Remote para-C-H Functionalization of Arenes by a D-Shaped Biphenyl Template-Based Assembly

Article abstract of DOI:10.1021/jacs.5b06793

Site-selective C-H functionalization has emerged as an efficient tool in simplifying the synthesis of complex molecules. Most often, directing group (DG)-assisted metallacycle formation serves as an efficient strategy to ensure promising regioselectivity. A wide variety of ortho- and meta-C-H functionalizations stand as examples in this regard. Yet despite this significant progress, DG-assisted selective para-C-H functionalization in arenes has remained unexplored, mainly because it involves the formation of a geometrically constrained metallacyclic transition state. Here we report an easily recyclable, novel Si-containing biphenyl-based template that directs efficient functionalization of the distal p-C-H bond of toluene by forming a D-shaped assembly. This DG allows the required flexibility to support the formation of an oversized pre-transition state. By overcoming electronic and steric bias, para-olefination and acetoxylation were successfully performed while undermining o- and m-C-H activation. The applicability of this D-shaped biphenyl template-based strategy is demonstrated by synthesizing various complex molecules.

Full text of DOI:10.1021/jacs.5b06793

Communication
pubs.acs.org/JACS
Remote para-C−H Functionalization of Arenes by a D‑Shaped
Biphenyl Template-Based Assembly
Sukdev Bag, Tuhin Patra, Atanu Modak, Arghya Deb, Soham Maity, Uttam Dutta, Aniruddha Dey,
Rajesh Kancherla, Arun Maji, Avijit Hazra, Milan Bera, and Debabrata Maiti*
Department of Chemistry, Indian Institute of Technology Bombay, Powai, Mumbai 400076, India
*
S Supporting Information
ABSTRACT: Site-selective C−H functionalization has
emerged as an efficient tool in simplifying the synthesis
of complex molecules. Most often, directing group (DG)-
assisted metallacycle formation serves as an efficient
strategy to ensure promising regioselectivity. A wide
variety of ortho- and meta-C−H functionalizations stand
as examples in this regard. Yet despite this significant
progress, DG-assisted selective para-C−H functionaliza-
tion in arenes has remained unexplored, mainly because it
involves the formation of a geometrically constrained
metallacyclic transition state. Here we report an easily
recyclable, novel Si-containing biphenyl-based template
that directs efficient functionalization of the distal p-C−H
bond of toluene by forming a D-shaped assembly. This
DG allows the required flexibility to support the formation
of an oversized pre-transition state. By overcoming
electronic and steric bias, para-olefination and acetox-
ylation were successfully performed while undermining o-
and m-C−H activation. The applicability of this D-shaped
biphenyl template-based strategy is demonstrated by
synthesizing various complex molecules.
nnovations and subsequent improvisations play the major
role in the fascinating chemistry of C−H activation. The past
I
three decades have witnessed an unprecedented upsurge in
controlling positional selectivity of inert C−H bonds by
adopting strategies that deliver easier choices for retrosynthetic
1
−5
disconnections.
Directing group (DG)-assisted transition-
metal-catalyzed reactions have been formulated to become a
celebrated class in this regard. This approach provided the
required impetus for ortho-C−H functionalization reactions in
arenes, relieving them of the strict governance of electronic and
Figure 1. Template-directed p-C−H activation. (A) Gradual evolution
of template-directed functionalization: (I) directed o-C−H activation;
6
(
II) directed m-C−H activation; (III and IV) distal p-C−H activation
steric bias (Figure 1A). Template-directed meta-C−H
using a D-shaped assembly; DG = directing group and T. S. =
transition state. (B) Screening of directing scaffolds for model
olefination reaction. The red bond in each structure highlights the
target C−H bond of interest. Ratios of para:others were determined
activation also adds to the success story, where it solicits a7
metallacycle larger than a seven-membered ring (Figure 1A).
