Pd-Catalyzed C?H Alkylation of Arenes Using PyrDipSi, a Transformable and Removable Silicon-Tethered Directing Group

Article abstract of DOI:10.1002/chem.201602513

An efficient Pd-catalyzed ortho-C?H alkylation reaction of arenes using a transformable and removable Si-tethered pyridyldiisopropylsilyl (PyrDipSi) directing group has been developed. In addition, the PyrDipSi directing group allows for an efficient sequential double-fold C?H alkylation/oxygenation of arenes to produce meta-alkylated phenols. This directing group can easily be removed or converted into valuable functionalities, such as aryl, iodo, boronic ester, or phenol.

Full text of DOI:10.1002/chem.201602513

A Journal of
Accepted Article
Title: Pd-Catalyzed C-H Alkylation of Arenes Using PyrDipSi, Transforma-
ble/Removable Silicon-Tethered Directing Group
Authors: Vladimir Gevorgyan; Dhruba Sarkar
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To be cited as: Chem. Eur. J. 10.1002/chem.201602513
Link to VoR: http://dx.doi.org/10.1002/chem.201602513
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Pd-Catalyzed CH Alkylation of Arenes Using PyrDipSi,
Transformable/Removable Silicon-Tethered Directing Group
Dhruba Sarkar and Vladimir Gevorgyan*
Abstract: An efficient Pd-catalyzed ortho CH alkylation reaction of
arenes using transformable/removable Si-tethered pyridyldiisopro-
pylsilyl (PyrDipSi) directing group has been developed. In addition,
PyrDipSi directing group allows for an efficient sequential double-
fold CH alkylation/oxygenation of arenes to produce meta-alkylated
phenols. This directing group can easily be removed or converted
into valuable functionalities, such as aryl-, iodo-, boronic ester, or
phenol.
(PyrDipSi)10 directing groups for a diverse Cheteroatom bond
formation reactions of arenes. Herein, we report the first C–C
bond forming reaction, using PyrDipSi directing group, namely
the Pd-catalyzed ortho C−H alkylation of arenes. This method
features high regioselectivity, exclusive mono-selectivity, and a
broad functional group tolerance (eq. 3).
Pd-catalyzed oxazoline-directed ortho C−H alkylation of
arenes with alkyl tin reagents was first developed by Yu.7i Later,
the same group reported that pyridine-7j and carboxylic acid7p
directing groups enable ortho-alkylation reaction with alkyl
boronic esters. Encouraged by this, we hypothesized that our
easily removable/functionalizable pyridine-containing PyDipSi-
directing group could also be efficient for alkylation reaction of
arenes, which is arguably, the most challenging C−H
functionalization reaction. Accordingly, alkylation of PyDipSi-
benzene 1a was examined in alkylation reaction with n-
butylboronic acid (Table 1).11 Gratifyingly, the reaction of 1a
under the Pd-catalyzed alkylation conditions developed by Yu7k
delivered 2a in 58% GC yield (entry 1). Employment of other
silver-based oxidants was found to be inefficient (entries 2, 3).
Although increase of Ag2O load was not beneficial (entry 4),
employment of the Ag2O/Li2CO3 combination led to the
noticeable improvement of the yield (entry 5). Further
improvement was achieved with higher loading of Ag2O/Li2CO3
(83 %, entry 6). Notably, similar efficiency was obtained
employing pyrimidyl-containing directing group PyrDipSi (82%,
entry 9).12
Alkylarenes are key motifs broadly found in pharmaceutically
active molecules1 and natural products2. Traditionally, alkyl
groups were introduced into arenes via Friedel-Crafts reaction
(eq. 1a).3 Though widely used, this method suffers from major
limitations, such as over-alkylation, harsh conditions, limited
scope, and low selectivity. Alternatively, alkylated arenes can be
synthesized via
a sequential halogenation/cross coupling
strategy (eq. 1b).4 The requisite extra prefunctionalization of
arenes, however, significantly limits the wide application of this
approach. Recently, a transition metal-catalyzed directed ortho
CH alkylation approach has emerged as attractive alternative
to the aforementioned methods.5,6 A range of directing groups
efficiently enable this important transformation (eq. 2).7 Although,
most directing groups are important functionalities by their own,
difficulties of their removal or further modification often limit the
synthetic usefulness of these methods.8 We have previously
developed
the
removable/modifiable8
silicon-tethered9
pyridyldiisopropylsilyl (PyDipSi)10 and pyrimidyldiisopropylsilyl
Table 1. Optimization of C−H alkylation
Entry
DG
Oxidant, eq.
Ag2O, 1.0
Ag2CO3, 1.0
AgOAc, 1.0
Ag2O, 2.0
Ag2O, 1.0
Ag2O, 2.0
Ag2O, 2.5
Ag2O, 2.0
Ag2O, 2.5
Base, eq.
None
None
None
None
Li2CO3, 1.0
Li2CO3, 2.0
Li2CO3, 2.5
Li2CO3, 2.0
Li2CO3, 2.5
Yield, %a,b
58
trace
15
52
65
83(76)
76
79
82(79)
1
2
3
4
5
6
7
8
9
PyDipSi
PyDipSi
PyDipSi
PyDipSi
PyDipSi
PyDipSi
PyDipSi
PyrDipSi
PyrDipSi
[a] GC yields are given, [b] Isolated yields are given in parentheses.
With the optimized conditions in hand, the scope of the Pd-
catalyzed C−H alkylation reaction was examined (Table 2). It
was found that both PyDipSi and PyrDipSi group were equally
efficient to afford the products 2a-b. However, due to easier
isolation of the products, alkylation reactions of PyrDipSi- arenes
(2c-x) were explored. Aryl silanes possessing meta substituents
were selectively converted into products of C–H functionalization
at the less hindered site 2d,e in good yields. Para-substituted
aryl silanes containing methyl, phenyl, benzyl and 2-acetate
[] D. Sarkar, Prof. Dr. V. Gevorgyan
Department of Chemistry
University of Illinois at Chicago
845 W Taylor St, Rm 4500, Chicago, IL 60607 (USA)
Fax: (+1) 312-355-0836
E-mail: vlad@uic.edu
Homepage: http://www.chem.uic.edu/vggroup
were
efficiently
transformed
to
the
corresponding

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Table 2. Alkylation of PyrDipSi/PyDipSi-arenes [a] [b]
nBu
PyDipSi
Me
PyrDipSi
nBu
PyrDipSi
Me
nBu
PyrDipSi
MeO
nBu
PyrDipSi
nBu
nBu
PyDipSi
2c, 79%
Me
2a, 76% [c]
2b, 72% [c]
2d, 77%
2e, 71%
2f, 84%
PyrDipSi
PyrDipSi
nBu
PyrDipSi
nBu
PyrDipSi
nBu
PyrDipSi
nBu
nBu
Ph
CO2Et
2i, 62%
OMe
CF3
COMe
2h, 66%
2j, 85%
2k, 67%
2l, 77%
nBu
PyrDipSi
nBu
PyrDipSi
nBu
PyrDipSi
nBu
PyrDipSi
CONiPr2
CO2Me
2n, 48% [d]
Br
Cl
2m, 61%
2q, 64%
2p, 65%
[a] See Supporting Information for experimental details. [b] Isolated yields unless otherwise noted. [c] Reactions were performed with 2 equiv Ag2O and 2 equiv
Li2CO3. [d] Reaction was run for 96 h. [e] Reactions were performed at 70 oC. [f] Reactions were performed at 80 oC. [g] Yield is reported after replacement of
pyrimidine with fluoride.
alkylated products 2f-i. PyrDipSi-arenes possessing either
electron- releasing (methoxy 2e, 2j), or electron-withdrawing
(trifluoromethyl, 2k; acyl, 2l; amide, 2m; and carbomethoxy, 2n)
substituents were equally compatible in this transformation.
Moreover, pinacol-protected formyl group was also tolerated to
produce o-butyl arene 2o in moderate yield. Expectedly,
halogenated aryl silanes were also capable substrates, providing
the corresponding haloarenes 2p-r, compounds possessing an
additional handle for further functionalization, in reasonable
yields. 2-napthalene derivative was successfully converted into
the corresponding alkylated product 2s.13 Furthermore, this new
protocol allowed for C–H functionalization of arenes with other
alkyl groups, such as methyl (2t), ethyl (2u), hexyl (2v),
homobenzyl (2w), and isobutyl (2x).14
Scheme 1. Synthesis of meta-alkylphenols. [a] Pd(OAc)2 (10 mol%), Boc-L-
Leu-OH (10 mol%), Ag2O (2.5 equiv), Li2CO3 (2.5 equiv), BQ (0.5 equiv) THF,
60 oC. [b] Pd(OAc)2 (5 mol%), PhI(OPiv)2 (1.25 equiv), LiOAc (30 mol%) DCE,
80 oC.
broad opportunities for subsequent modifications. Furthermore,
the aryl silanes underwent Hiyama-Denmark cross-coupling
reaction to efficiently produce biaryl 7. On the other hand, 2d
was efficiently converted to the synthetically valuable arylboronic
ester 8 via a one-pot sequence involving borodesilylation
We have also performed an unsymmetrical double-fold C−H
fuctionalization of PyrDipSi-arenes via
a sequential C−H
alkylation followed by a pivaloxylation reaction, previously
developed in our group12a,d (Scheme 1). We were pleased to find
that this novel 2-step protocol allowed for efficient transformation
of PyrDipSi-arenes into meta-alkylphenols 3c,f,j in good yields.
followed by
a
pinacol protection. Moreover,
a
one-pot
borodesilylation/ oxidation sequence produced o-alkylphenol 9 in
reasonable yield. The overall synthetic usefulness of the
developed methodology could be illustrated by the efficient
unprecedented 3-steps conversion of 3-iodotoluene into the 3-
iodo-4-butyltoluene 10.
Next, transformations of the PyrDipSi directing group in the
products 2 into other groups were explored (Scheme 2).
Pyrimidine group in 2l,q was replaced with fluoride to produce
aryl fluorosilanes 2l’,q’ in quantitative yields. Subsequently, the
silyl group was tracelessly removed to produce 4 or its
deuterated analog 5 in excellent yields. Alternatively, the silyl-
group could easily be substituted with iodide (6), which opens
In addition, we investigated transformations of the PyrDipSi
group in the product 3f toward 1,2,3-functionalized arenes
(Scheme 3). Naturally, the silyl group could cleanly be replaced
with iodide (11). Furthermore, the Hiyama-Denmark cross-

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COMMUNICATION
coupling reaction of aryl silane 3f with phenyl iodide produced
tetrasubstituted benzene 12 in good yield.
The support of the National Science Foundation (CHE-1362541)
is gratefully acknowledged.
Keywords: C-H functionalization • palladium • CH alkylation •
catalysis • silicon-tether • directing group
[1]
[a) J. S. Carey, D. Laffan, C. Thomson, M. T. Williams, Org. Biomol.
Chem. 2006, 4, 2337-2347; b) N. A. McGrath, M. Brichacek, J. T.
Njardarson, J. Chem. Educ. 2010, 87, 1348-1349; c) H. Schönherr, T.
Cernak, Angew. Chem. Int. Ed. 2013, 52, 12256-12267; Angew. Chem.
2013, 125, 12480-12492; d) E. J. Barreiro, A. E. Kümmerle, C. A. M.
Fraga, Chem. Rev. 2011, 111, 5215-5246.
[2]
a) G. M. Cragg, P. G. Grothaus, D. J. Newman, Chem. Rev. 2009, 109,
3012-3043; b) J. Kobayashi, M. Ishibashi, Chem. Rev. 1993, 93, 1753-
1769; c) D. J. Newman, G. M. Cragg, J. Nat. Prod. 2004, 67, 1216-
1238; d) B. R. Rosen, L. R. Simke, P. S. Thuy-Boun, D. D. Dixon, J.-Q.
Yu, P. S. Baran, Angew. Chem. Int. Ed. 2013, 52, 7317-7320; B. R.
Rosen, L. R. Simke, P. S. Thuy-Boun, D. D. Dixon, J.-Q. Yu, P. S.
Baran, Angew. Chem. 2013, 125, 7458-7461.
[3]
[4]
[5]
Reviews on Friedel-Crafts reaction: a) N. O. Calloway, Chem. Rev.
1935, 17, 327-392; b) T. B. Poulsen, K. A. Jørgensen, Chem. Rev.
2008, 108, 2903-2915.
Scheme 2. Modification of directing groups in 2. [a] HF, THF, 0 oC to rt. [b]
AgF (3 equiv), D2O in MeOH, rt. [c] AgF (3.0 equiv), CD3OD, rt. [d] ICl (1.5
equiv), DCM, 0 oC to rt. [e] PhI (1.5 equiv), Pd(PPh3)4 (5 mol%), Ag2O (1.1
equiv), THF, 60 oC. [f] BCl3 (5 equiv), DCM 0 oC to rt then pinacol (1.5 equiv),
Et3N, DCM, rt. [g] BCl3 (5 equiv), DCM 0 oC to rt then pinacol (1.5 equiv), Et3N,
DCM, rt then H2O2/NaOH. [h] PyrDipSiH (1.3 equiv), Rh2(OAc)4 (2.5 mol%),
K3PO4 (2 equiv), dioxane, 90 oC. [i] Pd(OAc)2 (10 mol%), Boc-L-Leu-OH (10
mol%), Ag2O (2.5 equiv), Li2CO3 (2.5 equiv), BQ (0.5 equiv) THF, 60 oC. [j] HF,
THF, 0 oC to rt then ICl (1.5 equiv), DCM, 0 oC to rt.
Reviews on cross-coupling reaction, see: a) H. Doucet, Eur. J. Org.
Chem. 2008, 2008, 2013-2030; b) R. Jana, T. P. Pathak, M. S. Sigman,
Chem. Rev. 2011, 111, 1417-1492.
Reviews on C-H alkylation of arenes: a) K. M. Engle, T.-S. Mei, M.
Wasa, J.-Q. Yu, Acc. Chem. Res. 2012, 45, 788-802; b) D. A. Colby, R.
G. Bergman, J. A. Ellman, Chem. Rev. 2010, 110, 624-655; c) X. Chen,
K. M. Engle, D.-H. Wang, J.-Q. Yu, Angew. Chem. 2009, 121, 5196-
5217; Angew. Chem. Int. Ed. 2009, 48, 5094-5115; d) G. Rouquet, N.
Chatani, Angew. Chem. 2013, 125, 11942-11959; Angew. Chem. Int.
Ed. 2013, 52, 11726-11743; e) T. W. Lyons, M. S. Sanford, Chem. Rev.
2010, 110, 1147-1169; f) P. B. Arockiam, C. Bruneau, P. H. Dixneuf,
Chem. Rev. 2012, 112, 5879-5918.
[6]
[7]
For most recent works on C–H alkylation, published after submission of
this manuscript, see: a) B. Xiong, S. Zhang, H. Jiang, M. Zhang, Org.
Lett. 2016, 18, 724-727; b) L. Hu, X. Chen, Q. Gui, Z. Tan, G. Zhu,
Chem. Commun. 2016, 52, 6845-6848; c) Y. Zhang, H. Jiang, D. Chen,
Y. Zhang, Org. Biomol. Chem. 2016, 14, 4585-4589. b) X. Zhou, S. Yu,
Z. Qi, L. Kong, X. Li. J. Org. Chem. 2016, DOI:
10.1021/acs.joc.6b00650
For examples of directed C–H alkylation of arenes, see: a) S. J.
Tremont, R. Hayat Ur, J. Am. Chem. Soc. 1984, 106, 5759-5760; b) J.
Stuart McCallum, J. R. Gasdaska, L. S. Liebeskind, S. J. Tremont,
Tetrahedron Lett. 1989, 30, 4085-4088; c) L. Ackermann, P. Novák, R.
Vicente, N. Hofmann, Angew. Chem. 2009, 121, 6161-6164; Angew.
Chem. Int. Ed. 2009, 48, 6045-6048; d) D. Shabashov, O. Daugulis, J.
Am. Chem. Soc. 2010, 132, 3965-3972; e) K. Gao, N. Yoshikai, J. Am.
Chem. Soc. 2013, 135, 9279-9282; f) Q. Chen, L. Ilies, E. Nakamura, J.
Am. Chem. Soc. 2011, 133, 428-429; g) Y. Zhao, G. Chen, Org. Lett.
2011, 13, 4850-4853; h) Y. Aihara, N. Chatani, J. Am. Chem. Soc.
2013, 135, 5308-5311; i) X. Chen, J.-J. Li, X.-S. Hao, C. E. Goodhue,
J.-Q. Yu, J. Am. Chem. Soc. 2006, 128, 78-79; j) X. Chen, C. E.
Goodhue, J.-Q. Yu, J. Am. Chem. Soc. 2006, 128, 12634-12635; k) B.-
F. Shi, N. Maugel, Y.-H. Zhang, J.-Q. Yu, Angew. Chem. 2008, 120,
4960-4964; Angew. Chem. Int. Ed. 2008, 47, 4882-4886; l) H. Wang, S.
Yu, Z. Qi, X. Li, Org. Lett. 2015, 17, 2812-2815; m) S. R. Neufeldt, C. K.
Seigerman, M. S. Sanford, Org. Lett. 2013, 15, 2302-2305; n) E. R.
Fruchey, B. M. Monks, S. P. Cook, J. Am. Chem. Soc. 2014, 136,
13130-13133; o) J. M. Wiest, A. Pöthig, T. Bach, Org. Lett. 2016, 18,
852-855; p) P. S. Thuy-Boun, G. Villa, D. Dang, P. Richardson, S. Su,
J.-Q. Yu, J. Am. Chem. Soc. 2013, 135, 17508-17513; q) Y.-H. Zhang,
B.-F. Shi, J.-Q. Yu, Angew. Chem. 2009, 121, 6213-6216; Angew.
Chem., Int. Ed. 2009, 48, 6097-6100; r) G. Cera, T. Haven, L.
Scheme 3. Modification of directing groups in 3. [a] HF, THF, 0 oC to rt, then
ICl (1.5 equiv), DCM, 0 oC to rt. [b] HF, THF, 0 oC to rt, then PhI (1.5 equiv),
Pd(PPh3)4 (5 mol%), Ag2O (1.1 equiv), THF, 60 oC.
In conclusion, we have developed a general and efficient
ortho-C–H alkylation of arenes using PyrDipSi, a silicon-tethered
directing group. This transformation features broad substrate
scope, high functional group tolerance, and mild reaction
conditions. We also developed a two-steps protocol for an
efficient synthesis of meta-alkylphenols. Most importantly, this
directing group could efficiently be cleaved or converted into a
number of valuable functional groups such as iodo-, hydroxyl-,
and boronate; whereas a direct Hiyama-Denmark cross-coupling
reaction provided efficient access to biaryl building blocks.
Acknowledgements

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Ackermann, Angew. Chem. 2016, 128, 1506-1510; Angew. Chem. Int.
Ed. 2016, 55, 1484-1488; s) J. M. Wiest, A. Pöthig, T. Bach, Org. Lett.
2016, 18, 852-855; t) L. Ackermann, J. Org. Chem. 2014, 79, 8948-
8954; u) B. M. Monks, E. R. Fruchey, S. P. Cook, B. M. Monks, E. R.
Fruchey, S. P. Cook, Angew. Chem 2014, 126, 11245-11249; Angew.
Chem. Int. Ed. 2014, 53, 11065-11069; v) R.-Y. Zhu, J. He, X.-C.
Wang, J.-Q. Yu, J. Am. Chem. Soc. 2014, 136, 13194-13197.
Organomet. Chem. 2002, 653, 105-113; b) K. Itami, J.-i. Yoshida,
Synlett 2006, 2006, 157-180.
[10] For PyDipSi and PyrDipSi directed C H functionalization reactions,
see: a) N. Chernyak, A. S. Dudnik, C. Huang, V. Gevorgyan, J. Am.
Chem. Soc. 2010, 132, 8270-8272; b) A. S. Dudnik, N. Chernyak, C.
Huang, V. Gevorgyan, Angew. Chem. 2010, 122, 8911-8914; Angew.
Chem. Int. Ed. 2010, 49, 8729-8732; c) C. Huang, N. Chernyak, A. S.
Dudnik, Gevorgyan, V. Adv. Synth. Catal. 2011, 353, 1285; d) A. V.
Gulevich, F. S. Melkonyan, D. Sarkar, V. Gevorgyan, J. Am. Chem. Soc.
2012, 134, 5528; e) D. Sarkar, F. S. Melkonyan, A. V. Gulevich, V.
Gevorgyan, Angew. Chem. 2013, 125, 11000-11004; Angew. Chem.
Int. Ed. 2013, 52, 10800-10804; f) D. Sarkar, A. V. Gulevich, F. S.
Melkonyan, V. Gevorgyan, ACS Catal. 2015, 5, 6792-6801.
[11] See the Supporting Information for details.
[8]
For reviews on removable/modifiable directing groups, see: a) S.
Bracegirdle, E. A. Anderson, Chem. Soc. Rev. 2010, 39, 4114-4129; b)
C. Wang, Y. Huang, Synlett 2013, 24, 145-149; c) F. Zhang, D. R.
Spring, Chem. Soc. Rev. 2014, 43, 6906-6919; See, also: d) H. Ihara,
M. Suginome, J. Am. Chem. Soc. 2009, 131, 7502-7503; e)
omero- evilla, arc a-Rubia, R. Goméz Arrayás, M. Á. Fernández-
Ibáñez, J. C. Carretero, J. Org. Chem. 2011, 76, 9525-9530; f) A.
Hafner, S. Bräse, Angew. Chem. Int. Ed. 2012, 51, 3713-3715; Angew.
Chem. 2012, 124, 3773-3775; g) C. Wang, H. Chen, Z. Wang, J. Chen,
Y. Huang, Angew. Chem. Int. Ed. 2012, 51, 7242-7245; Angew. Chem.
2012, 124, 7354-7357; h) J. Cornella, M. Righi, I. Larrosa, Angew.
Chem. Int. Ed. 2011, 50, 9429-9432; Angew. Chem. 2011, 123, 9601-
9604; i) X. Sun, G. Shan, Y. Sun, Y. Rao, Angew. Chem. Int. Ed. 2013,
52, 4440-4444; Angew. Chem. 2013, 125, 4536-4540; j) H. Kinuta, M.
Tobisu, N. Chatani, J. Am. Chem. Soc. 2015, 137, 1593-1600; k) Y.
Zhang, H. Zhao, M. Zhang, W. Su, Angew. Chem. Int. Ed. 2015, 54,
3817-3821; Angew. Chem. 2015, 127, 3888-3892.
[12] Most likely, this method operates via a Pd(II)/Pd(0) catalytic cycle. For
details, see: ref. 7i-j.
[13] The alkylation reaction of heterocyclic C–H bonds using this protocol
was much less efficient. Among several heterocyclic substrates tested,
only 3-PyrDipSi-thiophene produced o-alkylated product in 25% NMR
yield.
[14] The alkylation reaction employing secondary and tertiary alkylboronic
acids using this method was not efficient. Thus, only 20% NMR yield of
the alkylated product was obtained when cyclopropylboronic acid was
used.
[9]
For review on pyridyldimethylsilyl-group driven reactions, see: a) K.
Itami, K. Mitsudo, T. Nokami, T. Kamei, T. Koike, J.-i. Yoshida, J.

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TOC
An efficient Pd-catalyzed ortho CH
alkylation reaction of arenes using Si-
tethered directing group (PyrDipSi)
has been developed. This
transformation can also be used for
synthesis of m-alkylphenols.
Importantly, the PyrDipSi directing
group can easily be removed or
converted into valuable functionalities,
such as aryl-, iodo-, boronic ester, or
phenol.
D. Sarkar, V. Gevorgyan*
Page No. – Page No.
Pd-Catalyzed
Arenes Using PyrDipSi,
Transformable/Removable Silicon-
Tethered Directing Group