A: Meta -selective-C-H alkenylation of phenol-derivatives employing a traceless organosilicon template

Article abstract of DOI:10.1039/c7cc07093d

A traceless organosilicon template-directed meta-selective-C-H alkenylation of phenols was realized with good yields and high selectivities. The template was readily removable through F^--promoted O-Si cleavage under extremely mild conditions or recyclable through a p-TSA catalyzed process. The product was successfully applied in the preparation of a series of meta-alkenylated aromatic compounds.

Full text of DOI:10.1039/c7cc07093d

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A meta-selective-C–H alkenylation of phenol-
derivatives employing a traceless organosilicon
Cite this:DOI: 10.1039/c7cc07093d
template†
Rui-Jie Mi,‡a Jing Sun,‡a Fritz E. Kuhn,
Received 11th September 2017,
Accepted 9th November 2017
b
Ming-Dong Zhou*a and
¨
c
Zhaoqing Xu
*
DOI: 10.1039/c7cc07093d
rsc.li/chemcomm
A traceless organosilicon template-directed meta-selective-C–H
alkenylation of phenols was realized with good yields and high
selectivities. The template was readily removable through FÀ-promoted
O–Si cleavage under extremely mild conditions or recyclable through a
p-TSA catalyzed process. The product was successfully applied in the
preparation of a series of meta-alkenylated aromatic compounds.
Fig. 1 The desired template directed meta-selective C–H functionaliza-
tion of phenols.
Phenol moieties are among the most ubiquitous building blocks
in bioactive natural products, polymers, and pharmaceuticals.1
Functionalization of phenols has received much attention owing phenols has been reported recently by Yu9 and Larrosa et al.,10
to the extensive applications of phenols both in organic synthesis in which a nitrile-based-template, norbornene, or carboxylic
and in the biosynthesis of a number of natural products.2 However, acid was employed as a temporary DG. These accomplishments
due to the strong electron-donating and directing effects of the are very encouraging and inspired people to make continuous
hydroxyl group, the functionalization of phenols usually leads to efforts in this field. However, to achieve a practical application
the ortho- and/or para-substituted products.3 The preparation of of this meta-C–H functionalization strategy, there are still two
meta-substituted phenols mostly relies on indirect methodologies, major challenges: (i) the directing group(s) attached on the
such as oxidation of cyclyohexanones4 or cycloaddition reactions.5 linkers should be easily removable; and (ii) it should be
Therefore, the direct meta-functionalization of phenols remains a possible for the products to be subjected to various functional
very challenging task.
group transformations (Fig. 1). Unfortunately, to the best of our
On the other hand, transition-metal catalyzed C–H bond knowledge, so far, most of the reported DGs connected to the
functionalization has emerged as an efficient approach to synthe- phenol ring are difficult to remove. In the case of the meta-
size useful organic molecules from inert C–H bonds in the past selective C–H alkenylation of phenols using a nitrile-based
few decades.6 In particular, significant achievements were made template or norbornene as the transient mediator, the removal
for the ortho-selective C–H bond activation7 and more recently for of the DGs requires either high temperature (refluxing toluene)9d
the meta-selective C–H bond activation of arenes,8 along with the or Pd-catalyzed hydrogenation under high pressure.9a For the
introduction of a broad range of directing groups (DGs). Notably, meta-C–H arylation of phenol using a carboxylic acid at the ortho-
a breakthrough with respect to the meta-functionalization of position as the temporary DG, the removal of the carboxylic acid
is unfortunately sluggish and has to be carried out under high
pressure (25 atm) and at relatively high temperature (190 1C).10
To overcome the current limitations, the development of an
a School of Chemistry and Materials Science, Liaoning Shihua University,
Fushun 113001, China. E-mail: mingdong.zhou@lnpu.edu.cn
b Molecular Catalysis, Department of Chemistry and Catalysis Research Center,
effective methodology for the meta-selective functionalization of
phenols using an easily introducible and removable directing
group is therefore highly desirable.
Recently, organosilicon groups have been successfully applied to
direct the Pd-catalyzed ortho-11 and para-C–H12 activation of phenols,
as well as meta- and para-selective functionalization of other arene
derivatives.13,14 However, the highly demanded meta-selective C–H
functionalization of phenols using a silicon template has not been
¨
¨
¨
Technische Universitat Munchen, Lichtenbergstr. 4, Garching bei Munchen,
D-85747, Germany
c Key Laboratory of Preclinical Study for New Drugs of Gansu Province,
School of Basic Medical Science, Lanzhou University, Lanzhou 730000, China.
