Selective arene functionalization through sequential oxidative and non-oxidative Heck reactions

Article abstract of DOI:10.1039/c2cc30752a

A sequence of acetamide directed oxidative Heck reaction and deacetylation-diazotation-Heck coupling allows the traceless removal of the acetamide group and its dual exploitation as a catalyst directing group and a leaving group. The Royal Society of Chem

Full text of DOI:10.1039/c2cc30752a

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COMMUNICATION
Selective arene functionalization through sequential oxidative and
non-oxidative Heck reactionsw
Bernd Schmidt* and Nelli Elizarov
Received 2nd February 2012, Accepted 14th March 2012
DOI: 10.1039/c2cc30752a
A sequence of acetamide directed oxidative Heck reaction and
deacetylation–diazotation–Heck coupling allows the traceless
removal of the acetamide group and its dual exploitation as a
catalyst directing group and a leaving group.
reagents in numerous Pd-catalyzed coupling and cross coupling
reactions,18–20 we thought that this would open up an interesting
opportunity to combine oxidative and non-oxidative Pd-catalyzed
C–C-bond forming reactions in a sequential, highly regioselective
synthesis of ortho-dialkenylated arenes. In a first step, we
investigated the oxidative Pd-catalyzed coupling of acetanilide
1a with methyl acrylate (Table 1).
The regioselective functionalization of arenes is an important issue
in numerous syntheses of dyes, pharmaceuticals or crop protecting
agents.1 With electrophilic and nucleophilic substitution reactions
still being the standard methods, Pd-catalysed coupling and cross
coupling reactions, such as the Heck-,2 Stille-, Suzuki-, Negishi-
and Sonogashira coupling,3 are becoming increasingly important
alternatives. In contrast, reactions involving oxidative Pd-catalyzed
C–H-activation steps, such as the Fujiwara–Moritani reaction,4–9
have attracted considerably less attention in organic synthesis.
These reactions proceed via electrophilic attack of Pd2+ at the
arene moiety, preferably in the presence of an electron donating
and catalyst directing group,10–13 e.g. an amide, in the ortho
position. This group not only activates the arene for electrophilic
palladation, but is also required to ensure high regioselectivity.14
From a synthetic point of view, the presence of a catalyst directing
group is clearly a limitation of the method, unless either its traceless
removal15 or its subsequent exploitation as a leaving group in a
conventional Pd-catalyzed coupling reaction is possible (Scheme 1).
Over the past few years, we investigated deacetylation–
diazotation sequences that allow the conversion of acetanilides
to isolable diazonium salts in an operationally simple one-flask
procedure.16,17 As arene diazonium salts are highly reactive
Originally, we planned to adapt the conditions previously
described by van Leeuwen et al., who described the oxidative
coupling of butylacrylate with 1a using benzoquinone (BQ) as an
oxidant.14 When we applied these conditions to our test reaction,
a yield of 57% of methyl cinnamate 2a was obtained.
Unfortunately, the separation of 2a from unreacted benzo-
quinone turned out to be very difficult and required repeated
chromatography. This prompted us to evaluate alternative
oxidizing agents, such as tert-BuOOH and MnO2 in combination
with a co-catalytic system of Pd(OAc)2 and benzoquinone, which
had previously been applied to the oxidative coupling of benzene
with various alkenes by Fujiwara et al.21 While these protocols
resulted in the formation of the desired coupling product 2a,
albeit in unsatisfactory rates of conversion (Table 1, entries 2
and 3), only trace amounts of 2a were observed with AgOAc as an
oxidant (entry 4).21 A first breakthrough was achieved when we
used Na2S2O8 in trifluoroacetic acid (TFA) at elevated tempera-
tures (entry 5). Under these conditions, inspired by a recently
reported oxidative ortho-arylation of phenyl carbamates,22
2a was conveniently isolated in 60% yield. Unfortunately, all
attempts to reduce the catalyst loading and to further improve
the yield by variation of the catalyst, the solvent and the
additive failed (entries 6–24). While these optimization studies
were in progress, Youn et al. disclosed conditions for the
alkenylation of various acetanilides 1 with methyl acrylate,
using K2S2O8 as an oxidizing agent and a TFA–CH2Cl2
solvent mixture.23 We then decided to test this protocol, and
were pleased to find that 2a can be obtained in 89% yield,
without the workup problems encountered with benzoquinone
as an oxidant (entry 25). We wondered if the success of Youn’s
protocol can be solely attributed to the special solvent mixture,
or if the counterion of the persulfate, K+ vs. Na+, has a
significant effect. Therefore, we repeated the reaction of 1a
with methyl acrylate using Na2S2O8 as an oxidant, under
otherwise identical conditions. Surprisingly, the yield of 2a
dropped to 31%, indicating a remarkable counterion effect
which will be investigated in more detail in the future.
Scheme 1 Sequential oxidative–non-oxidative Pd-catalyzed arene
functionalization.
Universitaet Potsdam, Institut fuer Chemie, Organische Synthesechemie,
Karl-Liebknecht-Straße 24-25, D-14476 Potsdam-Golm, Germany.
E-mail: bernd.schmidt@uni-potsdam.de
w Electronic supplementary information (ESI) available: Experimental
details for all new compounds and copies of 1H and 13C NMR spectra.
See DOI: 10.1039/c2cc30752a
c
4350 Chem. Commun., 2012, 48, 4350–4352
This journal is The Royal Society of Chemistry 2012

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Table 1 Optimization of oxidative Heck coupling
Entry
Catalyst/mol%
Solvent
Additive
Oxidant
Yield [%]
1
2
3
4
5
6
7
8
Pd(OAc)2 (2)
Pd(OAc)2 (0.5)
Pd(OAc)2 (1)
Pd(OAc)2 (1)
Pd(OAc)2 (10)
Pd(OAc)2 (5)
Pd(OAc)2 (2)
Pd(OAc)2 (1)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(O2CCF3)2 (5)
Pd(O2CCF3)2 (5)
Pd(dba)2 (5)
HOAc/Toluola
HOAc/Ac2Oc
HOAc
HOAc
TFA
TFA
TFA
TFA
HOAc
THF
DMF
HBF4
TFA
TsOHb
—
—
—
—
—
—
—
—
—
—
—
—
—
—
BQ
57
20
tBuOOH/BQd
MnO2/BQe
AgOAcg
n.d.f
Traces
60
h,i
Na2S2O8i
Na2S2O8i
Na2S2O8i
Na2S2O8i
Na2S2O8i
Na2S2O8i
Na2S2O8i
Na2S2O8i
Na2S2O8i
Na2S2O8i
Na2S2O8i
Na2S2O8i
Na2S2O8i
Na2S2O8i
Na2S2O8i
Na2S2O8i
Na2S2O8i
Na2S2O8i
Na2S2O8i
Na2S2O8
K2S2O8
52
36
21
43
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
28
7k; 5j,k
o5
21
HOAc
TFA
TFA
TFA
THF
22
40
[Pd(IMes)(NQ)]2 (5)
PdCl2 (5)
—
—
HBF4
17
15
m
Pd(OAc)2 (5)
Pd(OAc)2 (5)
Pd(OAc)2 (5)
Pd(OAc)2 (5)
Pd(OAc)2 (5)
Pd(OAc)2 (5)
Pd(OAc)2 (5)
Pd(OAc)2 (5)
Pd(OAc)2 (5)
0j
THF
THF
TFAm
TsOHb
TsOHb
TFAm
TsOHb
TsOHb
—
6j
7j
Toluol
Toluol
HOAc
HOAc/Toluola
TFA/DCMn
TFA/DCMn
3j
9j
37; 14l
22
89o
31o
—
Na2S2O8
a
b
c
d
e
f
Ratio 2 : 1 (v/v). 0.5 equiv. Ratio 3 : 1 (v/v). 1.3 equiv. tBuOOH; 5 mol% BQ. 1.2 equiv. MnO2; 5 mol% BQ. Not determined; ratio of
g
h
i
j
k
1a : 2a = 3 : 1 (GC-MS). 1.1 equiv. AgOAc. 3.0 equiv. Reaction temperature: 70 1C. Reaction temperature: 160 1C. Conversion (GC-MS).
l
m
n
o
Reaction temperature: 20 1C. 1.0 equiv. HBF4 or TFA. Ratio 4 : 1 (v/v). 2.0 equiv. of methyl acrylate.
In the following step the one-flask conversion of acetanilide 2a
to arene diazonium salt 3a was investigated. Based on our
previous results, we first tested a sequence of deacetylation in
ethanol and hydrochloric acid, followed by diazotation with
NaNO2 and precipitation of the resulting diazonium salt as a
tetrafluoroborate.16 Separation of 3a from inorganic byproducts
required repeated washing with water, resulting in a moderate
yield of 42%, presumably due to a rather high solubility of the
diazonium salt in water. Therefore, the deacetylation–diazotation
sequence was conducted in methanol, using the BF3ÁMeOH
complex as a Lewis acid for both the deacetylation and
the subsequent diazotation24 with tert-butyl nitrite.16 Pure
diazonium salt 3a was obtained in 76% yield, simply by
filtration of the precipitate formed upon diazotation. The
subsequent Mizoroki–Heck-reaction of 3a with methyl acrylate
proceeded smoothly in methanol under base-free conditions
with Pd(OAc)2 as a catalyst, and the 1,2-dialkenylated benzene
4a was isolated in 90% yield (Scheme 2).
Scheme 2 Deacetylation–diazotation sequence for 2a and subsequent
Mizoroki–Heck-reaction of 3a.
because 4a could be isolated in a yield of 61% from 2a. Notably,
the Pd-catalyzed coupling proceeds heterogeneously and the
diazonium salt slowly dissolves during the reaction (Scheme 2).
As methanol is a suitable solvent for the deacetylation–
diazotation sequence and for the subsequent Mizoroki–
Heck-reaction, we thought that it might be possible to synthesize
ortho-dialkenylated benzenes 4 in a one-flask sequence from
acetanilides 2, thereby avoiding the isolation of the diazonium
salt. Thus, 2a was converted in one flask to 4a by conducting the
deacetylation–diazotation as described above using BF3ÁMeOH
and tert-butyl nitrite, followed by addition of Pd(OAc)2 and methyl
acrylate after completion of the diazotation. This method turned
out to be indeed a viable alternative to the two step synthesis,
Ortho-dialkenylated benzenes
4 have previously been
synthesized from 1,2-dibromobenzene and used as starting
materials for stereoselective sequential Michael additions25,26
and other cyclizative reactions.27 The sequential oxidative–
non-oxidative Pd-catalysed ortho-dialkenylation described
above should be a useful alternative, and we were therefore
interested to extend the scope of this sequence to other
examples (Table 2). For example, diazonium salt 3a reacts
with styrene or para-nitrostyrene, to stilbenes 4ab and 4ac in
68% and 76% yield, respectively. While the one-flask route
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 4350–4352 4351

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Table 2 Scope of the sequential Pd-catalyzed oxidative–non-oxidative twofold alkenylation of acetanilides 1
Entry
1
R1
R2
R3
2 (yield)
3 (yield)
R4
4 (yield)a
4 (yield)b
1
2
3
4
5
6
7
8
1a
–H
–H
–H
2a (89%)
3a (76%)
–CO2CH3
-para-C6H5
-para-C6H4NO2
–CO2CH3
–CO2CH3
–CO2CH3
–CO2CH3
–CO2CH3
–CO2CH3
–CO2CH3
–CO2CH3
4a (90%)
4ab (68%)
4ac (76%)
4b (quant.)
4c (quant.)
4d (quant.)
4e (quant.)
4f (76%)
4a (61%)
4ab (66%)
4ac (34%)
4b (40%)
4c (51%)
4d (43%)
4e (49%)
4a (49%)
4g (14%)
4h (56%)
4i (57%)
1b
1c
1d
1e
1f
1g
1h
1i
–H
–H
–H
–H
–H
–H
–H
–CF3
–H
–OMe
–H
–OH
–Br
–Cl
–H
–H
–C6H5
2b (85%)
2c (80%)
2d (55%)c
2e (49%)
2f (73%)
2g (40%)
2h (72%)
2i (60%)
3b (94%)
3c (65%)
3d (92%)
3e (70%)
3f (43%)
3g (50%)
3h (77%)
3i (60%)d
–OMe
–H
–H
–H
–Cl
–H
9
10
11
4g (37%)
4h (quant.)
4i (52%)
–H
a
b
Yields of isolated products 4 obtained from diazonium salts 3. Yields of isolated products 4 obtained through one-flask sequence from
c
acetanilides 2. Reagents and conditions: BQ (1.0 equiv.), p-TSA (0.5 equiv.), Pd(OAc)2 (2.0 mol%), methyl acrylate (1.2 equiv.), acetic acid/
d
toluene (2 : 1), 20 1C. 2.0 equiv. of tert-BuONO were required.
gives an improved overall yield of 4ab, the yield of 4ac is somewhat
lower (entries 2 and 3). As can be seen from entries 4 to 11, the
oxidative–non-oxidative Heck coupling sequence can be realized
for various substituted acetanilides 1b–i in acceptable yields.
A notable exception is ortho-chloro acetanilide 1g. For this
derivative only moderate yields of approximately 40% were
obtained for each individual step, and a low yield of 14% of 4g
if the one-flask conditions were applied (entry 9). In the case of
paracetamol (1d, entry 6) K2S2O8 turned out to be an unsuitable
oxidant for the oxidative Heck reaction, because 2d was observed
only in minor amounts, along with numerous unidentified
byproducts. We assume that due to the para-OH group the
aromatic core is easily oxidized, inducing various side reactions.
Therefore, van Leeuwen’s conditions were used for this particular
example, providing 2d in 55% yield. Diazonium salt formation
and subsequent Heck reaction to 4d worked very well for this
derivative, without the necessity to protect the OH-group. Finally,
we applied the sequence to biaryl 1i (entry 11), which was
synthesized from 1e using a Suzuki–Miyaura coupling with phenyl
boronic acid. The conversion of 2i to 4i was achieved in 57% yield.
Thus, the triple substituted benzene 4i was obtained from 1e via
three consecutive mechanistically distinct Pd-catalyzed C–C-bond
forming reactions. In summary, we have shown that an acetamide
group attached to an aromatic core may serve as a catalyst
directing and leaving group, and that acetanilides can be converted
by a sequence of mechanistically distinct Pd-catalyzed coupling
reactions to dialkenylated arenes.
3 G. P. McGlacken and I. J. S. Fairlamb, Eur. J. Org. Chem., 2009,
4011–4029.
4 Y. Fujiwara, I. Noritani, S. Danno, R. Asano and S. Teranishi,
J. Am. Chem. Soc., 1969, 91, 7166–7169.
5 Y. Fujiwara, K. Tabaki and Y. Taniguchi, Synlett, 1996, 591–599.
6 E. M. Ferreira, H. Zhang and B. M. Stoltz, in The Mizoroki–Heck
Reaction, ed. M. Oestreich, Wiley, Chichester, 2009, pp. 345–382.
7 M. Miura and T. Satoh, Top. Organomet. Chem., 2005, 14, 55–83.
8 C. Jia, T. Kitamura and Y. Fujiwara, Acc. Chem. Res., 2001, 34,
633–639.
9 T. W. Lyons and M. S. Sanford, Chem. Rev., 2010, 110, 1147–1169.
10 Y. Ie, N. Chatani, T. Ogo, D. R. Marshall, T. Fukuyama,
F. Kakiuchi and S. Murai, J. Org. Chem., 2000, 65, 1475–1488.
11 M. Miura, T. Tsuda, T. Satoh, S. Pivsa-Art and M. Nomura,
J. Org. Chem., 1998, 63, 5211–5215.
12 F. W. Patureau and F. Glorius, J. Am. Chem. Soc., 2010, 132,
9982–9983.
13 G. T. Lee, X. Jiang, K. Prasad, O. Repic and T. J. Blacklock, Adv.
Synth. Catal., 2005, 347, 1921–1924.
14 M. D. K. Boele, G. P. F. van Strijdonck, A. H. M. de Vries, P. C.
J. Kamer, J. G. de Vries and P. W. N. M. van Leeuwen, J. Am.
Chem. Soc., 2002, 124, 1586–1587.
15 G. Rousseau and B. Breit, Angew. Chem., Int. Ed., 2011, 50, 2450–2494.
16 B. Schmidt, R. Berger and F. Holter, Org. Biomol. Chem., 2010, 8,
¨
1406–1414.
17 B. Schmidt, F. Holter, R. Berger and S. Jessel, Adv. Synth. Catal.,
¨
2010, 352, 2463–2473.
18 A. Roglans, A. Pla-Quintana and M. Moreno-Manas, Chem. Rev.,
2006, 106, 4622–4643.
19 J. G. Taylor, A. V. Moro and C. R. D. Correia, Eur. J. Org. Chem.,
2011, 1403–1428.
20 F.-X. Felpin, L. Nassar-Hardy, F. Le Callonnec and E. Fouquet,
Tetrahedron, 2011, 67, 2815–2831.
21 C. Jia, W. Lu, T. Kitamura and Y. Fujiwara, Org. Lett., 1999, 1,
2097–2100.
22 X. Zhao, C. S. Yeung and V. M. Dong, J. Am. Chem. Soc., 2010,
132, 5837–5844.
23 B. S. Kim, C. Jang, D. J. Lee and S. W. Youn, Chem.–Asian J.,
2010, 5, 2336–2340.
This work was generously supported by the DFG. We thank
Evonik Oxeno for generous donations of solvents, and Umicore
for generous donations of Pd-catalysts.
24 M. P. Doyle and W. J. Bryker, J. Org. Chem., 1979, 44, 1572–1574.
25 K. Voigt, A. Lansky, A. de Meijere and M. Noltemeyer, Liebigs
Ann., 1996, 899–911.
26 C. L. Oswald, J. A. Peterson and H. W. Lam, Org. Lett., 2009, 11,
4504–4507.
27 B. Chao and D. C. Dittmer, Tetrahedron Lett., 2000, 41, 6001–6004.
Notes and references
1 Modern Arylation Methods, ed. L. Ackermann, Wiley-VCH, Weinheim,
2009.
2 The Mizoroki–Heck Reaction, ed. M. Oestreich, Wiley, Chichester,
2009.
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4352 Chem. Commun., 2012, 48, 4350–4352
This journal is The Royal Society of Chemistry 2012