Intuitively, a template-based approach for targeting exclusive
para-selectivity would entail a significantly larger metallacycle,
with a consequent rise in strain energy. In our attempts to
investigate the intriguing possibility of DG-facilitated remote
para-C−H functionalization (Figure 1A), we encountered some
conceptual as well as synthetic challenges: (1) forming a large
yet less strained macrocylic transition state; (2) fine-tuning the
chain length of the template that governs selective para-
functionalization; and (3) regulating the proximity of the donor
heteroatom in the DG towards the target C−H bond. The
1
on the basis of H NMR of the crude reaction mixture.
design of the template was primarily aimed at facilitating
delivery of a metal through a conformationally flexible
assembly. The increased electrophilicity of a donor-heteroa-
Received: July 15, 2015
©
XXXX American Chemical Society
A
DOI: 10.1021/jacs.5b06793
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
Scheme 1. Essential Features in Template Morphology
Table 2. Template-Assisted p-C−H Olefination of Toluene
10
with Different Alkenes
10
Table 1. Arene Scope for Olefination Reaction
dominance of para-functionalization over possible formation of
ortho- and meta-products must be well ensured.
As a foremost step to satisfy all these requirements, a
biphenyl group was included as part of the template so that it
would contain an easily coordinating heteroatom. Incorpo-
ration of biphenyl was thought to be crucial in regulating the
chain length of the macrocylic assembly. Moreover, o- and/or
m-C−H activation would then mean a highly strained,
kinetically disfavored cyclophane assembly owing to the rigidity
of the biphenyl moiety. More than proximity to the target
bond, appropriate positioning of the donor moiety coupled
with an adequate choice of tethering group seemed essential for
achieving the desired selectivity. Of all the possibilities (Figure
a
For di-olefination reaction, all reagents were doubled except the arene
substrate.
1
B), a carbonyl tether, S1, where the projection of the donor
tom-coordinated metal followed by prompt formation of a C−
X bond (e.g., X = C, O, etc.) was presumed to alleviate the cost
of an entropically demanding pre-transition state. This would
also lower the enthalpic cost of cleaving a thermodynamically
quite stable C−H bond. The donor moiety in the DG was
imagined to anchor to the metal, thereby activating the p-C−H
group with respect to the biphenyl axis is 120°, was first
employed. However, this provided poor selectivity. Changing
the projection angle to 60° led to S2, which increased the yield
but still failed to improve selectivity. Increasing the bulk and
changing the hybridization at the adhering center was pre-
supposed to affect the approach of the donor center near the p-
8
2
3
bond through an agostic interaction. Most importantly, the
C−H bond. Replacing an sp carbonyl by a larger sp sulfonyl
B
DOI: 10.1021/jacs.5b06793
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
Table 3. Para-Acetoxylation of Substituted Toluene
Derivatives
template S7 are its simplicity, ease of preparation, and ability to
overcome innate strain in forming the inevitable macrocyclic
transition state. With the D-shaped silyl-biphenyl-based
assembly S7, we performed a Pd-catalyzed olefination reaction
using an electronically unbiased substrate such as toluene. The
10
combination of Pd(OAc) as catalyst and AgOAc as oxidant in
2
conjunction with N-acetyl-L-phenylalanine ligand provided 75%
NMR yield (isolated, 71%; p:others = 8:1), with a significant
para-selectivity (gram scale, 58%). The alkanoyl-protected
amino acid likely played two major roles. First, dianionic
ligands could chelate with the metal to generate an active pre-
catalyst. Second, alkanoyl protection facilitated the C−H
activation step by acting as an internal base. Additionally,
coordinative interaction of the fluorinated alcohols with Pd
catalyst was presumed to stabilize the macrocyclic transition
state. Control experiments performed with S8 (see Table 2)
revealed a complete loss of selectivity. This aided in justifying
the primal role of template morphology and coordination of
heteroatom to Pd as essential prerequisites for this chemical
transformation (Scheme 1).
With the optimized conditions, we contemplated the scope
of substrates that displayed the first template-facilitated p-C−H
functionalization of electronically unbiased arenes (Table 1).