E-mail: zqxu@lzu.edu.cn
† Electronic supplementary information (ESI) available: Experimental procedures
and spectral data for all compounds are provided. See DOI: 10.1039/c7cc07093d
‡ These authors contributed equally to this work.
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and more rigid. It can be assumed that the Et substituent provides a
bond angle expansion between the phenyl ring and the nitrile, thus
favoring a better meta-selectivity. In order to further optimize the
selectivity, we attempted to modify the substituents located at the
silicon atom. Unfortunately, the preparation of substrates bearing
diethylsilyl or diphenylsilyl groups was not successful, which yielded
inseparable mixtures with a large variety of byproducts.
Therefore, 1a was chosen for further reaction optimizations
(Table 2, see the ESI† for details). Different solvents were first
screened, by applying 20 mol% Pd(OAc)2, 40 mol% Ac–Gly–OH,
and 3 equiv. AgOAc at 60 1C. However, only a comparatively low
yield of alkenylated product 2a was obtained through the reactions
performed in DCE, HFIP, TFA, and tert-butylbenzene (entries 1–5).
To our delight, the yield was increased to 80% when the reaction
was performed in DCE/HFIP mixed solvents with a ratio of 1 : 0.3
(entry 6). Higher temperature did not improve the yield, and the
reaction was not effective at room temperature (entries 7–9).
Further studies indicated that good yields and selectivities could
also be maintained by reducing the loading of the catalyst and the
oxidant to 10 mol% and 2 equiv., respectively (entry 12).
With the optimized conditions in hand, the scopes of this
reaction were explored. The meta-C–H alkenylation of phenols
bearing various substituents was first studied (Table 3). Mono-
substituted phenols bearing electron-donating and electron-
withdrawing groups at the o-, m-, or p-position, such as methyl,
ÀOCH3, ÀCO2Me, and ÀCF3 groups all resulted in high yields
and meta-selectivities (2a–g and 2m–n). It is worth mentioning
that good to excellent yields and selectivities were achieved for
halo-substituted phenols as well, rendering the meta-alkenylated
products for further transformations, e.g., transition-metal catalyzed
C–Br bond functionalization (2h–l). Notably, the more sterically
demanding dimethyl/dichloro substituted phenols and naphthol
derivatives also led to satisfactory results (2o–t).
Fig. 2 Organosilicon template directed C–H functionalization of phenols.
reported yet. Herein, we report the first example of a traceless
organosilicon template directed meta-selective C–H alkenylation
of phenols via Pd(II) catalysis (Fig. 2).
Employing this temporary organosilicon template is beneficial
not only because it provides a convenient methodology to access a
broad range of meta-alkylated phenols in high selectivity, but also
because of the ease of its deprotection under very mild and neutral
conditions. Moreover, the meta-alkenylated phenol products can be
readily converted to a broad range of meta-functionalized aromatic
compounds, which are not easily achieved by other meta-selective
C–H activation methodologies.
To find an effective DG for meta-selective C–H activation, a
series of silicon-based DGs bearing a nitrile moiety were synthe-
sized. An encouraging selectivity towards meta-alkenylation was
observed for 1aa, albeit in a low yield (Table 1, entry 1). Further
tests suggested that the meta-selectivity could be adjusted by
varying the R groups at the carbon atom adjacent to the nitrile.
The ethyl group seems to be ideally suited, furnishing 2a in 88%
meta-selectivity (1a, entry 2). Interestingly, in the case of meta-
functionalization of benzyl alcohol using the same template, Tan
et al. demonstrated that the bulkier sec-butyl group was superior
to the ethyl group owing to the compressed angle between the
phenyl ring and the nitrile group. Compared to benzyl alcohol,
the distance between the oxygen atom and the aryl ring is closer
Table 2 Optimization of reaction conditionsa
AgOAc
(equiv.)
