Palladium(ii)-catalyzed coupling reactions with a chelating vinyl ether and arylboronic acids: A new Heck/Suzuki domino diarylation reaction

Article abstract of DOI:10.1039/b918358b

A mild and novel palladium(ii)-catalyzed domino Heck/Suzuki α,β-diarylation-reduction of a dimethylaminoethyl substituted chelating vinyl ether was developed by using electron-rich arylboronic acids in combination with p-benzoquinone. Based on the prepara

Full text of DOI:10.1039/b918358b

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Palladium(II)-catalyzed coupling reactions with a chelating vinyl ether
and arylboronic acids: a new Heck/Suzuki domino diarylation reactionw
Alejandro Trejos, Ashkan Fardost, Samir Yahiaoui and Mats Larhed*
Received (in Cambridge, UK) 7th September 2009, Accepted 20th October 2009
First published as an Advance Article on the web 5th November 2009
DOI: 10.1039/b918358b
A mild and novel palladium(II)-catalyzed domino Heck/Suzuki
a,b-diarylation-reduction of a dimethylaminoethyl substituted
chelating vinyl ether was developed by using electron-rich
arylboronic acids in combination with p-benzoquinone. Based
on the preparative results, a catalytic cycle is proposed. Further,
highly regioselective palladium(II)-catalyzed a- or b-monoaryl-
ation of the chelating vinyl ether was achieved using either a
bidentate ligand or by employing ligand-less conditions.
investigating Pd(II)-catalyzed reactions of N,N-dimethyl-
(2-ethenyloxy)ethanamine (1).
Previous research under Pd(0)-conditions has demonstrated
that bidentate ligands disrupt the chelating ability of the
dimethylamino moiety, changing the regioselectivity from
terminal b-arylation into internal a-arylation.11
A protocol consisting of 1, p-tolylboronic acid (2a), the
bidentate ligand dppp13 and Pd(O2CCF3)2 in 1,4-dioxane at
25 1C, using O2(g) as reoxidant was developed (Method A),
affording the branched product 3a in good yield (Table 1,
entry 1). The results obtained showed that selective electronically
controlled arylation14 of vinyl ether 1 using 2a is achievable
using dppp to hinder internal nitrogen–metal coordination in
the insertion process (Scheme 1, I to II). Next, we attempted to
perform selective mono b-arylation of 1. After investigation of
different reaction conditions, it was found that stirring a
mixture of 1, 2a–d and Pd(OAc)2 in DMF at 60 1C, using
O2(g) as reoxidant yielded the desired b-arylated 4a–d in
acceptable yields and with high terminal regioselectivity
(Method B, Table 1, entries 2–5). Hence, under ligand-less
conditions the chelation-control, proceeding via intermediates
III and IV, was found to be excellent as no product 3 was
detected. The stereoselectivity was less impressive as a mixture
of E and Z isomers of 4 was persistently obtained.
In the class of palladium(0)-catalyzed C–C coupling reactions,
the Mizoroki–Heck reaction has emerged as an efficient and
selective method for arylation and vinylation of alkenes.1 The
palladium(II)-mediated counterpart of this method for vinylic
substitution was first discovered by Heck in 1975, utilizing a
vinylboronic acid and stoichiometric amounts of palladium
acetate.2 Although reoxidizing agents for enabling palladium(II)
catalysis were already used in the late 60s,3 it was the pioneering
work conducted by Mori et al.4 using arylboronic acids, a
catalytic amount of palladium and Cu(OAc)2 as the reoxidant5
that rendered the oxidative Heck reaction preparatively
feasible. In 2003, Jung6 reported that oxygen gas could act
as an efficient reoxidant of palladium in oxidative Heck
reactions. In 2004 we introduced the first ligand-modulated
oxidative Heck reaction employing 2,9-dimethyl-1,10-phenan-
throline (dmphen) to facilitate regeneration of palladium(II),
to increase the catalytic stability and to control the regio-
selectivity with electron-rich olefins.7 In addition, palladium
loadings could be reduced and atmospheric air could be used
as the sole reoxidant.8 Further development led to the
base-free oxidative Heck reactions with vinyl- and arylboron
substrates.9
While investigating different conditions for achieving a
highly b-selective reaction between 1 and 2a (solvents,
Table 1 Regioselective internal a- and terminal b-arylations of olefin
1 with boronic acids 2 by oxidative Heck reactions
During the last two decades, chelation-controlled
palladium(0)-catalyzed Mizoroki–Heck couplings have been
developed, emerging as powerful strategies to control the
regio- and stereoselectivity of this reaction.10,11 Similar
auxiliary-controlled transformations have recently been developed
for palladium(II)-catalyzed oxidative Heck reactions, providing
a variety of new synthetic opportunities.12 However, the
oxidative Heck methodology has not been studied using
chelating vinyl ethers. Consequently, we decided to explore
the arylation of a chelating electron-rich olefin using arylboronic
acids as arylating agents. We herein report our results
Isolated a : b
E : Z
Time/h yield (%) selectivitya ratiob Method
Entry Ar
1
2
3
2a 6
3a (75)
19 : 1
—
A
B
B
2b 12
2a 12
4b (56) >1 : 50
4a (51) >1 : 50
1 : 6
2 : 3
4
5
2c 24
2d 24
4c (53) >1 : 50
4d (47) >1 : 50
2 : 3
3 : 2
B
B
Organic Pharmaceutical Chemistry, Department of Medicinal
Chemistry, Uppsala Biomedical Centre, Uppsala University, Box 574,
SE-751 23 Uppsala, Sweden. E-mail: mats@orgfarm.uu.se;
Fax: +46 18 4714474; Tel: +46 18 4714667
w Electronic supplementary information (ESI) available: Experimental
details, UV/ELSD, ESI-MS, 1H and 13C NMR spectra of products.
