Phosphinic Amide as Directing Group Enabling Palladium(II)-Catalyzed ortho C-H Alkenylation of Anilines without and with Alkylation at the Nitrogen Atom

Article abstract of DOI:10.1002/asia.201500829

A phosphinic amide is introduced as a directing group for the ortho C-H alkenylation of anilines. The new donor group distinguishes itself from existing ones by assisting the C-H bond activation of anilides without (NH group) and with alkylation (NMe group) at the amide nitrogen atom. The reactivity is even reversed with the methyl-substituted anilide being more reactive than its unsubstituted counterpart. Electron-donating substituents at the arene ring enhance their reactivity while halogenation is not tolerated. The phosphinic amide also enables the C-7-selective C-H alkenylation of indoline.

Full text of DOI:10.1002/asia.201500829

DOI: 10.1002/asia.201500829
Communication
CÀH Activation
Phosphinic Amide as Directing Group Enabling Palladium(II)-
Catalyzed ortho CÀH Alkenylation of Anilines without and with
Alkylation at the Nitrogen Atom
Lin-Yu Jiao, AndrØ V. Ferreira, and Martin Oestreich*[a]
Abstract: A phosphinic amide is introduced as a directing
group for the ortho CÀH alkenylation of anilines. The new
donor group distinguishes itself from existing ones by as-
sisting the CÀH bond activation of anilides without (NH
group) and with alkylation (NMe group) at the amide ni-
trogen atom. The reactivity is even reversed with the
methyl-substituted anilide being more reactive than its
unsubstituted counterpart. Electron-donating substituents
at the arene ring enhance their reactivity while halogena-
tion is not tolerated. The phosphinic amide also enables
the C-7-selective CÀH alkenylation of indoline.
Anilines are often-used arenes in various CÀH bond functionali-
zation reactions,[1–3] also because of the ease of transforming
the amino group into a directing group. For example, the
straightforward acetylation of aniline yields an anilide that un-
dergoes palladium(II)-catalyzed CÀH bond alkenylation at room
temperature (1a!3aa, Scheme 1, top).[2a] However, the same
setup applied to cognate 1b did not form any 3ba.[2a] It turns
out that substitution of the amide nitrogen atom leads to an
Scheme 1. Reactivity difference between aniline with NH and NMe groups in
entirely different behavior in CÀH bond activation, and general
procedures for the CÀH bond functionalization of both are rare
and have remained largely unexplored. A recent report dem-
onstrates that it is possible to overcome the lower reactivity of
the tertiary amide with higher catalyst loading (1a/1b!3ab/
3bb, Scheme 1, middle).[2e] An interesting case is the CÀH alke-
nylation of anilides directed by a sulfonyl-tethered pyridyl
group where it is 4b with an NMe group that participates in
the catalysis while 4a with an NH group is totally unreactive
(Scheme 1, bottom).[2h]
directed palladium(II)-catalyzed CÀH bond alkenylation. [a] Pd(OAc)2
(10 mol%) in TFA. [b] N-Fluoro-2,4,6-trimethylpyridinium triflate. BQ=1,4-
benzoquinone, PTSA=4-toluenesulfonic acid, py=pyridin-2-yl, TFA=tri-
fluoroacetic acid.
Recently, a diverse range of phosphorus-based donors
groups was applied to directed transition-metal-catalyzed CÀH
bond functionalization (Figure 1),[4–6] and these performed effi-
ciently in, for example, palladium(II)-catalyzed CÀH alkenylati
on[4a,c,d] and arylation[4b,f] of arenes. Amide derivatives had
been included into these reports but not to enable CÀH bond
activation at the amide nitrogen substituent. We therefore em-
barked on an investigation of a chemically robust phosphinic
amide as a directing group for the palladium(II)-catalyzed CÀH
[a] L.-Y. Jiao,+ A. V. Ferreira,+ Prof. Dr. M. Oestreich
Institut für Chemie
Technische Universität Berlin
Strasse des 17. Juni 115, 10623 Berlin (Germany)
Fax: (+49)30-314-28829
E-mail: martin.oestreich@tu-berlin.de
[+] These authors contributed equally to this work.
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under http://dx.doi.org/10.1002/asia.201500829.
This manuscript is part of a special issue on catalysis and transformation
of complex molecules. Click here to see the Table of Contents of the special
issue.
Figure 1. Literature-known phosphorus-based donors used as directing
groups in palladium(II)-catalyzed CÀH bond activation.
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alkenylation of anilines without and with alkylation of the
amide nitrogen atom.
running this CÀH bond alkenylation in the presence of an
MPAA in either AcOH or HFIP as solvent was without effect.
Compared to anilides 1a and 1b (cf. Scheme 1),[2a,e] the reactiv-
ity is reversed for 6a and 6b.
Initial experiments were done with anilide 6a containing
a free NH group using acrylate 2b as the alkene component
(6a!12ab, Table 1, entries 1–9). We quickly found that, at
With these optimized conditions at hand, we began investi-
gating the scope of these transformations with differently sub-
stituted anilides 6a–11 a (908C for 4 h, Table 1, entry 8) and
6b–11 b (408C for 21 h, Table 1, entry 14). The results are sum-
marized in Scheme 2. Electron-donating substituents such as
methyl and methoxy groups were generally tolerated but halo-
genated anilides did not react at all (not shown, see the Sup-
porting Information for details). A methoxy group at C-3 en-
hanced the reactivity dramatically, and 8a was fully converted
at room temperature (908C before) within 3 h and 8b at 408C
within 5 h (21 h before). Two more observations are particular-
ly noteworthy (gray box): 10a with a methoxy group at C-4
fully decomposed whereas 10b afforded 16bb in 71% isolated
yield. This electronic effect is not understood. Conversely, the
steric situation in 3,5-dimethyl-substituted 11 a and 11 b led to
completely different reactivity. Compound 11 a with the NH
group furnished 17ab in 70% yield but 11 b yielded only trace
amounts of the ortho alkenylated arene. We explain this by the
NMe group that hampers optimal orientation of the directing
group to allow for the CÀH bond activation.
Table 1. Identification of the terminal oxidant.
Entry
Anilide Oxidant
T [8C] t [h] Conv. [%][a] Yield [%][b]
1
2
3
4
6a
6a
6a
6a
6a
6a
6a
6a
6a
6b
6b
6b
6b
6b
BQ
60
18
18
18
18
18
18
12
4
51
29
24
25
71
74
78
98
100
98
99
99
96
96
34
15
Cu(OAc)2 60
[c]
AgOAc
Ag2CO3
Na2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
BQ
Na2S2O8
K2S2O8
K2S2O8
K2S2O8
60
60
60
60
75
90
100
60
60
60
50
40
–
–
[c]
5
54
57
57
71
55
53
58
59
64
81
6[d]
7
8[e]
9
6
10
11
12
13
14
15
15
15
15
21
The faster reaction of NMe compared to NH anilides was
also verified in an intermolecular competition experiment be-
[a] Determined by GLC analysis with tetracosane as internal standard.
[b] Isolated yield after purification by flash column chromatography on
silica gel. [c] Not determined. [d] Other palladium sources such as
Pd(TFA)2 and Pd2dba3 worked equally well. [e] Yield did not deteriorate at
longer reaction times, e.g., 6 h for comparison with entry 9.
608C in acetic acid, the ortho-selective CÀC bond formation oc-
curred in moderate yield with 1,4-benzoquinone (BQ) as the
terminal oxidant and 4-toluenesulfonic acid (PTSA) as an addi-
tive (entry 1). Acetic acid was superior to other solvents that
gave either lower or no conversion (see the Supporting Infor-
mation for a solvent screen). Other mild oxidants such as
Cu(OAc)2, AgOAc, and Ag2CO3 were not effective (entries 2–4).
In turn, the use of peroxydisulfates Na2S2O8 and K2S2O8 greatly
improved conversion and isolated yield (entries 5 and 6).[7] Full
conversion was achieved in shorter reaction times at higher
temperatures, and 71% isolated yield was obtained at 908C
(entries 7–9). The use of a mono-protected amino acid[8]
(MPAA) such as Ac-l-tert-Leu-OH (20 mol%) as ligand had little
effect on conversion and yield; results were better in AcOH
than in 1,1,1,3,3,3-hexafluoropropan-2-ol (HFIP).