Pd(OAc)2
(mol%)
Yieldb (%)
Table 1 Modification of the directing groupa
Entry
Solvent
(m : others)c
1
2
3
4
5
6
7
8
DCE
HFIP
Toluene
TFA
tert-Butylbenzene
DCE/HFIP (1 : 0.3)
DCE/HFIP (1 : 0.3)d
DCE/HFIP (1 : 0.3)e
DCE/HFIP (1 : 0.3) f
DCE/HFIP (1 : 0.3)
DCE/HFIP (1 : 0.3)
DCE/HFIP (1 : 0.3)
3
3
3
3
3
3
3
3
3
3
3
2
20
20
20
20
20
20
20
20
20
10
5
31 (88 : 12)
25 (90 : 10)
0
16 (86 : 14)
22 (84 : 16)
80 (88 : 12)
0
79 (81 : 19)
77 (80 : 20)
80 (90 : 10)
65 (85 : 15)
82 (92 : 8)
Entry
R
Yieldb (%)
meta : othersc
9
1
2
3
4
Me (1aa)
Et (1a)
i-Pr (1ac)
Cy (1ad)
17
31
22
25
70 : 30 (2aa)
88 : 12 (2a)
65 : 35 (2ac)
57 : 43 (2ad)
10
11
12
10
a
The reactions were carried out using 1a (0.1 mmol), ethyl acrylate
a
The reactions were carried out using 1 (0.1 mmol), ethyl acrylate (0.15 mmol), AgOAc, Pd(OAc)2, and Ac–Gly–OH (2 equiv. to the amount
b
(0.15 mmol), AgOAc (3 equiv.), Pd(OAc)2 (20 mol%), and Ac–Gly–OH (40 mol%) of Pd catalyst) in 1 mL solvent at 60 1C for 24 h. Isolated yield for the
c
in DCE (1 mL) at 60 1C for 24 h. b Isolated yield for the mono-alkenylated mono-alkenylated product. Regioselectivity was determined by crude
d
e
f
product. c Regioselectivity was determined by crude 1H NMR spectroscopy.
1H NMR spectroscopy. rt. 90 1C. 120 1C.
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Table 3 Arene scope of meta C–H alkenylation of phenolsa–c
Table 4 Alkene scope of meta C–H alkenylation of phenolsa–c
a
The reactions were carried out using 1 (0.5 mmol), ethyl acrylate
(0.75 mmol), AgOAc (2 equiv.), DCE (5 mL), HFIP (1.5 mL), Pd(OAc)2
b
(10 mol%), Ac–Gly–OH (20 mol%) at 60 1C for 24 h. Isolated yields for
c
mono-alkenylated products. Regioselectivities were determined by
crude 1H NMR.
a
The reactions were carried out using 1 (0.5 mmol), ethyl acrylate
(0.75 mmol), AgOAc (2 equiv.), DCE (5 mL), HFIP (1.5 mL), Pd(OAc)2
Fig. 3 Deprotection and reinstallation of the organosilicon group.
b
(10 mol%), Ac–Gly–OH (20 mol%) at 60 1C for 24 h. Isolated yields
c
for mono-alkenylated products. Regioselectivities were determined by
crude 1H NMR.
its advantage in the maintenance of the ester functional group
for further transformations. For example, the deprotection of
Next, the alkene substrate scopes were examined (Table 4). the U-shaped nitrile template by LiOH readily leads to the
The reaction was capable of producing various functionalized hydrolysis of an ester functional group to acid.9e The removal
alkene substrates along with good yields and meta-selectivities. of the organosilicon template using LiOH also leads to similar
Linear a,b-unsaturated esters with different ester groups gave results, furnishing 80% of 6 and the recovered template 4 in
compatible yields and excellent meta-selectivities (3a–b). It 83% yield.16
should be noted that the geometry of internal alkenes was
To further demonstrate the application of this meta-C–H
maintained under standard conditions (3c). Cyano, phospho- functionalization, a series of transformations using the deprotected
nate, and sulfone substituted alkenes all performed well and compound 7 were conducted (Fig. 4). Biaryl ethers are widely used in
produced 3d–f in good yields and satisfactory meta-selectivities. material and pharmaceutical chemistry.17 Under Chan-Lam-Evans
Interestingly, acrolein, which was proven to be not effective for conditions, 7 was converted into meta-alkenyl substituted biaryl 8 in
the direct ortho-C–H alkenylation was also reactive for this good yield (75%, eqn (1)).18 Moreover, the hydroxyl group was
meta-C–H alkenylation (3g).11c,15
triflated in excellent yield (9, 96%, eqn (2)), which could directly
After meta-alkenylation, the deprotection and recyclability of serve as the coupling partner for various transition-metal catalyzed
the organosilicon template was studied (Fig. 3). The template reactions without further purification, such as Pd-catalyzed Suzuki
could be removed at 100 1C for 12 h in the presence of 10 mol % coupling and Sonogashira coupling (10 and 11, eqn (3)).