Both electron-donating and -withdrawing groups (2b−2g)
were well tolerated with distinguished levels of para-selectivity.
Distinctive para-functionalization (mono- and di-) was also
possible in the presence of multiple C−H bonds (2i and 2j).
However, in such a case, control over the amount of reagents
was vital in obtaining the desired ratio for di-olefination
compared to mono-olefination.
10
Scheme 2. Removal of Directing Group
Successful para-olefination with 2k paved a new way for the
synthesis of hexa-substituted arenes. A closer look at the X-ray
crystal structure of 2k (Table 1) further supports our initial
hypothesis for the requirement of a D-shaped assembly for the
para-selective C−H functionalization reaction.
We then explored the scope of the reaction with various
olefinic coupling partners (Table 2). Appreciable selectivity for
para-olefinated products was obtained in the presence of α,β-
unsaturated esters, sulfone, and amide (3a−3l). Tolerance
toward bulky olefin partners was exemplified by para-
olefination with acrylates of vitamin E (3d) and cholesterol
(3j). Para-olefinated products were obtained even with five- or
six-membered rings containing substituted endocyclic double
group (S4) yielded a 1:1 ratio for para-product relative to other
possibilities. A dialkyl-substituted Si atom was then envisaged as
9
a ligating bridge between the substrate and biphenyl (S5 and
S6). Because a larger Si atom results in elongated Si−C and Si−
O bonds, the distance between the anchoring atom and target
C−H bond is bound to be more. Increasing the rotational
barrier between the two rings in biphenyl was anticipated to
establish intimacy between the donor-atom-containing benzene
ring and the appended substrate. Incorporating methyl groups
at the 3,5-positions of biphenyl (S6) led to diminished
selectivity, as the donor-heteroatom-coordinated Pd center
would then face increased steric hindrance from ortho-methyl
groups while coordinating to the chelating ligand. This
reinforced the importance of proper placement of the donor
moiety in the DG with respect to the Si tether, bringing us to
S7 (Figure 1B) as the final choice.
Installing two sterically incumbent isopropyl moieties at the
Si center in S7 effectively favored the Thorpe−Ingold effect,
which might allow closer approach of the coordinating group to
the p-C−H bond by a domino-like “steric push” (Scheme 1).
The desired D-shaped assembly S7 was thus successfully
conceived, achieving improved yield and para-selectivity. Other
factors that effectively underscore the significance of the
bonds (2b , 3k, and 3l).
1
The versatility of this functionalization strategy was extended
to carbon−heteroatom bond-forming processes by performing
para-acetoxylation (Table 3) in quantifiable yields. Excellent
levels of para-selectivity were obtained with various ortho- and/
or meta-substituted toluene derivatives. As expected, the control
experiment without the DG (S8) failed to deliver the para-
acetoxylation product.
Cleavage of the template was performed by hydrolysis with
TBAF, yielding para-functionalized product 5a (yield 90%)
along with recovery of the nitrile-containing biphenyl (Scheme
2
). Treatment of 2a under acid-catalyzed deprotection
conditions led to 7a, along with recovery of the directing
11
moiety 6a (Scheme 2).
In summary, remote p-C−H functionalization of arene was
executed using a biphenyl-silyl-tethered D-shaped assembly.
The intricate template morphology helped us to sustain a large
transition state that favored exquisite site selectivity in
performing successful para-olefination and acetoxylation.
C
DOI: 10.1021/jacs.5b06793
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
L. J. Am. Chem. Soc. 2013, 135, 5877. (l) Dai, F.; Gui, Q.; Liu, J.; Yang,
Z.; Chen, X.; Guo, R.; Tan, Z. Chem. Commun. 2013, 49, 4634.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.5b06793.
