization of
aromatic amines, however, these protocols suffer from the
disadvantage of requiring prefunctionalized starting materials.3
In the last decades, metal-catalyzed CH functionalization
reactions have become a powerful tool to efficiently function-
alize organic molecules.4 The vast majority of CH functional-
ization reactions of aniline derivatives rely on the use of di-
recting groups attached to the nitrogen atom, which results in
the ortho-functionalized products.5 However, selective CH
functionalization reactions of aniline derivatives at remote
positions are rare.6 In the particular case of metal-catalyzed
para-selective CH functionalization of anilines, the reported
transformations are limited to unsubstituted anilines or to ani-
lines bearing electron-donating groups (Scheme 1 a).7 Few
exceptions to this trend have been reported (Scheme 1 b). For
instance, anilides with an ester group or halogen atom have
been para-difluoromethylated using a Ru(II)-catalyst.8 Also, a
highly para-selective copper (II)-catalyzed arylation of elec-
tron-rich and poor anilines was described by Gaunt and
coworkers.9 In the context of Pd-catalyzed para CH olefina-
tion of anilines, only two examples using unsubstituted tertiary
anilines have been reported (Scheme 1c). In the example de-
scribed by Ishii et al.,7b 7.5 equiv. of tertiary aniline are neces-
sary to obtain the olefinated products in good yields and para-
selectivities using Pd/HPMoV as catalyst and 2,4,6-
trimethylbenzoic acid as an additive. In the second example,
Scheme 1. Metal-Catalyzed para-CH Functionalizations
of Anilines
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Scheme 2. S,O-Ligand Promoted Pd-Catalyzed para-
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Selective CH Olefination of N,N-dimethylaniline
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To investigate the substrate scope of this transformation,
various aniline derivatives were examined (Table 1). We first
explored the olefination reaction of several tertiary aniline
derivatives. N,N-Diethyl-, N,N-dibenzylaniline and 1-
phenylpyrrolidine (1b–1d) were olefinated in excellent yield
(73–85%) and excellent selectivity toward their para posi-
tions. Good yields and slightly deteriorated selectivities were
observed using 4-phenylmorpholine (1e) and N-
methyldiphenylamine (1f). Julolidine reacted to form only the
para-olefinated product 3g in 60% isolated yield. Having
proved the compatibility of the method with a variety of ter-
tiary aniline derivatives, different meta-substituted N,N-
dimethylanilines were then tested. The reaction of m-methyl
N,N-dimethylaniline (1h) provided the olefinated product 3h
in good yield (70%) and para-selectivity (>10:1). Good yield
(75%) and moderate para-selectivity was observed in the reac-
tion of the m-methoxy N,N-dimethylaniline (1i). In contrast,
the reaction of the m-phenoxy N,N-dimethylaniline (1j) exhib-
ited a perfect para-selectivity, obtaining the product 3j in 66%
isolated yield. The corresponding para-olefinated products of
N,N-dimethylaniline derivatives bearing electron withdrawing
substituents such as F, Cl and CO2Me (1k–m), were obtained
in good yields (51–65%). Similarly, the reaction tolerated two
fluorine atoms at the meta position of the aniline, providing
the para-olefinated product 3n in 42% isolated yield. Interest-
ingly, and in accordance with the high para-selectivity ob-
served in these transformations, only 3% of the ortho-
olefinated product was detected when using p-methyl N,N-
dimethylaniline (1o). To extend the substrate scope of the re-
action, we tested the reaction of o-methyl N,N-dimethylaniline
(1p) under standard reaction conditions, but only traces
amount of product were detected by 1H-NMR spectroscopy.11
Recently, we have discovered that bidentate S,O-ligands are
capable of promoting Pd-catalyzed CH olefination reactions
of nondirected arenes.10 In these reactions, the site-selectivity
was mainly dictated by the substrate and controlled by elec-
tronic factors, with preferential functionalization at the most
electron-rich position in the arene. We found out that besides
accelerating the reaction, the presence of the S,O-ligand influ-
ences the site-selectivity of the process. With this in mind, we
speculated that using our Pd/S,O-ligand catalyst, both the reac-
tivity and the site-selectivity of the CH olefination of aniline
derivatives could be enhanced.