of p-toluene sulfonic acid (p-TSA), affording 5 and 91% of
In summary, we have developed the first example of meta-
recycled template 4. Moreover, the template could also be C–H alkenylation of phenols using an organosilicon group as a
removed by reacting with TBAF for 1 h at room temperature, traceless template. The employed silicon template was able to
giving compound 5 in 95% isolated yield. Apparently, the override the intrinsic ortho/para-directing effect of the phenolic
established organosilicon template strategy also demonstrated hydroxyl group and provide a variety of meta-alkenylated phenol
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41, 3651; (e) I. A. I. Mkhalid, J. H. Barnard, T. B. Marder,
J. M. Murphy and J. F. Hartwig, Chem. Rev., 2010, 110, 890.
7 (a) D. Alberico, M. E. Scott and M. Lautens, Chem. Rev., 2007,
107, 174; (b) T. W. Lyons and M. S. Sanford, Chem. Rev., 2010,
110, 1147; (c) I. V. Seregin and V. Gevorgyan, Chem. Soc. Rev., 2007,
36, 1173; (d) D. A. Colby, R. G. Bergman and J. A. Ellman, Chem. Rev.,
2010, 110, 624.
8 (a) R. J. Phipps and M. J. Gaunt, Science, 2009, 323, 1593; (b) D. Leow,
G. Li, T.-S. Mei and J.-Q. Yu, Nature, 2012, 486, 518; (c) R.-Y. Tang,
G. Li and J.-Q. Yu, Nature, 2014, 507, 215; (d) X.-C. Wang, W. Gong,
L.-Z. Fang, R.-Y. Zhu, S. Li, K. M. Engle and J.-Q. Yu, Nature, 2015,
519, 334; (e) Y. Kuninobu, H. Ida, M. Nishi and M. Kanai, Nat.
Chem., 2015, 7, 712; ( f ) N. Hofmann and L. Ackermann, J. Am.
Chem. Soc., 2013, 135, 5877; (g) H. A. Duong, R. E. Gilligan,
M. L. Cooke, R. J. Phipps and M. J. Gaunt, Angew. Chem., Int. Ed.,
2011, 50, 463; (h) O. Saidi, J. Marafie, A. E. W. Ledger, P. M. Liu,
¨
M. F. Mahon, G. Kociok-Kohn, M. K. Whittlesey and C. G. Frost,
J. Am. Chem. Soc., 2011, 133, 19298; (i) Z. Dong, J. Wang and
G. Dong, J. Am. Chem. Soc., 2015, 137, 5887; ( j) J. Zhang, Q. Liu,
X. Liu, S. Zhang, P. Jiang, Y. Wang, S. Luo, Y. Li and Q. Wang, Chem.
Commun., 2015, 51, 1297; (k) M. Bera, A. Modak, T. Patra, A. Maji
and D. Maiti, Org. Lett., 2014, 16, 5760; (l) G. Yang, P. Lindovska,
D. Zhu, J. Kim, P. Wang, R.-Y. Tang, M. Movassaghi and J.-Q. Yu,
J. Am. Chem. Soc., 2014, 136, 10807; (m) Z. Zhang, K. Tanaka and
J.-Q. Yu, Nature, 2017, 543, 538.
Fig. 4 Synthetic applications.
9 (a) P. Wang, M. E. Farmer, X. Huo, P. Jain, P.-X. Shen, M. Ishoey,
J. E. Bradner, S. R. Wisniewski, M. D. Eastgate and J.-Q. Yu, J. Am.
Chem. Soc., 2016, 138, 9269; (b) P. Wang, G.-C. Li, P. Jain,
M. E. Farmer, J. He, P.-X. Shen and J.-Q. Yu, J. Am. Chem. Soc.,
2016, 138, 14092; (c) H. Shi, P. Wang, S. Suzuki and M. E. Farmer,
J. Am. Chem. Soc., 2016, 138, 14876; (d) H.-X. Dai, G. Li, X.-G. Zhang,
A. F. Stepan and J.-Q. Yu, J. Am. Chem. Soc., 2013, 135, 7567;
(e) L. Wan, N. Dastbaravardeh, G. Li and J.-Q. Yu, J. Am. Chem.
Soc., 2013, 135, 18056.