■
*
S
(m) Cong, X.; Tang, H.; Wu, C.; Zeng, X. Organometallics 2013, 32,
6
4
565. (n) Luo, J.; Preciado, S.; Larrosa, I. J. Am. Chem. Soc. 2014, 136,
109. (o) Martínez-Martínez, A. J.; Kennedy, A. R.; Mulvey, R. E.;
Experimental details, characterization data, and spectra
O’Hara, C. T. Science 2014, 346, 834. (p) Schranck, J.; Tlili, A.; Beller,
M. Angew. Chem., Int. Ed. 2014, 53, 9426. (q) Cheng, C.; Hartwig, J. F.
Science 2014, 343, 853. (r) Wang, X.-C.; Gong, W.; Fang, L.-Z.; Zhu,
R.-Y.; Li, S.; Engle, K. M.; Yu, J.-Q. Nature 2015, 519, 334.
(
PDF)
X-ray crystallographic data for 2k (CIF)
X-ray crystallographic data for 3a (CIF)
X-ray crystallographic data for 3b (CIF)
(
4) For selected examples of C−H activation using frustrated Lewis
pairs, see: (a) Men
́
ard, G.; Stephan, D. W. Angew. Chem., Int. Ed. 2012,
5
1, 4409. (b) Men
́
ard, G.; Hatnean, J. A.; Cowley, H. J.; Lough, A. J.;
AUTHOR INFORMATION
Corresponding Author
dmaiti@chem.iitb.ac.in
Rawson, J. M.; Stephan, D. W. J. Am. Chem. Soc. 2013, 135, 6446.
c) Winkelhaus, D.; Stephan, D. W. Angew. Chem., Int. Ed. 2014, 53,
414. (d) Holthausen, M. H.; Mahdi, T.; Schlepphorst, C.; Hounjet, L.
■
(
5
*
J.; Weigand, J. J.; Stephan, D. W. Chem. Commun. 2014, 50, 10038.
(5) For examples of p-C−H activation, see: (a) Tsai, C.-C.; Shih, W.-
C.; Fang, C.-H.; Li, C.-Y.; Ong, T.-G.; Yap, G. P. A. J. Am. Chem. Soc.
Notes
The authors declare the following competing financial
interest(s): Two patent applications are filed based on the
work described in this manuscript.
2
010, 132, 11887. (b) Ciana, C.-L.; Phipps, R. J.; Brandt, J. R.; Meyer,
F.-M.; Gaunt, M. J. Angew. Chem., Int. Ed. 2011, 50, 458. (c) Sun, K.;
Li, Y.; Xiong, T.; Zhang, J.; Zhang, Q. J. Am. Chem. Soc. 2011, 133,
1
1
694. (d) Wang, X.; Leow, D.; Yu, J.-Q. J. Am. Chem. Soc. 2011, 133,
3864. (e) Imahori, T.; Tokuda, T.; Taguchi, T.; Takahata, H. Org.
ACKNOWLEDGMENTS
This activity was supported by SERB, India (No.SB/S5/GC-
5/2013). Financial support received from UGC-India (fellow-
ship to S.B. and T.P.), CSIR-India (fellowship to A. Modak,
A.D., S.M., and A. Maji), and DST Fast Track Scheme (R.K.
and M.B.) is gratefully acknowledged.
■
0
Lett. 2012, 14, 1172. (f) Kamata, K.; Yamaura, T.; Mizuno, N. Angew.
Chem., Int. Ed. 2012, 51, 7275. (g) Wu, Z.; Luo, F.; Chen, S.; Li, Z.;
Xiang, H.; Zhou, X. Chem. Commun. 2013, 49, 7653. (h) Liu, W.;
Ackermann, L. Org. Lett. 2013, 15, 3484. (i) Yu, Z.; Ma, B.; Chen, M.;
Wu, H.-H.; Liu, L.; Zhang, J. J. Am. Chem. Soc. 2014, 136, 6904.