See DOI: 10.1039/b918358b
Method A: 1 (1 equiv., 0.43 mmol), 2a (2 equiv.), Pd(O2CCF3)2
(5 mol%) and dppp (18 mol%) in 1,4-dioxane (3 mL) 25 1C, O2 (balloon).
Method B:
1 (1 equiv., 0.17 mmol), 2 (2 equiv.), Pd(OAc)2
(5 mol%) in DMF (1.0 mL) at 60 1C using O2 (balloon).a By
GC-MS. By NMR.
b
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Table 2 Oxidative Heck/Suzuki domino diarylation of olefin 1 with
boronic acids 2
Isolated
yield
Entry Ar
Time/h Yield 4 (%) 5 (%)
1
2
2e
2b
12
24
4e (n.d.)
4b (10)a
5e (49)
5b (66)
3
4
5
2f
24
12
24
4f (1)b
5f (48)
5a (82)
5c (66)
2a
2c
4a (n.d.)
4c (6)a
Scheme 1 Oxidative Heck arylation pathways of 1 with 2. S = Solvent,
acetate, trifluoroacetate; X = Acetate, trifluoroacetate. L - L = dppp.
6
7
2g
2h
12
24
4g (n.d.)
4h (n.d.)
5g (92)
5h (50)
reoxidants, catalyst and temperature), it was found that the
choice of reoxidating agent had a major impact on the product
outcome. Thus, a small amount of an unknown compound
was observed only when p-benzoquinone (BQ) was used as
reoxidant. The compound was isolated and the structure 5a
was confirmed by NMR-spectrometry (Table 2, entry 4).
In the literature, it has previously been noted that the
presence of a catalyst-coordinating group can prevent competing
b-hydride elimination after the carbopalladation step.15
Therefore, we hypothesized that if the s-alkyl palladium(II)-
intermediate was stabilized16 not only by intramolecular
amine coordination but also by a weak ligand such as BQ,17
transmetallation of complex VI with boronic acids should
yield product 5 in a Heck/Suzuki type domino reaction
(Scheme 2).18
8
2i
12
24
18
24
24
4i (n.d.)
4j (15)a
5i (81)
5j (11)
5k (66)
5l (28)
5m (47)
9
2j
10
11
12
2k
2l
4k (o1)b
4l (15)a
2m
4m (n.d.)
13
2n
12
4n (n.d.)
5n (65)
Method C: 1 (1 equiv., 0.35 mmol), 2 (3 equiv.), BQ (1 equiv.)
and Pd(O2CCF3)2 (5 mol%) in 1,4-dioxane (2.4 mL) at 40 1C. a By
An attempt to identify reaction conditions favouring the
formation of 5 was initiated. It was quickly noted that a 3 : 1
ratio of 2a/1 was appropriate and that 1,4-dioxane was the
solvent of choice. More polar solvents like acetonitrile, DMSO
and DMF increased the amount of monoarylated product,
while toluene slowed down the reaction rate to unacceptable
levels. A quick scan of different Pd-sources showed that
Pd(O2CCF3)2 rendered 5a in superior yields compared to
other Pd-sources, such as Pd(acac)2 or Pd(OAc)2. A reaction
temperature of 40 1C was found suitable, as lower temperatures
decreased the reaction rate drastically while higher temperatures
resulted in larger amounts of b-monoarylated product.
To evaluate the selected conditions (Method C), a set of
arylboronic acids were selected. The preparative results for
the difunctionalization of 1 are presented in Table 2.
1H-NMR of the crude product. By GC-MS. n.d. = not detected.
b
Overall, the selectivity and yields of 5 were fairly good to
excellent with electron-rich and neutral arylboronic acids.
