Comparative catalytic C-H vs. C-Si activation of arenes with Pd complexes directed by urea or amide groups

Article abstract of DOI:10.1039/b905717j

Analysis of regiocontrol in Pd-catalysed C-H activation leads to observations of aryltrimethylsilyl activation and to superior results with urea-based substrates.

Full text of DOI:10.1039/b905717j

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Comparative catalytic C–H vs. C–Si activation of arenes
with Pd complexes directed by urea or amide groupswz
Waqar Rauf, Amber L. Thompson and John M. Brown*
Received (in Cambridge, UK) 23rd March 2009, Accepted 13th May 2009
First published as an Advance Article on the web 4th June 2009
DOI: 10.1039/b905717j
Analysis of regiocontrol in Pd-catalysed C–H activation leads to
observations of aryltrimethylsilyl activation and to superior
results with urea-based substrates.
acrylate Michael adduct. By employing the weaker base
Na2HPO4, the desired compound 3a was formed, indicating
that the required palladated intermediate from 1c is readily
accessible.
The next step involved synthesis of the relevant pallada-
cycles, and this proved straightforward for both regioisomers
in the 1b series. The palladacycle 4 was readily prepared as a
bridged dimer, and characterised by NMR in d6-DMSO.
Crystallisation from CH3CN afforded X-ray quality crystals
of the salt 5. In order to prepare the regioisomeric series, a
different approach was developed. Van Koten and co-workers
had shown that under the right conditions, tertiary amine
directed aromatic palladadesilylation predominates over Pd
Among mild methods for catalytic aromatic C–H activation,
the oxidative Heck (Fujiwari–Moritani) reaction holds a
prominent position.1 The presence of an anilide that functions
as a directing group for palladation permits ortho-specific C–C
bond formation, as first shown stoichiometrically by Horino,2
and developed into a useful catalytic reaction by de Vries and
co-workers.3 Several developments have been reported in the
interim period.4 In the course of a mechanistic study of this
system, we examined the regiochemistry of the alkene coupling
reactions shown in Scheme 1.
substitution at
a a related
protonated site.8 Adopting
approach starting with compound 6,9 it was initially shown
that palladation occurred smoothly and with complete
chemoselectivity for displacement of SiMe3 (Scheme 2).
Initially the reaction was carried out without added p-TsOH
and required temperatures of 60 1C, giving a bridged acetate
that was characterised only in solution. At ambient temperature
in the presence of p-TsOH however, the isolable complex 7 was
formed and converted into the corresponding ionic species 8.
The X-ray structure of compound 8 is shown superimposed on
5 in Fig. 1.y Comparison of the two palladacyclic X-ray
structures reveals a likely reason for the observed preference
for the formation of 2 rather than 3 in alkenylation. In 8, the
N–F distance of 2.54 A reveals an unfavourable 1,5 interaction,
not present in structure 5, that distorts the coordination of the
nitriles. Replacing H6 in structure 5 with a dummy fluorine
atom (C–F = 1.36 A) results in a short N–F distance of
2.25 A, and hence rationalises the distortion seen in structure
8. The same will be true of any square planar cyclopalladated
complex involved in the catalytic cycle; an o-F or indeed
any other ortho-substituent cannot avoid unfavourable
non-bonded interactions.
The complete absence of the alternative products was
surprising, given the small size of sp2 C–F,5 and an expected
inductive stabilisation of the adjacent Pd–C bond in an
intermediate. It raised questions, and specifically the point of
inhibition of the second pathway leading to compound 3a. The
enthalpies of the two planar conformers of the anilide with the
CQO group in proximity to C2 and C6 respectively are within
0.2 Kcal of one another (DFT; B3LYP 6-31G*) excluding a
ground-state conformational bias. In order to secure an
authentic sample of 3a, iodide 1c was conventionally prepared
from 2-fluoro-6-nitrophenol,6 and subjected to Jeffrey’s
conditions for the Heck reaction with K2CO3 as base.7 Under
these conditions the main product was the undesired N–H
Scheme 1 Reagents and conditions: (i) Pd(OAc)2, p-benzoquinone
(1 equiv.), p-TsOH (1 equiv.), butyl acrylate (Z1 equiv.), AcOH,
toluene; 83% for 1a - 2a (3 mol% Pd), 60% for 1b - 2b (5 mol% Pd);
(ii) 9 mol% Pd(OAc)2, Bu4NCl, Na2HPO4, DMF, 60% for 1c - 3a.
Chemical Research Laboratory, 12 Mansfield Rd, Oxford, UK OX2 7BL.
E-mail: john.brown@chem.ox.ac.uk; Fax: +44 (0)1865285002
w This article is part of a ChemComm ‘Catalysis in Organic Synthesis’
web-theme issue showcasing high quality research in organic
chemistry. Please see our website (http://www.rsc.org/chemcomm/
organicwebtheme2009) to access the other papers in this issue.
z Electronic supplementary information (ESI) available: Experimental
details, NMR, MS and crystallographic data. CCDC 724788–724790.
For ESI and crystallographic data in CIF or other electronic format
see DOI: 10.1039/b905717j
Scheme 2 Reagents and conditions: (i) Pd(OAc)2, p-TsOH, C7H8,
C3H6O, 85% for 4, 95% for 7; (ii) CH3CN xs. recryst.
ꢀc
This journal is The Royal Society of Chemistry 2009
3874 | Chem. Commun., 2009, 3874–3876

yield. The urea proved to be a good substrate for alkenylation
and reacted rapidly. During the early stages of the reaction
only the desired product 10 was formed, but desilylation
competed progressively such that the regioisomer 11, formed
via C–H activation of the desilylated product, was produced.
Small quantities of the disubstituted product 12 were also
1
formed, this minor product being characterised by H NMR
and GC/HRMS. This second coupling had not previously
been observed in the anilide series, in the course of intensive
investigations by several groups.3,4 The observation indicated
that the urea might be especially powerful as a directing group,
in line with the high basicity of its carbonyl group.13 Ureas
also possess strongly activating properties towards an internal
TMS group, permitting palladium-catalysed methyl transfer
from silicon to alkenes.1,14 They have recently been successfully
employed as directing groups in palladium-catalysed
carbonylation and amination,15 and stereocontrolled hydro-
Fig. 1 Overlay of compounds 5 (red) and 8 (blue), showing the
distortion caused of the MeCN in 8. The overlay was carried out by
performing a best fit, based on the amide nitrogen atom and the
coordinating oxygen and carbon atoms.
genations.16 The palladium work indicated
a superior
reactivity over amides in cyclopalladation based catalysis.
Urea activation was surveyed with ‘‘difficult’’ electron-poor
substituted ureas as a corollary of published work (Table 1,
entries 1–5). For these cases, the proportion of catalyst was
mainly limited to 2 mol% (as in ref. 3 rather than 5 mol% as in
ref. 4b), and yields were recorded without optimisation.
Reported yields from the corresponding acetanilides are
recorded alongside. Additional catalyst was required for
entry 5, otherwise the yields from ureas are superior to the
analogous acetanilides, with lower catalyst loading. It was
verified that ureas 13f and 13g were superior reactants in
catalytic alkenylation, both giving 90% of product under
conditions where the corresponding acetanilides gave lower
yields. For the parent case, reaction with 2 equiv. of all
reagents gave 35% of the doubly substituted product 15; a
similar yield was obtained in a stepwise reaction.
Scheme 3 Contrasting pathways for the palladium-catalysed alkenyl-
ation of silanes 6 and 9. Reagents and conditions: (i) 10 mol%
Pd(OAc)2, p-TsOH (1 equiv.), BQ (1 equiv.), butyl acrylate (Z1 equiv.),
C3H6O, 24 h; (ii) as (i) 5 mol% Pd(OAc)2.
With characterised palladacycle 8 in hand, it was demon-
strated that it did indeed participate in catalytic alkenylation.