(j) Pialat, A.; Berges, J.; Sabourin, A.; Vinck, R.; Liegault, B.; Taillefer,
M. Chem. - Eur. J. 2015, 21, 10014. (k) Li, J.; De Sarkar, S.;
Ackermann, L. Topics in Organometallic Chemistry; Springer: Berlin,
REFERENCES
■
(
1) For selected examples of undirected C−H activation, see: (a) Jia,
C.; Kitamura, T.; Fujiwara, Y. Acc. Chem. Res. 2001, 34, 633.
b) Hartwig, J. F. Chem. Soc. Rev. 2011, 40, 1992. (c) Ritleng, V.;
Sirlin, C.; Pfeffer, M. Chem. Rev. 2002, 102, 1731. (d) Sun, C.-L.; Li,
H.; Yu, D.-G.; Yu, M.; Zhou, X.; Lu, X.-Y.; Huang, K.; Zheng, S.-F.; Li,
B.-J.; Shi, Z.-J. Nat. Chem. 2010, 2, 1044. (e) Zhou, L.; Lu, W. Chem. -
Eur. J. 2014, 20, 634.
2) For selected reviews on o-C−H activation, see: (a) Daugulis, O.;
Do, H.-Q.; Shabashov, D. Acc. Chem. Res. 2009, 42, 1074. (b) Chen,
X.; Engle, K. M.; Wang, D.-H.; Yu, J.-Q. Angew. Chem., Int. Ed. 2009,
8, 5094. (c) Colby, D. A.; Bergman, R. G.; Ellman, J. A. Chem. Rev.
010, 110, 624. (d) Satoh, T.; Miura, M. Synthesis 2010, 2010, 3395.
e) Lyons, T. W.; Sanford, M. S. Chem. Rev. 2010, 110, 1147. (f) Cho,
S. H.; Kim, J. Y.; Kwak, J.; Chang, S. Chem. Soc. Rev. 2011, 40, 5068.
g) Liu, C.; Zhang, H.; Shi, W.; Lei, A. Chem. Rev. 2011, 111, 1780.
h) Sun, C.-L.; Li, B.-J.; Shi, Z.-J. Chem. Rev. 2011, 111, 1293.
i) Yeung, C. S.; Dong, V. M. Chem. Rev. 2011, 111, 1215.
j) Arockiam, P. B.; Bruneau, C.; Dixneuf, P. H. Chem. Rev. 2012,
2
(
2
015.10.1007/3418_2015_130.
6) (a) Brasche, G.; García-Fortanet, J.; Buchwald, S. L. Org. Lett.
008, 10, 2207. (b) Chen, X.; Engle, K. M.; Wang, D.-H.; Yu, J.-Q.
(
Angew. Chem., Int. Ed. 2009, 48, 5094. (c) Rakshit, S.; Grohmann, C.;
Besset, T.; Glorius, F. J. Am. Chem. Soc. 2011, 133, 2350. (d) Deb, A.;
Bag, S.; Kancherla, R.; Maiti, D. J. Am. Chem. Soc. 2014, 136, 13602.
(
7) For examples of m-C−H activation by chelation assistance, see:
(
(
(
(
a) Leow, D.; Li, G.; Mei, T.-S.; Yu, J.-Q. Nature 2012, 486, 518.
b) Lee, S.; Lee, H.; Tan, K. L. J. Am. Chem. Soc. 2013, 135, 18778.
c) Dai, H.-X.; Li, G.; Zhang, X.-G.; Stepan, A. F.; Yu, J.-Q. J. Am.
4
2
(
Chem. Soc. 2013, 135, 7567. (d) Tang, R.-Y.; Li, G.; Yu, J.-Q. Nature
2
014, 507, 215. (e) Yang, Y.-F.; Cheng, G.-J.; Liu, P.; Leow, D.; Sun,
T.-Y.; Chen, P.; Zhang, X.; Yu, J.-Q.; Wu, Y.-D.; Houk, K. N. J. Am.
Chem. Soc. 2014, 136, 344. (f) Yang, G.; Lindovska, P.; Zhu, D.; Kim,
J.; Wang, P.; Tang, R.-Y.; Movassaghi, M.; Yu, J.-Q. J. Am. Chem. Soc.
