Weak Coordination Enabled Switchable C4-Alkenylation and Alkylation of Indoles with Allyl Alcohols

Article abstract of DOI:10.1021/acs.orglett.9b04612

A weak carbonyl coordination facilitated tunable reactivity between alkenylation and alkylation of indoles at the C4 C-H site is presented using readily accessible allylic alcohols in the presence of Rh catalysis by switching the additives or directing group. Exclusive site selectivity, functional group tolerance, and late-stage modifications are the important practical features.

Full text of DOI:10.1021/acs.orglett.9b04612

pubs.acs.org/OrgLett
Letter
Weak Coordination Enabled Switchable C4-Alkenylation and
Alkylation of Indoles with Allyl Alcohols
Sourav Pradhan, Manmath Mishra, Pinaki Bhusan De, Sonbidya Banerjee,
and Tharmalingam Punniyamurthy*
Cite This: https://dx.doi.org/10.1021/acs.orglett.9b04612
Read Online
sı
*
Metrics & More
Article Recommendations
Supporting Information
ACCESS
ABSTRACT: A weak carbonyl coordination facilitated tunable
reactivity between alkenylation and alkylation of indoles at the C4
C−H site is presented using readily accessible allylic alcohols in the
presence of Rh catalysis by switching the additives or directing
group. Exclusive site selectivity, functional group tolerance, and
late-stage modifications are the important practical features.
Scheme 1. C4 Functionalization of Indoles with Allyl
Alcohols
he indole framework is one of the most studied organic
T
templates in the realm of organic synthesis,1 as it features
in plentiful natural products and pharmaceuticals.2 The pursuit
for expedited synthetic elaborations of the six available C−H
functionalization sites on the indole backbone has thus
emerged as a burgeoning research area. Owing to the inherent
nucleophilic nature of the pyrrole type ring, C2 and C3 C−H
functionalizations are replete with examples in the literature.3
In contrast, the functionalization of the benzenoid segment
(C4−C7) remains underdeveloped.4 Along this line, selective
editing at the C4-site of indole requires a directing group at the
C3 position, which imposes an appreciable hurdle by
prompting a competing C−H metalation pathway. The
formation of five-membered cyclometalation at C2 is favored
compared to the corresponding high energy six-membered
cyclometalation at C4 (Scheme 1a). Hence, C4 functionaliza-
tion of indole has garnered much attention and several groups
devoted their efforts5 to gain perspicuity of the above unsolved
problem. Accordingly, olefination,5a,b arylation,5c,d amidation,5e
fluoroalkylation,5f borylation,5g and allylation5h has been
demonstrated at the C4 site of indoles. However, the
development of an efficient and robust catalytic system
which enables a switch in multiple reactive pathways by
tuning the reactivity of substrates is desirable.6 In this context,
allylic alcohols are realized as a staple coupling partners in C−
H functionalization as they are capable of selectively
undergoing manifold reaction pathways by tuning the reactivity
of the organometallic intermediate (Scheme 1b).7 The use of
allylic alcohols in C−H functionalization regulating either β-
hydride or β-hydroxy elimination pathway has attracted
considerable attention in recent years.8 In addition, the
implementation of a weakly coordinating directing group9 to
attain such tunable reactivity would be valuable. Here we
report a carbonyl coordination guided controllable chemo-
selectivity between C4-alkenylation and alkylation of indoles
with allyl alcohols by altering the additives and directing group
in the presence of Rh catalysis (Scheme 1c).10 In the case of
Ag2CO3, selective β-hydride elimination provided alkenylation,
whereas the presence of NaOPiv led to the alkylated product.
When tertiary allyl alcohol was employed as a coupling partner
selective allylation was achieved.
Received: December 24, 2019
https://dx.doi.org/10.1021/acs.orglett.9b04612
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