2. RESULTS AND DISCUSSION
2.1. Scope of Pd/S,O-ligand catalyzed CH olefination of
aniline derivatives. Initially, we applied our standard condi-
tions for the CH olefination of nondirected arenes (5 mol%
of Pd(OAc)2, 5 mol% of 3-methyl-2-(phenylthio)butanoic acid
Table 1. para-Selective CH Olefination of N,N-
Dialkylanilines
t
(L), 10 equiv. of arene and 1 equiv. of PhCO3 Bu as oxidant in
AcOH at 100 °C for 6 h) on the model substrate, N,N-
dimethylaniline (1a). Unfortunately, no olefinated product was
observed under these conditions. Different reaction parame-
ters, including solvents, temperatures, reaction stoichi-
ometries, oxidants, concentrations and ligands were screened
(see Supporting Information). We were pleased to find out that
the reaction of N,N-dimethylaniline (1a, 1 equiv.) with ethyl
acrylate, using the Pd/S,O-ligand (L) as catalyst, in DCE at 40
°C, furnished the olefinated product 3a in 81% NMR yield
with excellent para-selectivity (p:o >19:1) (71% isolated yield
of the para-olefinated product 3a, Scheme 2). In contrast, the
reaction without ligand, under the same conditions, gave the
olefinated product 3a in 18% NMR yield as a mixture of the 3
possible isomers (o:m:p = 1:1:16).
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After proving the efficiency of the new catalytic system in
anilines bearing both electron donating and withdrawing
groups we evaluated a variety of di- and tri-substituted N-
benzylaniline derivatives. Disubstituted anilines with an ortho
methyl ester group and different substituents at the meta-
position, i.e. F, OMe and Me, underwent C–H olefination to
provide the para-olefinated products 3w–3y in good yields
(57–75%). N-Benzyl- m-methyl-o-(trifluoromethyl)aniline
(1z) and o-chloro-m-methoxyaniline (1aa) were also compati-
ble with this system, providing the para-olefinated products in
53% and 52% isolated yield, respectively. Slightly higher
yields for the olefinated products 3ab and 3ac were obtained
when 2,5-dichloro- and 2,3-dichloro aniline derivatives were
used. The reaction of the trisubstituted o-methyl ester m,m’-
difluoroaniline derivative provided the para-olefinated prod-
uct 3ad in 60% isolated yield.
Alternatively, N-benzyl ortho-substituted aniline derivatives
were efficiently para-olefinated using our Pd/S,O-ligand
based catalyst (Table 2). The reaction of o-Me-,OMe-,Cl-,CF3-
,CO2Me-, and COMe-substituted N-benzyl aniline derivatives
1q–1v exhibited perfect para-selectivities, providing the para-
olefinated products in good yields (47–70%). Only traces
amounts of the C–H olefinated product occurring at the ortho
position of the benzene ring of the benzyl group were detect-
ed. In contrast, this byproduct was formed in greater quantity
when the reactions were performed without ligand (see Sup-
porting Information).
Table 2. para-Selective CH Olefination of N-
Benzylanilines
Finally, we studied the compatibility of the current catalytic
system with primary anilines (Table 3). We observed that the
efficiency of the reaction is highly dependent on the substitu-
ents attached to the aromatic ring. The reaction of ortho-
disubstituted anilines bearing two electron donating groups
provided the olefinated product in low yields. In these reac-
tions, we detected the formation of the oxidative amination
product (see Supporting Information for further details).12 To
our delight, the olefinated products were obtained in high
yields and with perfect para-selectivities with ortho-
disubstituted anilines bearing one ester group at the ortho-
position. Thus, different substituents at the other ortho-
position such as CO2Me, Me, OMe and Cl were compatible in
the reaction, providing the olefinated products 3ae-3ah in
good isolated yields (64-71%). The reaction of the trisubstitut-
ed aniline 1ai bearing two fluorine atoms and a methyl ester
furnished the olefinated aniline 3ai in 70% isolated yield. A
fair yield (45%) was obtained in the reaction of the disubsti-
tuted (o-CF3 and o-OMe) aniline.
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15% yield. To our delight, the reaction using 2 bar of oxygen
Table 3. para-Selective CH Olefination of primary ani-
lines
1
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3
provided the desired product in 57% yield in good para-
selectivity. These results show the potential of this methodol-
ogy to be implemented in the chemical industry.
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Scheme 3. CH Olefination of N,N-Dimethylaniline under
aerobic conditions
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2.2. Comparison of the Pd/S,O-ligand catalytic system
with the reported catalytic systems for the para-CH ole-
fination of anilines. As mentioned in the introduction, only
two examples were reported for the Pd-catalyzed para CH
olefination of anilines.7b,7f To demonstrate that this catalytic
system is a unique method to olefinate a broad range of ani-
lines we compared our catalytic system with previously de-
scribed protocols. We performed the reaction of N,N-
dimethylaniline with methyl acrylate under the conditions
described by Moghaddam et al.,7f Pd(OAc)2 (5 mol%),
Cu(OAc)2 (1.5 equiv.) in a mixture of DCE/HOAc (1.5:1) at
60 °C; however, in our hands only trace amount of olefinated
product was detected by 1H-NMR spectroscopy. We then test-
ed different anilines under the conditions described by Obora
and Ishii using 7.5 equiv. of aniline, Pd(OAc)2, (5 mol%),
H6PMo9V3O40.30H2O (0.5 mol%) and 0.5 equiv. of 2,4,6-
trimethylbenzoic acid in DMF (Table 5).7b The reaction of
N,N-dimethylaniline under these conditions gave the olefinat-
ed product in good yield and with slightly lower para-
selectivity than using our catalytic system. When we per-
formed the reaction of m-methyl N,N-dimethylaniline (1h)
only 24% 1H-NMR yield and moderate para-selectivity (4.6:1)
was observed using Ishii’s conditions. Using our catalytic
system we obtained the olefinated product 3h in 70% yield
and high para-selectivity (10.7:1). Remarkably, under Ishii’s
conditions, no reaction or only trace amount of product was
detected when m-methoxy- or m-methyl esther N,N-
dimethylaniline (1i, 1m) were employed. Similarly, the reac-
tion of N-benzyl ortho-substituted anilines (3q and 3u) under
Ishii’s conditions provided only trace amount of product in
contrast to our catalytic system that furnished the olefinated
products in good yields and perfect para-selectivities. Overall,
Ishii’s conditions are suitable for the olefination of unsubsti-
tuted tertiary anilines and therefore, we can confirm that our
catalytic system based on Pd/S,O-ligand is at present the only
efficient protocol for the direct CH olefination of a broad
range of anilines.
It is worth mentioning that in all these reactions (Tables 1,2
and 3), the presence of the S,O-ligand is crucial to achieve
good yield and high para-selectivity (see Supporting Infor-
mation for the results of the reactions in the absence of the
S,O-ligand).
Next, we investigated the scope of olefins as depicted in
Table 4. The reaction of N,N-diethylaniline with methyl, cy-
clohexyl and phenyl acrylates provided the products 4a–4c in
high yield (85–96%) and selectivity. α-Methylene-γ-
butyrolactone afforded compound 4d in excellent yield as a
mixture of 4dA and 4dB in 1.4 to 1 ratio. Likewise, other acti-
vated olefins, i.e. vinyl amide, methyl vinyl ketone, vinyl
phosphonate and vinyl sulfonate, were also employed to pro-
vide products 4e–4h in good yields.
Table 4. Scope of Olefines
Table 5. Comparison of Pd/S,O-ligand catalyst with Ishii’s
catalyst.
To prove the applicability of the present catalytic system, a
half-gram-scale reaction of N,N-dimethylaniline (1a) was con-
ducted to afford 3a in comparable yield (64%) to that of the
original value (for further details, see Supporting Information).
t
In addition, we explored the possibility of replacing PhCO3 Bu
by oxygen (Scheme 3). The reaction of N,N-dimethylaniline
(1a) under otherwise identical conditions using a balloon of
oxygen showed the formation of the olefinated product 3a in
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a consequence, the C atoms at the ortho and para positions of
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1q (-85 and -88 me., respectively) are more negatively
charged than the equivalent ones in 1p (-77 and -74 me., re-
spectively). Therefore, the lack of reactivity observed in o-
substituted N,N-dialkylanilines is a direct consequence of the
lower nucleophilicity of these anilines compared with unsub-
stituted N,N-dialkylanilines or with o-substituted N-benzyl
anilines.
2.4. Preliminary mechanistic investigations. To gain some
insights into the role of the S,O-ligand in this transformation
we conducted some additional experiments (Scheme 4). We
considered 2 different scenarios to explain the observed accel-
eration in the presence of the ligand: i) the ligand causes a
change in the mechanism of CH bond cleavage or ii) the
ligand accelerates the rate-limiting step. First, we determined
the hydrogen/deuterium isotopic effect in the reaction with and
without ligand (Scheme 4 a). Without ligand we observed a
kH/kD of 9.2 and in the presence of the S,O-ligand (L) a kH/kD
of 6.2. The observed primary kinetic isotopic effect suggests
that the CH bond cleavage is the turnover-limiting step in
both cases. Furthermore, we performed intramolecular compe-
tition experiments between an electron-poor aniline, namely
N,N-dimethyl-3-(trifluoromethyl)aniline (1ak), and an electron
rich-aniline, namely N,N,3-trimethylaniline (1h) (Scheme 4 b).
We found out that in in both cases, the most electron-rich ani-
line 1h reacted preferentially. These results are consistent with
two possible mechanisms: i) the reaction proceeds via an elec-
trophilic palladation mechanism with the deprotonation of the
Wheland intermediate being the rate-limiting step,14 or ii) the
reaction proceeds via base-assisted internal electrophilic-type
substitution (BIES) mechanism.15 At present, we cannot rule
out either mechanism but it seems reasonable to postulate that
the reaction proceeds via the same mechanism with and with-
out ligand and that the S,O-ligand accelerates the CH bond
cleavage, which is the rate limiting step.
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2.3. Explanation of the difference in reactivity of tertiary
and secondary anilines respect to the ortho-substituent. As
shown in Table 1, the reaction of o-methyl N,N-
dimethylaniline (1p) under optimal conditions provided only
traces amount of olefinated product. In contrast, N-benzyl
ortho-substituted anilines were efficiently para-olefinated
using our Pd/S,O-ligand based catalyst (Table 2). The lack of
reactivity of ortho-substituted N,N-dialkylanilines in aromatic
electrophilic substitution reactions has been observed before.13
It has been postulated that the ortho-substituent clashes with
the N-methyl group of the N,N-dimethylaniline forcing the
nitrogen to twist out of the plane with the aromatic ring reduc-
ing the conjugation of the nitrogen lone pair and therefore
deactivating the aniline derivative towards electrophilic aro-
matic substitution. To corroborate this, we calculated the tor-
sion angle and the Voronoi deformation density (VDD) charg-
es of 1p and 1q (Chart 1) at dispersion-corrected density func-
tional theory (DFT) level (see Supporting Information).
Scheme 4. Mechanistic Studies
Chart 1. Dihedral angle and VDD charges (in me.) for 1p
and 1q.
3. CONCLUSION
In conclusion, we have developed the first general para-
selective CH olefination of aniline derivatives by Pd/S,O-
ligand catalysis. The reaction proceeds under mild reaction
conditions with a broad range of anilines, including mono-, di-
and trisubstituted anilines bearing electron donating and with-
drawing groups. In total, 42 aniline derivatives underwent
In the case of o-methyl N-benzyl aniline (1q), the H of the
NHBn almost remains in the plane (∂ = 18º), and point to-
wards the o-methyl group. In contrast, one of the Me groups of
the NMe2 of 1p is twisted out of the plane (∂ = 69º) to avoid
the interaction with the methyl group at the ortho position. As
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methylphenylphenylamino)triphenylamine (m‐MTDATA), as hole‐
para-selective CH olefination in good yields using the devel-
oped methodology. We have also shown that it is possible to
use oxygen as the only oxidant and that this methodology is
operationally simple and scalable. The S,O-ligand is responsi-
ble for the dramatic improvements in substrate scope and the
high para-selectivity observed in this transformation. Prelimi-
nary mechanistic studies suggest that the ligand promotes the
CH bond cleavage, which is the rate-limiting step. Further
applications and mechanistic studies are currently ongoing in
our laboratory
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ASSOCIATED CONTENT
Supporting Information.
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Experimental procedures and compounds characterization. Mech-
anistic studies.
Computational studies.
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Complex Organic Synthesis Science 2006, 312, 67-72;
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Chen, X.; Engle, K. M.; Wang, D. H.; Yu, J. Q. Palladium (II)‐
Catalyzed C–H Activation/C–C Cross‐Coupling Reactions:
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5115; (d) Yu, J.-Q.; Shi, Z. C–H activation; Springer, 2010; Vol. 292;
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Directed C−H Functionalization Reactions Chem. Rev. 2010, 110,
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developments in natural product synthesis using metal-catalysed C–H
bond functionalisation Chem. Soc. Rev. 2011, 40, 1885-1898; (g)
Kuhl, N.; Hopkinson, M. N.; Wencel‐Delord, J.; Glorius, F. Beyond
Directing Groups: Transition‐Metal‐Catalyzed C–H Activation of
Simple Arenes Angew. Chem. Int. Ed. 2012, 51, 10236-10254; (h)
Neufeldt, S. R.; Sanford, M. S. Controlling Site Selectivity in
Palladium-Catalyzed C–H Bond Functionalization Acc. Chem. Res.
2012, 45, 936-946; (i) Hartwig, J. F. Evolution of C–H Bond
Functionalization from Methane to Methodology J. Am. Chem. Soc.
2015, 138, 2-24; (j) Dixneuf, P. H.; Doucet, H. C−H Bond Activation
AUTHOR INFORMATION
Corresponding Author
*m.a.fernandezibanez@uva.nl
ACKNOWLEDGMENT
We acknowledge financial support from NWO through a VIDI
grant (723.013.006). J.P. thanks the Spanish MINECO
(CTQ2016-77558-R and MDM-2017-0767). We thank Nick
Westerveld for the synthesis of some protected aniline derivatives
and Nippon Inorganic Colour & Chemical Co., Ltd. for providing
us H6PMo9V3O4030H2O.
and
Catalytic
Functionalization
I;
Springer,
2016;
(5) For a general review of ortho C–H functionalization of aniline
derivatives, see: (a) Tischler, M.; Tóth, M.; Novák, Z. Mild Palladium
Catalyzed ortho C–H Bond Functionalizations of Aniline Derivatives
Chem. Rec. 2017, 17, 184-199; For selected examples of C–H
olefination of anilines using anilide as directing group, see: (b)
Tremont, S. J.; Rahman, H. U. Ortho-alkylation of acetanilides using
alkyl halides and palladium acetate J. Am. Chem. Soc. 1984, 106,
5759-5760; (c) Boele, M. D.; van Strijdonck, G. P.; De Vries, A. H.;
Kamer, P. C.; de Vries, J. G.; van Leeuwen, P. W. Selective Pd-
Catalyzed Oxidative Coupling of Anilides with Olefins through C−H
Bond Activation at Room Temperature J. Am. Chem. Soc. 2002, 124,
1586-1587; (d) Nishikata, T.; Lipshutz, B. H. Cationic Pd (II)-
Catalyzed Fujiwara−Moritani Reactions at Room Temperature in
Water Org. Lett. 2010, 12, 1972-1975; (e) Patureau, F. W.; Glorius, F.
Rh Catalyzed Olefination and Vinylation of Unactivated Acetanilides
J. Am. Chem. Soc. 2010, 132, 9982-9983; For a selected example of
C– H olefination of anilines using guanidine as directing group, see:
(f) Shao, J.; Chen, W.; Giulianotti, M. A.; Houghten, R. A.; Yu, Y.
Palladium-Catalyzed C–H Functionalization Using Guanidine as a
Directing Group: Ortho Arylation and Olefination of Arylguanidines
Org. Lett. 2012, 14, 5452-5455; For a selected example of C–H
olefination of anilines using sulfonamide as directing group, see: (g)
García‐Rubia, A.; Urones, B.; Gómez Arrayás, R.; Carretero, J. C.
PdII‐Catalyzed C–H Olefination of N‐(2‐Pyridyl)sulfonyl Anilines and
Arylalkylamines Angew. Chem. Int. Ed. 2011, 50, 10927-10931; For a
selected example of C–H olefination of anilines using carbamate as
directing group, see: (h) Uhlig, N.; Li, C. J. Aniline Carbamates: A
Versatile and Removable Motif for Palladium‐Catalyzed Directed C–
H Activation Chem. Eur. J. 2014, 20, 12066-12070; For a selected
example of C–H olefination of anilines using N-oxide as directing
group, see: (i) Huang, X.; Huang, J.; Du, C.; Zhang, X.; Song, F.;
You, J. N‐Oxide as a Traceless Oxidizing Directing Group: Mild
Rhodium (III)‐Catalyzed C–H Olefination for the Synthesis of ortho‐
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12970-12974; For a selected example of C–H olefination of anilines
using pyrazole as directing group, see: (j) Ackermann, L.; Pospech, J.;
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ChemRxiv.
Reprint.
https://doi.org/10.26434/chemrxiv.7496306.v2
Palladium-Catalyzed
C–H
Functionalization
Reactions
of
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