10 J. Luo, S. Preciado and I. Larrosa, J. Am. Chem. Soc., 2014, 136, 4109.
11 (a) C. Huang and V. Gevorgyan, J. Am. Chem. Soc., 2009, 131, 10844;
(b) C. Huang, B. Chattopadhyay and V. Gevorgyan, J. Am. Chem. Soc.,
2011, 133, 12406; (c) C. Huang, N. Ghavtadzem, B. Chattopadhyayand
and V. Gevorgyan, J. Am. Chem. Soc., 2011, 133, 17630.
products in good yields and high meta-selectivities. More impor-
tantly, the organosilicon moiety can be easily removed under mild
conditions or be recovered under acidic conditions. The products
could be transformed into a wide range of meta-functionalized
aromatic compounds, which are not easily accessible via other
meta-selective C–H activation methodologies.
M. D. Z. thanks the NSFC (21101085) and Liaoning Excellent
Talents Program in University (LJQ2012031) for financial support.
Z. X. is grateful for the grants from the NSFC (No. 21432003).
12 T. Patra, S. Bag, R. Kancherla, A. Mondal, A. Dey, S. Pimparkar, S. Agasti,
A. Modak and D. Maiti, Angew. Chem., Int. Ed., 2016, 55, 7751.
13 (a) S. Lee, H. Lee and K. L. Tan, J. Am. Chem. Soc., 2013, 135, 18778;
(b) S. Bag, T. Patra, A. Modak, A. Deb, S. Maity, U. Dutta, A. Dey,
R. Kancherla, A. Maji, A. Hazra, M. Bera and D. Maiti, J. Am. Chem.
Soc., 2015, 137, 11888.
Conflicts of interest
There are no conflicts to declare.
14 (a) S. Bracegirdle and E. A. Anderson, Chem. Soc. Rev., 2010,
39, 4114; (b) F. Zhang and D. R. Spring, Chem. Soc. Rev., 2014,
43, 6906; (c) M. Parasram and V. Gevorgyan, Acc. Chem. Res., 2017,
50, 2038; (d) Y. Wang and V. Gevorgyan, Angew. Chem., Int. Ed., 2015,
54, 2255.
15 Y. Deng and J.-Q. Yu, Angew. Chem., Int. Ed., 2015, 54, 888.
16 Experiment for the removal of organosilicon template using LiOH:
Notes and references
1 J. H. P. Tyman, Synthetic and Natural Phenols, Elsevier, 1996.
2 (a) Z. Huang, L. Jin, Y. Feng, P. Peng, H. Yi and A. Lei, Angew. Chem.,
Int. Ed., 2013, 52, 7151; (b) A. Kirste, M. Nieger, I. M. Malkowsky,
F. Stecker, A. Fischer and S. R. Waldvogel, Chem. – Eur. J., 2009, 15, 2273;
(c) I. M. Malkowsky, C. E. Rommel, R. Froehlich, U. Griesbach, H. Puetter
and S. R. Waldvogel, Chem. – Eur. J., 2006, 12, 7482; (d) K. Zerbe,
K. Woithe, D. B. Li, F. Vitali, L. Bigler and J. A. Robinson, Angew. Chem.,
Int. Ed., 2004, 43, 6709.
3 (a) C. Friedel and J. M. Crafts, J. Chem. Soc., 1877, 32, 725;
(b) C. Friedel and Crafts, Compt. Rend., 1877, 84, 1392.
4 (a) Y. Izawa, D. Pun and S. S. Stahl, Science, 2011, 333, 209;
(b) Y. Izawa, C. Zheng and S. S. Stahl, Angew. Chem., Int. Ed., 2013,
52, 3672.
¨
5 A.-L. Auvinet and J. P. A. Harrity, Angew. Chem., Int. Ed., 2011, 17 (a) K. C. Nicolaou, C. N. C. Boddy, S. Brase and N. Winssinger,
50, 2769.
Angew. Chem., Int. Ed., 1999, 38, 2096; (b) J. Blankenstein and J. Zhu,
Eur. J. Org. Chem., 2005, 1949.
6 (a) L. Ackermann, Chem. Rev., 2011, 111, 1315; (b) J. Wencel-Delord,
¨
T. Droge, F. Liu and F. Glorius, Chem. Soc. Rev., 2011, 40, 4740; 18 (a) D. Chan, K. Monaco, R. Wang and M. Winter, Tetrahedron Lett.,
(c) L. McMurray, F. O’Hara and M. J. Gaunt, Chem. Soc. Rev., 2011,
40, 1885; (d) G. Song, F. Wang and X. Li, Chem. Soc. Rev., 2012,
1998, 39, 2933; (b) D. Evans, J. Katz and T. West, Tetrahedron Lett.,
1998, 39, 2937.
Chem. Commun.
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