We then turned our attention to tertiary anilide 6b with the
same directing group (6b!12bb, Table 1, entries 10–14).
Much to our surprise, we found 6b to be more reactive than
6a even with BQ as terminal oxidant (entry 10 vs. entry 1).
Changing to the stronger oxidants Na2S2O8 and K2S2O8 showed
no improvement at 608C but isolated yields increased signifi-
cantly at lower temperature (entries 11–14). At 408C, 81% iso-
lated yield at full conversion was obtained (entry 14). Again,
Scheme 2. Palladium(II)-catalyzed CÀH bond alkenylation directed by phos-
phinic amide groups.[a,b] [a] Conversions determined by GLC analysis with
tetracosane as internal standard. [b] Isolated yields after purification by flash
column chromatography on silica gel. [c] Reaction performed at room tem-
perature for 3 h. [d] Reaction performed at 408C for 5 h.
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Compound 9a did not couple with styrene (2d) but reacted
cleanly with the more electron-rich a-methylstyrene (2 f). The
situation with 9b was the exact opposite. CÀH alkenylation oc-
curred with 2d and the C6F5-substituted derivate 2e, but no
cross-coupling was seen with 2 f.
We also applied the new directing group to the C-7-selective
CÀH alkenylation of indolines that we and others had devel-
oped recently (Scheme 5).[9–11] Again, steric effects emerged as
Scheme 3. Competition experiment. [a] Monitored by GLC analysis with tet-
racosane as internal standard. [b] Isolated yield after separation by flash
column chromatography on silica gel.
tween 9a and 9b (Scheme 3). As expected, 9b was consumed
at higher rate than 9a. What is interesting here though is that
the reaction times were shorter than in the individual experi-
ments (cf. Scheme 2, bottom left).
Scheme 5. Application of the phosphinic amide directing group to the C-7
alkenylation of indolines.
To examine the compatibility of this protocol with different
alkenes, we tested various acrylates 2a–2c and styrenes 2d–
2 f with the very reactive substrates 8a and 8b under the pre-
viously established mild conditions (Scheme 4). Yields were
consistently good with acrylates at full conversion, although
tertiary anilide 9b did not react with benzyl acrylate (2c, gray
box, top). This was not the only peculiarity. The results with
styrenes were in fact unforeseeable (gray boxes, bottom).
crucial for the success of the coupling. The parent indoline 18
gave an excellent result (18!20) whereas 19 with a methyl
group at C-2 decomposed rather than forming any desired 21.
In summary, we reported here the palladium(II)-catalyzed CÀ
H alkenylation of aniline-derived phosphinic amides. The new
directing group enables couplings of both secondary (with NH
group) and tertiary (with NMe group) anilides. This is a rare
case of a directed CÀH bond activation of anilines where alky-
lation of the amide nitrogen atom does not lead to completely
different reactivity (cf. Scheme 1).[2a,e,h] The tertiary amide is
even more reactive. While the methodology is not general at
this stage and the removal of the directing group not estab-
lished yet,[12] it revealed several interesting features. Depending
on the electronic and steric situation of the arene, the NH and
NMe anilides show (in an unpredictable way) opposite reactivi-
ty. Their reactivity toward styrenes is particularly remarkable.
The anilide with an NH group reacts with a-methylstyrene but
not styrene itself. For the NMe anilide, it is the other way
round.
Acknowledgements
L.-Y.J. thanks the China Scholarship Council (CSC) for a predoc-
toral fellowship (2011–2015), and A.V.F was supported by the
Brazilian Council for Scientific and Technological Development
(CNPq, Science without Borders Program, 2013–2015). M.O. is
indebted to the Einstein Foundation (Berlin) for an endowed
professorship. We are grateful to Jonas Scharfbier (TU Berlin)
for his initial experimental contributions.
Keywords: alkenylation
dehydrogenative coupling · homogeneous catalysis · palladium
·
CÀH
activation
·
cross-
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Manuscript received: August 9, 2015
Accepted Article published: September 15, 2015
Final Article published: September 24, 2015
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