Electron-deficient arylboronic acids furnished lower reactivity
and were removed from the test series. As expected, o-substituted
substrates gave a lower yield compared to their unhindered
counterparts. p-Iodophenylboronic acid (2j) resulted in
poor yields and relatively high amounts of 4j (Table 2, entry 9).
Scheme 2 Proposed catalytic cycle for the Heck/Suzuki domino
diarylation of vinyl ether 1 using Method C. DHQ = 1,4-dihydro-
benzoquinone. L = BQ, 1,4-dioxane (or O2CCF3À).
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The poor yield using p-iodophenylboronic acid was mainly
attributed to the extensive dehalogenation of this substrate
together with large amounts of homocoupled biaryl product.
p-Bromophenylboronic acid (2k) performed considerably
better, smoothly yielding 66% of 5k and only trace amounts
of 4k, proving high chemoselectivity and no activation of the
bromo group (Table 2, entry 10). The different outcome
with thiophene substrates 2l and 2m, respectively, might be
attributed to palladium coordination of the sulfur atom in the
2-position of 2l, competing with the amino moiety for free
coordination sites at the metal centre, thereby increasing the
formation of the Heck product 4l (Table 2, entries 11 and 12).
Finally, trans-2-phenylvinylboronic acid was tested successfully,
yielding 65% of 5n and no detectable amount of 4n (Table 2,
entry 13).
Heck a-monoarylation, or fully selective b-monoarylation.
Continued studies to extend the domino reaction to include
electron-poor arylating agents and the use of chiral catalyst
presenting auxiliaries are currently ongoing in the laboratory.
We thank the Swedish Research Council, Knut and Alice
Wallenberg’s Foundation, Dr P. Nilsson and Dr L. Odell.
Notes and references
1 T. Mizoroki, K. Mori and A. Ozaki, Bull. Chem. Soc. Jpn., 1971,
44, 581–581; R. F. Heck and J. P. Nolley, Jr., J. Org. Chem., 1972,
37, 2320–2322; J. P. Knowles and A. Whiting, Org. Biomol. Chem.,
2007, 5, 31–44; M. Oestreich, The Mizoroki-Heck Reaction, John
Wiley & Sons, 2009.
2 H. A. Dieck and R. F. Heck, J. Org. Chem., 1975, 40, 1083–1090.
3 Y. M. Fujiwara, Ichiro, Matsuda, Masaoki, Teranishi and Shiichiro,
Tetrahedron Lett., 1968, 9, 3863–3865.
Next, we focused our attention on the importance of BQ
and the catalyst-directing dimethylamino group for the
difunctionalization of olefin 1. As previously mentioned, when
the reoxidation agent was changed from BQ to O2(g), or other
reoxidants such as Cu(OAc)2 and AgOAc, only b-monoary-
lated product 4a was produced. Further, by employing
100 mol% of Pd(O2CCF3)2 and without BQ, only 4a was
obtained. In additional reactivity studies, 1 was exchanged to
n-butyl vinyl ether and t-butyl vinyl ether, respectively. These
non-chelating vinyl ethers did not provide full conversion and
yielded solely a mixture of a- and b-monoarylated Heck
products.
4 X. Du, M. Suguro, K. Hirabayashi and A. Mori, Org. Lett., 2001,
3, 3313–3316.
5 M. M. S. Andappan, P. Nilsson and M. Larhed, Mol. Diversity,
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Based on these results we propose the catalytical cycle
depicted in Scheme 2, in which 5 is formed by an oxidative
Heck/Suzuki domino diarylation. In the process following the
initial transmetallation, the olefin is chelating to the Pd(II)
centre (intermediate V). The p-coordinated olefin further
rotates to an in-plane position to allow a syn insertion, leading
to palladacycle VI. The most critical step in the catalytic cycle
is when intermediate VI reacts with 2, forming intermediate
VII via a Suzuki type transmetallation. Most likely, BQ is
playing a key-role in this event, stabilizing the six-membered
complex VI in order to prevent b-hydride elimination and
formation of 4. Tandem product 5 is produced via a reductive
elimination reaction and the released Pd(0) species is oxidized
to Pd(II) by BQ (or by molecular oxygen) and can now initiate
the next catalytic cycle.
10 C. M. Andersson, J. Larsson and A. Hallberg, J. Org. Chem., 1990,
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In summary, a domino oxidative Heck/Suzuki reaction has
for the first time been developed, delivering a series of
diarylated dimethylaminoethyl ethers in high selectivity and
good yields at low temperature and base-free conditions.
We have also demonstrated that the reactivity of the chelating
olefin 1 can be controlled, allowing either highly regioselective
16 R. McCrindle, G. Perguson, A. J. McAlees and B. L. Ruhl,
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Chem. Commun., 2009, 7587–7589 | 7589