The stoichiometric reaction with butyl acrylate in Me2CO at
ambient temperature gave the anticipated product 3b in 80%
yield. This encouraged an attempt at catalysis starting with
silane 6, successfully realised under standard oxidative Heck
conditions (Scheme 3). The best results were obtained by
carrying out the reaction with 10 mol% Pd(OAc)2, when the
desired product 3b was isolated in 85% yield, accompanied by
13% of 1b formed by competing desilylation, but no 2b. The
amine precursor of 6 proved unreactive, indicating the need
for a directing group. At lower [Pd] correspondingly more
desilylation occurs. It is normally the case that aromatic TMS
groups are robust under the conditions of the Heck reaction.10
This strongly indicates that the amide directing-group is
responsible for activation, since it can facilitate the addition
of electrophilic palladium to the ring with ensuing cleavage of
the C–Si bond under turnover conditions. It is difficult to
avoid catalytic protodesilylation in this case,11 however.
It is unfeasible to ring-lithiate acetanilides as a means to
introduce the TMS group directly, and this encouraged the use
of alternative N-activating groups. Initial attempts using the
N-Boc analogue of silane 6 were unsuccessful. A related
dimethylurea was readily available from the corresponding
isocyanate,12 and was smoothly converted into silane 9 in 63%
This encouraged a quantitative comparison between the two
directing groups, and Fig. 2 records both internal and external
Table 1 Reactivity of ureas in F–M coupling
Yield Lit. data for
Entry Reactant mol% Pd Product (conversion) acetanilides
1
2
3
4
5
6
7
8
13a
13b
13c
13d
13e
13f
13f
13g
2
2
2
14a
14b
14c
14d
14e
14f
15
50 (58)
33 (45)
50 (72)
52 (58)
40 (65)
90
38b
(28)c
(70)c
(48)c
(25)c
72b
2
10a
5
10
5
35
90d
—
11
83d
Conditions: 1 equiv. BQ, 1 equiv. p-TsOH, 1.2 equiv. butyl acrylate,
acetone, 20 1C, 20 h. Under these conditions urea X = 3-OMe (13h)
decomposed, and X = 4-CF3 (13i) reacted very slowly.a After
b
c
36 h. From ref. 3, 2 mol% Pd(OAc)2. From ref. 4b, 5 mol%
d
Pd(OAc)2. This work; some disubstitution observed for urea.
ꢀc
This journal is The Royal Society of Chemistry 2009
Chem. Commun., 2009, 3874–3876 | 3875

m = 1.062 mmꢂ1; Dcalc = 1.726 g cmꢂ3. Reflections collected =
14 648; independent reflections = 4643 (Rint = 0.043); R values
[I 42s(I), 4061 reflections]: R1 = 0.0356, wR2 = 0.0815. For 8 (cls,
0.06 ꢁ 0.09 ꢁ 0.38 mm): C21H22F2N4O4PdS, Mr = 570.89; triclinic,
ꢀ
P1;
a
a
=
= 7.5810(2),
77.4887(11),
b
=
=
12.6494(3),
82.2803(12),
c
g
=
=
13.2132(4) A,
73.9961(12)1,
b
V = 1185.29(6) A3; T = 150 K; Z = 2; m = 0.921 mmꢂ1; Dcalc
=
1.599 g cmꢂ3. Reflections collected = 16 083; independent reflections
= 5124 (Rint = 0.127); R values [I 42s(I), 4225 reflections]: R1
0.0679, wR2 = 0.0794. For 16 (cls, 0.01 ꢁ 0.02 ꢁ 0.02 mm):
=
C
20H23FN4O4PdS, Mr = 540.89; monoclinic, P21/n; a = 7.4418(1),
b = 14.5003(2), c = 20.7460(3) A, b = 96.2239(5)1, V = 2225.47(5) A3;
T = 150 K; Z = 4; m = 0.970 mmꢂ1; Dcalc = 1.614 g cmꢂ3. Reflections
collected
=
41 900;
independent
reflections
=
5061
(Rint = 0.046); R values [I 42s(I), 3944 reflections]: R1 = 0.0330,
wR2 = 0.0727.
1 The first Pd-catalysed alkenylation involving CH activation
(2 turnovers) was carried out in 1968: Y. Fujiwara, I. Moritani,
M. Matsuda and S. Teranishi, Tetrahedron Lett., 1968, 9,
3863–3865; Heck’s first oxidative catalysis with C–Hg activation
appeared in the same year: R. F. Heck, J. Am. Chem. Soc., 1968,
90, 5518–5526.
Fig. 2 Comparison between directing groups; (a) separate reactions,
6.5 mol% cat., 0.2 mmoles reactant, 1 equiv. reagents, X = F;
(b) internal competition fluorourea 13g vs. acetanilide, 0.1 mmole
each reactant, 10 mol% cat., 2 equiv. reagents.
2 H. Horino and N. Inoue, J. Org. Chem., 1981, 46, 4416–4422.
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B. Guay and F. Scheuermeyer, J. Org. Chem., 1997, 62, 758–760.
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2008, 73, 7996–8000; (b) X. Zeng, M. Tavasli, I. F. Perepichka,
A. S. Batsanov, M. R. Bryce, C.-J. Chiang, C. Rothe and
A. P. Monkman, Chem.–Eur. J., 2008, 14, 933–943; (c) X. Feng,
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2226–2229.
13 B. Kallies and R. Mitzner, THEOCHEM, 1998, 428, 267–282;
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comparisons of their relative reactivity. In both cases reaction
of the urea is close to completion before the acetanilide-
directed reaction is half-complete. In a separate 1H NMR
experiment, urea 13g and acetanilide were allowed to compete
for Pd(OAc)2/p-TsOH, and the urea-based palladacycle was
formed faster; this is significant, because the turnover-limiting
step for the overall reaction is formation of palladacycle.3,17
It should be noted that the m-F group exerts sufficient
electron-withdrawing influence such that the reaction is slower
than the parent case, indicating that the urea directing effect
could be synthetically useful. Ureas of the structure
ArNHC(O)NR2 are hydrolysed under moderate conditions
in acid or base.18
In order to understand the difference between ureas and
amides as directing groups in C–H activation, the X-ray
structure of the palladacycle 16, directly analogous to the
anilide-derived palladacycles
5 and 8, was obtained.y
(See ESIz; cf. ref. 15b). There are differences in the geometry
of the metallacyclic rings, with cation 16 showing a longer
carbonyl C–N bond (1.344 A vs. 1.321, 1.318 A) reflecting
lower amidic conjugation. Overall the differences are small
and not obviously correlated with reactivities, although
arylureas are more electron-rich than anilides.19
Two interconnected developments are described here, both
arising from the initial aim of understanding the regio-
selectivity of aryl CH activation. Firstly, amide or urea
neighbouring groups can activate a TMS–aryl bond towards
Pd-catalysed coupling. For general synthetic utility, further
refinement is underway to overcome competing desilylation.
Secondly, neighbouring ureas are superior directing groups to
acetanilides in a comparison of their potential for catalytic
Fujiwara–Moritani coupling, with practical repercussions.
We thank the Pakistan Government (Scholarship, WR) and
the Leverhulme Trust (Fellowship, JMB). Johnson-Matthey
kindly provided a loan of Pd salts.
Notes and references
y Crystal data for 5: (cls, 0.03 ꢁ 0.06 ꢁ 0.18 mm): C19H19F2N3O4PdS,
ꢀ
529.84; triclinic, P1;
Mr
c
=
=
a
90.7614(17),
=
7.2492(2),
b
b
=
8.7969(3),
= 101.0913(17),
16.6174(6) A,
a
=
g = 100.9648(19)1, V = 1019.55(6) A3; T = 150 K; Z = 2;
19 C. Hansch, A. Leo and R. W. Taft, Chem. Rev., 1991, 91, 165–195.
ꢀc
This journal is The Royal Society of Chemistry 2009
3876 | Chem. Commun., 2009, 3874–3876