(
(
(
(
2
014, 136, 10807. (g) Bera, M.; Modak, A.; Patra, T.; Maji, A.; Maiti,
D. Org. Lett. 2014, 16, 5760. (h) Deng, Y.; Yu, J.-Q. Angew. Chem., Int.
Ed. 2015, 54, 888. (i) Bera, M.; Maji, A.; Sahoo, S. K.; Maiti, D. Angew.
Chem., Int. Ed. 2015, 54, 8515. (j) Li, S.; Ji, H.; Cai, L.; Li, G. Chem.
Sci. 2015, DOI: 10.1039/C5SC01737H.
1
12, 5879. (k) Kuhl, N.; Hopkinson, M. N.; Wencel-Delord, J.;
Glorius, F. Angew. Chem., Int. Ed. 2012, 51, 10236. (l) Neufeldt, S. R.;
Sanford, M. S. Acc. Chem. Res. 2012, 45, 936. (m) Sigman, M. S.;
Werner, E. W. Acc. Chem. Res. 2012, 45, 874. (n) Ackermann, L. Acc.
Chem. Res. 2014, 47, 281. (o) De Sarkar, S.; Liu, W.; Kozhushkov, S. I.;
Ackermann, L. Adv. Synth. Catal. 2014, 356, 1461. (p) Zhang, F.;
Spring, D. R. Chem. Soc. Rev. 2014, 43, 6906. (q) Topczewski, J. J.;
Sanford, M. S. Chem. Sci. 2015, 6, 70.
3) For selected examples of m-C−H activation, see: (a) Cho, J.-Y.;
Tse, M. K.; Holmes, D.; Maleczka, R. E.; Smith, M. R. Science 2002,
95, 305. (b) Ishiyama, T.; Takagi, J.; Ishida, K.; Miyaura, N.; Anastasi,
N. R.; Hartwig, J. F. J. Am. Chem. Soc. 2002, 124, 390. (c) Phipps, R. J.;
Grimster, N. P.; Gaunt, M. J. J. Am. Chem. Soc. 2008, 130, 8172.
d) Do, H.-Q.; Khan, R. M. K.; Daugulis, O. J. Am. Chem. Soc. 2008,
30, 15185. (e) Phipps, R. J.; Gaunt, M. J. Science 2009, 323, 1593.
f) Zhang, Y.-H.; Shi, B.-F.; Yu, J.-Q. J. Am. Chem. Soc. 2009, 131,
(
8) Brookhart, M.; Green, M. L. H.; Parkin, G. Proc. Natl. Acad. Sci.
U.S.A. 2007, 104, 6908.
9) Sarkar, D.; Melkonyan, F. S.; Gulevich, A. V.; Gevorgyan, V.
Angew. Chem., Int. Ed. 2013, 52, 10800.
(
(
(
10) See the Supporting Information for a detailed description.
11) (a) Vorbruggen, H.; Krolikiewicz, K. Tetrahedron Lett. 1983, 24,
(
8
7
89. (b) Boebel, T. A.; Hartwig, J. F. J. Am. Chem. Soc. 2008, 130,
534. (c) Wang, C.; Ge, H. Chem. - Eur. J. 2011, 17, 14371.
2
(d) Huang, C.; Ghavtadze, N.; Godoi, B.; Gevorgyan, V. Chem. - Eur. J.
2
012, 18, 9789. (e) Das, M.; O’Shea, D. F. Tetrahedron 2013, 69,
6
448.
(
1
(
5072. (g) Cornella, J.; Righi, M.; Larrosa, I. Angew. Chem., Int. Ed.
2011, 50, 9429. (h) Ye, M.; Gao, G.-L.; Yu, J.-Q. J. Am. Chem. Soc.
2011, 133, 6964. (i) Zhou, L.; Lu, W. Organometallics 2012, 31, 2124.
(
j) Wang, Y.-N.; Guo, X.-Q.; Zhu, X.-H.; Zhong, R.; Cai, L.-H.; Hou,
X.-F. Chem. Commun. 2012, 48, 10437. (k) Hofmann, N.; Ackermann,
D
DOI: 10.1021/jacs.5b06793
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX