Aerobic direct C-H arylation of nonbiased olefins

Article abstract of DOI:10.1021/ol501924t

An efficient ligand-promoted biomimetic aerobic oxidative dehydrogenative cross-coupling between arenes and nonbiased olefins is presented. Acridine as a ligand was found to significantly enhance the rate, the yield, and the scope of the reaction under ambient oxygen pressure, providing a variety of alkenylarenes via an environmentally friendly procedure.

Full text of DOI:10.1021/ol501924t

Letter
pubs.acs.org/OrgLett
Aerobic Direct C−H Arylation of Nonbiased Olefins
Nicolas Gigant and Jan-E. Backvall*
̈
Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University, SE-106 91 Stockholm, Sweden
S
* Supporting Information
ABSTRACT: An efficient ligand-promoted biomimetic aerobic
oxidative dehydrogenative cross-coupling between arenes and
nonbiased olefins is presented. Acridine as a ligand was found to
significantly enhance the rate, the yield, and the scope of the
reaction under ambient oxygen pressure, providing a variety of
alkenylarenes via an environmentally friendly procedure.
irect functionalization of C−H bonds has emerged as a
nonbiased olefins. There are several challenges to deal with
Dpromising tool to create new C−C bonds, and one of the during the development of this reaction, the two most critical
ideal ways is the oxidation of two simple C−H bonds.1,2
being the use of an environmentally friendly method and the
capacity to engage these much less reactive alkenes efficiently in
the coupling. Our laboratory is indeed involved in the
development of new sustainable transformations for the
creation of C−C bonds via a biomimetic approach.7 With
this strategy the electron transfer is facilitated between the
organic substrate and O2 under mild conditions, decreasing the
activation energy during the catalytic process.8 Following this
concept, we have shown that acrylates4d and allyl esters7a
efficiently undergo the Heck coupling with arenes; however,
nonbiased alkenes, such as protected allylamines, were
unfortunately not tolerated by our catalytic systems. Since the
beneficial effect of various nitrogen-containing ligands has
recently been demonstrated in the intermolecular dehydrogen-
ative Heck reaction,9 we sought to address the lack of reactivity
of unactivated alkenes by enhancing the rate of the reaction
through the use of ligands. Our attention was drawn to recent
work by Yu9d and Sanford,1j,9e emphasizing the use of pyridine-
type ligands. We now report our study regarding the ligand-
promoted aerobic dehydrogenative coupling of arenes and
nonbiased olefins via a biomimetic approach.
Among these catalytic dehydrogenative cross-couplings, the
“dehydrogenative Heck reaction” was originally disclosed by
Fujiwara and Moritani.3 Much progress has been achieved in
this field following this pioneering work, and this trans-
formation is now fully recognized as a powerful method for the
construction of valuable scaffolds.4 However, recent develop-
ments of this reaction have witnessed several restrictions in the
presence of simple arenes. Limitations of these approaches
include the requirement of a relatively high palladium loading
and the use of various inorganic salts as terminal oxidants that
provide stoichiometric amounts of reduced external oxidants as
waste. In addition, due to their low reactivity, arenes are usually
used in a large excess or even as the solvent, thus making the
process less attractive in terms of atom economy.5 The scope of
alkenes is also largely limited to “activated” coupling partners
such as acrylates and styrene derivatives. On the contrary,
electronically nonbiased olefins are not reactive enough to
promote the Pd-catalyzed dehydrogenative reaction.6 Finally,
the control of the selectivity is problematic: a mixture of
products can be obtained from the insertion of the alkene into
the Pd−Ar bond (internal vs external) and the β-hydride
elimination (β-Ha vs β-Hb) (Scheme 1). Consequently a
general and efficient protocol solving several of these problems
would be desirable.
We evaluated the feasibility of the proposed strategy in the
reaction of alkene 1a (1 equiv) with 1,4-dimethoxybenzene 2a
(6 equiv) using Pd(OAc)2 (2.5 mol %), p-benzoquinone (BQ)
(10 mol %), and iron phthalocyanine [Fe(Pc), 2.5 mol %] in a
mixture of acetic acid/dioxane (1:1, v:v) for 24 h at 90 °C
under ambient oxygen pressure (Scheme 2). In this reaction
BQ and Fe(Pc) serve as electron-transfer mediators. These
reaction conditions provided the desired product 3aa in low
yield. As noted above, this unactivated alkene exhibited poor
reactivity, and the protocol was further optimized by examining
the effect of pyridine (L1) as a ligand. The reaction was very
dependent on the palladium/pyridine ratio, and it was found
that a 1:1 ratio is optimal.10 Lower yields were observed with
different ratios, and a 20:1 ratio in favor of pyridine (50 mol %)
On the basis of these considerations, we have explored the
aerobic direct C−H functionalization of simple arenes using
Scheme 1. Competitive Pathways in the Heck Reaction
Received: July 3, 2014
© XXXX American Chemical Society
A
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Letter
ab
,
selectivity being mainly directed by electronic factors with a
preference for the most electron-rich carbon. Gratifyingly,
starting from veratrole 2b, acridine (L3) was not only the best
ligand to promote the reaction but also the best ligand to form
product 3ab as a single regioisomer. Other ligands gave a
mixture of isomers in 2:8 or 3:7 ratios in lower yields in favor of
the 3-alkenylated scaffold. The high site selectivity with ligand
L3 may be due to steric effects leading to reaction at the less
sterically hindered C−H bond. When the coupling was
performed in the presence of naphthalene 2c, a low selectivity
was obtained (3ac). However, we noticed some variations in
the site selectivity of the coupling depending on the ligand.
The arylation of other nonbiased olefins was next studied
(Scheme 3).11 Several alkenes bearing a doubly protected
Scheme 2. Ligand Screening
a b c
, ,
Scheme 3. Substrate Scope of Alkenes
a
Unless otherwise noted the reactions were carried out at 90 °C using
1a (0.30 mmol), 2a (1.80 mmol, 6 equiv), Pd(OAc)2 (2.5 mol %),
ligand (2.5 mol %), BQ (10 mol %), and Fe(Pc) (2.5 mol %) in
AcOH/dioxane (0.5 mL/0.5 mL) for 24 h under O2 (balloon). The
use of air in place of O2 gave low yields and poor reproducibility.
b
c
NMR yield using an internal standard. Isolated yield.
totally inhibited the reaction. A number of both electronically
and sterically different pyridine-type ligands (L2−L11) were
tested in combination with this catalytic system. Systematic
variation of the pyridine moiety revealed that acridine (L3)
provided the highest yield. It is interesting to note that no
correlation between either the electronic nature or the steric
encumbrance of the ligand was observed.10 Importantly, 3aa
was isolated with high levels of selectivity (E:Z = 18:1, L:B >
40:1).
Encouraged by these results, we sought to investigate the
regioselectivity of the reaction by examining the influence of
our previous best ligands on the site selectivity of the coupling
(Table 1). Indeed a mixture of isomers is usually formed during
the Pd-catalyzed alkenylation of simple arenes, the site
a
b
c
For reaction conditions, see Scheme 1. Isolated yield. Ratio of
a
Table 1. Effect of Ligand on Site Selectivity
isomers (styrenyl:allylic) determined by NMR spectroscopy of isolated
product. 2a (10 equiv).
d
terminal amine performed well in the present reaction with
satisfying to excellent selectivity (3aa−3da). Generally, the
selectivity decreases with an increased length of the alkyl chain.
The source of the loss in the selectivity can be rationalized by a
more complicated chelation between the metal and the imide
oxygen in the presence of longer alkyl chains.12 Other
functional groups on simple alkenes were suitable coupling
partners, including a ketone, an ester, an acetate, and protected
malonates (3ea, 3fb, and 3ga−3ia). Unfortunately 5-hexeneni-
trile 1j was functionalized in a low yield (3ja), probably due to
the low stability of the starting material in the reaction medium.
We were pleased to find that even a cyclic carbonate can be
accommodated under our conditions, giving 3ka in good yield
and complete selectivity. The use of purely aliphatic olefins
such as 1-octene or 1-undecene gave low yields and poor
selectivity.
b
3ab (from 2b)
selectivity
3ac (from 2c)
selectivity
c
d
c
d
entry ligand
(α:β)
yield (%)
(α:β)
yield (%)
1
2
3
4
5
6
7
none
L1
>5:95
19:81
>1:99
25:75
29:71
30:70
21:79
14
19
46:54
47:53
44:56
53:47
56:44
55:45
57:43
33
80
e
e
L3
53 (49)
23
82 (56)
36
L4
L5
25
27
L6
23
73
L11
36
37
a
b
c
For reaction conditions, see Scheme 1. 2b (2 equiv). Ratio of
regioisomers determined by NMR spectroscopy of crude mixture.
NMR yield using an internal standard. Isolated yield.
d
e
B
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Organic Letters
Letter
a b c
, ,
Scheme 4. Substrate Scope of Arenes
a
d
g
b
c
For reaction conditions, see Scheme 1. Isolated yield. Ratio of isomers (o:m:p or α:β) determined by NMR spectroscopy of isolated product.
e
f
Pd(OAc)2 (2.5 mol %), L3 (2.5 mol %). Pd(OAc)2 (1 mol %), L3 (1 mol %). Arene 2 (10 equiv), Pd(OAc)2 (5 mol %), L3 (5 mol %).
Pd(OAc)2 (5 mol %), L3 (5 mol %). Reaction performed at 70 °C. Pd(OAc)2 (3.5 mol %), L3 (3.5 mol %).
h
i
Alkenes 1a and 1i were selected as model substrates for the
arene scope evaluation as presented in Scheme 4.11
cleavage by Pd is involved in the rate-determining step of the
coupling.
To gauge the acridine effect, we measured the relative rate of
the reaction starting from 1a and 1h with or without ligand
(Scheme 5).16 The initial rate of the coupling was roughly 3.6
and 5.4 times faster for 1a and 1h, respectively, in the presence
of acridine when compared to the rate in the absence of
acridine. In addition, two competitive reactions between 1a and
1h with 1,4-dimethoxybenzene 2a without or with ligand were
also performed, giving a mixture of products 3aa and 3ha in a
Electron-rich arenes undergo smooth coupling with moder-
ate to complete site selectivity in the presence of unsymmetrical
substrates (3aa−3ag). Importantly, 3ab could be a relevant
synthetic intermediate for the short total synthesis of bioactive
compounds abamine and abamine SG.13 Starting from electron-
neutral or -poor arenes, a slight increase of the catalyst/ligand
loading as well as the amount of arene were necessary for
obtaining synthetically useful yields (3ah−3am and 3hn).
Additionally, several alkenylated multifluoroarenes were also
efficiently isolated (3ao−3aq), which are not commonly
obtained from direct olefination of this category of arenes.9c,14
Because of their high sensitivity to acidic conditions, hetero-
cycles such as thiophenes and furans are usually poor substrates
in the oxidative Heck reactions.15 In the present method, these
heterocycles efficiently react with unbiased alkenes (3ar−3au
and 3hu), leading the desired alkenylated scaffolds in good to
high yields at 70 °C.
Scheme 5. Acridine-Accelerated Reaction
To obtain mechanistic information, two parallel reactions
using 2i and 2i-d8 with protected allylamine 1a were
performed.16 The comparison of the initial rates gave a kinetic
isotope effect of 4.4, indicating that the aromatic C−H bond
C
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Organic Letters
Letter
5705. (g) García-Rubia, A.; Urones, B.; Arrayas
Angew. Chem., Int. Ed. 2011, 50, 10927−10931.
(5) For the sole Rh-catalyzed example using arene loading at 1 equiv,
see: Vora, H. U.; Silvestri, A. P.; Engelin, C. J.; Yu, J.-Q. Angew. Chem.,
Int. Ed. 2014, 53, 2683−2686.
́
, R. G.; Carretero, J. C.
1.9 and 1.4 ratio, respectively, after 2 h (at 3% and 9%
conversion, respectively). The slight increase of relative rate of
1a:1h (1.55:1.9 without L3) and (1.02:1.4 with L3) in the
competitive experiment compared to the separate experiment
in Scheme 5 suggests that there is a preference for coordination
of 1a over 1h in the competitive experiment.
In summary, we have documented a new aerobic alkenylation
of arenes through a biomimetic approach. The current work is a
major advance over existing methods for coupling of unbiased
olefins with simple arenes, perfluoroarenes, and heterocycles.
Finally, it is noteworthy that the coupling described proceeds
under relatively low catalyst loading at ambient oxygen
pressure.
(6) (a) For a Pd-catalyzed approach involving dihydropyrans, see:
Pawar, G. G.; Singh, G.; Tiwari, V. K.; Kapur, M. Adv. Synth. Catal.
2013, 355, 2185−2190. For Pd-catalyzed examples using strong
directing groups, see: (b) Zhu, Z.; Falck, J. R. Org. Lett. 2011, 13,
1214−1217. (c) Engle, K. M.; Wang, D.-H.; Yu, J.-Q. J. Am. Chem. Soc.
2010, 132, 14137−14151. For a Pd-catalyzed example with benzene,
see: (d) Lee, H. S.; Kim, K. H.; Kim, S. H.; Kim, J. N. Adv. Synth.
Catal. 2012, 354, 2419−2426. For a Rh-catalyzed example with
toluene, see: (e) Zheng, L.; Wang, J. Chem.Eur. J. 2012, 18, 9699−
9704. For Rh-catalyzed examples using strong directing groups, see:
(f) Rakshit, S.; Grohamann, C.; Besset, T.; Glorius, F. J. Am. Chem.
Soc. 2011, 133, 2350−2353. (g) Li, X.; Gong, X.; Zhao, M.; Song, G.;
Deng, J.; Li, X. Org. Lett. 2011, 13, 5808−5811.
ASSOCIATED CONTENT
* Supporting Information
■
S
(7) (a) Gigant, N.; Backvall, J.-E. Org. Lett. 2014, 16, 1664−1667.
̈
Experimental procedures and full characterization details
1
(b) Gigant, N.; Backvall, J.-E. Chem.Eur. J. 2014, 20, 5890−5894.
including H, 13C NMR and HRMS. This material is available
̈
(c) Volla, C. M. R.; Backvall, J.-E. Angew. Chem., Int. Ed. 2013, 52,
̈
free of charge via the Internet at http://pubs.acs.org.
14209−14213. (d) Gigant, N.; Backvall, J.-E. Chem.Eur. J. 2013, 19,
̈
́
10799−10803. (e) Persson, A. K. Å.; Backvall, J.-E. Angew. Chem., Int.
̈
AUTHOR INFORMATION
Corresponding Author
Ed. 2010, 49, 4624−4627. (f) Piera, J.; Persson, A.; Caldentey, X.;
■
Backvall, J.-E. J. Am. Chem. Soc. 2007, 129, 14120−14121.
̈
(8) A review: Piera, J.; Backvall, J.-E. Angew. Chem., Int. Ed. 2008, 47,
̈
*E-mail: jeb@organ.su.se.
Notes
3506−3523.
(9) For examples involving arenes, see: (a) He, J.; Li, S.; Deng, Y.;
Fu, H.; Laforteza, B. N.; Spangler, J. E.; Homs, A.; Yu, J.-Q. Science
2014, 343, 1216−1220. (b) Ying, C.-H.; Yan, S.-B.; Duan, W.-L. Org.
Lett. 2014, 16, 500−503. (c) Wu, C.-Z.; He, C.-Y.; Huang, Y.; Zhang,
X. Org. Lett. 2013, 15, 5266−5269. (d) Engle, K. E.; Yu, J.-Q. J. Org.
Chem. 2013, 78, 8927−8955 and references cited herein. (e) Kubota,
A.; Emmert, M. H.; Sanford, M. S. Org. Lett. 2012, 14, 1760−1763.
(f) Wang, D.-H.; Engle, K. M.; Shi, B.-F.; Yu, J.-Q. Science 2010, 327,
315−319. (g) Zhang, Y.-H.; Shi, B.-F.; Yu, J.-Q. J. Am. Chem. Soc.
2009, 131, 5072−5074. For other examples, see: (h) Lee, W.-C.;
Wang, T.-H; Ong, T.-G. Chem. Commun. 2014, 50, 3671−3673.
(i) Liu, W.; Yu, X.; Kuang, C. Org. Lett. 2014, 16, 1798−1801.
(j) Wen, Z.-K.; Xu, Y.-H.; Loh, T.-P. Chem. Sci. 2013, 4, 4520−4524.
(k) Wen, Z.-K.; Xu, Y.-H.; Loh, T.-P. Chem.Eur. J. 2012, 18, 13284−
13287.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from the European Research Council (ERC
AdG 247014), The Swedish Research Council, and The Knut
and Alice Wallenberg Foundation is gratefully acknowledged.
REFERENCES
■
(1) For selected reviews on C−H bond functionalization, see:
(a) Gigant, N.; Chausset-Boissarie, L.; Gillaizeau, I. Chem.Eur. J.
2014, 20, 7548−7564. (b) Ackermann, L. Acc. Chem. Res. 2014, 47,
281−295. (c) Li, B.; Dixneuf, P. H. Chem. Soc. Rev. 2013, 42, 5744−
5767. (d) Wencel-Delord, J.; Glorius, F. Nat. Chem. 2013, 5, 369−375.
(e) Kuhl, N.; Hopkinson, M. H.; Wencel-Delord, J.; Glorius, F. Angew.
Chem., Int. Ed. 2012, 51, 10236−10254. (f) Yamaguchi, J.; Yamaguchi,
A. D.; Itami, K. Angew. Chem., Int. Ed. 2012, 51, 8960−9009. (g) Chen,
D. Y.-K.; Youn, S. W. Chem.Eur. J. 2012, 18, 9452−9474.
(h) Neufeldt, S. R.; Sanford, M. S. Acc. Chem. Res. 2012, 45, 936−
946. (i) Engle, K. M.; Mei, T.-S.; Wasa, M.; Yu, J.-Q. Acc. Chem. Res.
2012, 4, 788−802. (j) Lyons, T. W.; Sanford, M. S. Chem. Rev. 2010,
110, 1147−1169.
(10) For complete optimization of the reaction and pyridine pKa
values, see the Supporting Information.
(11) All products were obtained in good to excellent E:Z and L:B
ratios, but for clarity, these results are not directly reported in the
paper. See the Supporting Information for complete assignment of the
selectivity.
(12) Pan, D.; Chen, A.; Su, Y.; Zhou, W.; Li, S.; Jia, W.; Xiao, J.; Liu,
Q.; Zhang, L.; Jioa, N. Angew. Chem., Int. Ed. 2008, 47, 4729−4732.
(13) Prediger, P.; Barbosa, L. F.; Gen
Org. Chem. 2011, 76, 7737−7749.
́
isson, Y.; Correia, C. R. D. J.
(2) For selected reviews on dehydrogenative Heck reactions, see:
(a) Zhou, L.; Lu, W. Chem.Eur. J. 2014, 20, 634−642. (b) Wu, Y.;
Wang, J.; Mao, F.; Kwong, F. K. Chem.Asian. J. 2014, 9, 26−47.
(c) Kozhushkov, S. I.; Ackermann, L. Chem. Sci. 2013, 4, 886−896.
(d) Shang, X.; Liu, Z.-Q. Chem. Soc. Rev. 2013, 42, 3253−3260.
(e) Yeung, C. S.; Dong, V. M. Chem. Rev. 2011, 111, 1215−1292.
(f) Le Bras, J.; Muzart, J. Chem. Rev. 2011, 111, 1170−1214.
(3) For seminal work, see: (a) Fujiwara, Y.; Moritani, I.; Danno, S.;
Asano, R.; Teranishi, S. J. Am. Chem. Soc. 1969, 91, 7166−7169.
(b) Moritani, I.; Fujiwara, Y. Tetrahedron Lett. 1967, 8, 1119−1122.
(4) For some selected representative or recent examples, see: (a) Lee,
S.; Lee, H.; Tan, K. L. J. Am. Chem. Soc. 2013, 135, 18778−18781.
(b) Dai, H.-X.; Li, G.; Zhang, X.-G.; Stepan, A. F.; Yu, J.-Q. J. Am.
Chem. Soc. 2013, 135, 7567−7571. (c) Huang, X.; Huang, J.; Du, C.;
Zhang, X.; Song, F.; You, J. Angew. Chem., Int. Ed. 2013, 52, 12970−
(14) For successful approaches, see: (a) Li, Z.; Zhang, Y.; Liu, Z.-Q.
Org. Lett. 2012, 14, 74−77. (b) Zhang, X.; Fan, S.; He, C.-Y.; Wan, X.;
Min, Q.-Q.; Yang, J.; Jiang, Z.-X. J. Am. Chem. Soc. 2010, 132, 4506−
4507.
(15) For successful approaches, see: (a) Jiang, Z.; Zhang, L.; Dong,
C.; Cai, Z.; Tang, W.; Li, H.; Xu, L.; Xiao, J. Adv. Synth. Catal. 2012,
354, 3225−3230. (b) Vasseur, A.; Muzart, J.; Le Bras, J. Chem.Eur. J.
2011, 17, 12556−12560. (c) Aouf, C.; Thiery, E.; Le Bras, J.; Muzart,
J. Org. Lett. 2009, 11, 4096−4099.
(16) See the Supporting Information for more details.
12974. (d) Babu, B. P.; Meng, X.; Backvall, J.-E. Chem.Eur. J. 2013,
̈
19, 4140−4145. (e) Shi, Z.; Schroder, N.; Glorius, F. Angew. Chem.,
̈
Int. Ed. 2012, 51, 8092−8096. (f) Pankajakshan, S.; Xu, Y.-H.; Chang,
J. K.; Low, M. T.; Loh, T.-P. Angew. Chem., Int. Ed. 2012, 51, 5701−
D
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