Organic Letters
pubs.acs.org/OrgLett
Letter
a b
,
First, our optimization studies commenced reacting 1-(1-
benzyl-1H-indol-3-yl)ethan-1-one 1a with but-3-en-2-ol 2a as
the test substrates (see Table S1 for details). To our delight,
the reaction occurred to give C4-alkenylated 3a in 17% yield
along with a trace of alkylated 4a when the substrates were
stirred with 2.5 mol % of [Cp*RhCl2]2, 20 mol % of AgSbF6,
and 2 equiv of Cu(OAc)2 in (CH2Cl)2 at 100 °C. Screening of
the ethereal solvents, such as THF and 1,4-dioxane, revealed
that the formation of 3a was facilitated. Addition of Ag2CO3 in
place of Cu(OAc)2 led to improve the yield of 3a to 74%,
whereas AgOAc produced inferior result. Thus, Ag2CO3 was
found to be the optimal additive11 to furnish the alkenylation
product selectively. Further screening of the alcoholic solvents
Scheme 2. Scope of C4 Alkenylation with Indoles
t
such as, HFIP, TFE, and BuOH favored the formation of 4a
compared to 3a. Switching the additive from Ag2CO3 to
NaOPiv·H2O and a combination with AgOTf selectively
produced the alkylated 4a as the sole product. PivOH was
also found to be effective, delivering 4a in 61% yield, whereas
AcOH was ineffective. Thus, NaOPiv·H2O was beneficial to
achieve alkylation selectively. Control experiments confirmed
that the combination of AgSbF6 or AgOTf and Rh(III) catalyst
is decisive and no product formation was observed in its
absence. Notably, C4 functionalization of indole was occurred
selectively and no C2-functionalized product was detected.
From the density functional theory (DFT) calculation, it was
proposed that introducing a carbonyl group at the C3 C−H
site can significantly increase the electron density at C4 site
compared to the C2 site.5i This may drive the selective C4
functionalization by an electrophilic metalation-type process.
With the optimal reaction conditions established, the scope
of C4 alkenylation was assessed for substituted indoles 1b−s
with allyl alcohol 2a as a standard substrate (Scheme 2). The
reaction of 2-methylindole 1b afforded 3b in 70% yield. 5-
Substituted indoles bearing bromo (1c) and methyl (1d)
functionalities were unsuccessful, which was presumably due to
the steric congestion near the C4 site. However, the substrates
containing substitution at the 6 position of indole, with fluoro
(1e), bromo (1f), p-tolyl (1g), and 1-pyrenyl (1h) groups
afforded the target alkenylated products 3e−h in 61−79%
yields. Delightfully, sensitive 6-allylated indole 1i afforded 3i in
69% yield. Similar results were obtained with 7-chloro (1j) and
7-methyl (1k) substituted indoles furnishing 3j and 3k in 71
and 74% yields, respectively. Fused indole congeners 1l and
1m produced 3l and 3m in 66 and 64% yields, respectively.
Interestingly, NH-free indole was successfully coupled to give
3n in 67% yield. Variation in N-protecting groups such as Boc
(1o), ethyl (1p), and octyl (1q), the former was ineffective,
while as others was amenable, delivering 3p and 3q in 69 and
74% yields, respectively. Likewise, 3-hexanoyl derivative 1r and
isobutyryl derivative 1s conveyed 3r and 3s in 73 and 78%
yields, respectively. These results suggest that C4 alkenylation
of indoles can be accomplished with functional group
tolerance.
a
Reaction conditions: 1b−s (0.1 mmol), 2a (0.2 mmol),
[Cp*RhCl2]2 (2.5 mol %), AgSbF6 (20 mol %), Ag2CO3 (0.2
b
mmol), 1,4-dioxane (1.5 mL), 100 °C, 6 h, air. Isolated yields.
occurring terpene alcohol isophytol 2i participated in the
reaction to give the C4 allylated product 3aa in 41% yield. The
reaction of tertiary allyl alcohol precludes the β-hydride
elimination pathway, and the reaction proceeds via β-hydroxy
elimination pathway to deliver allylated product.8d This result
confides that C4-selective allylation of indoles can be achieved
employing tert-allyl alcohols as a coupling partner.
Next, the C4 alkylation scope was investigated utilizing
diversely substituted indoles with allyl alcohol 2a as a standard
coupling partner (Scheme 4). The reaction of 2-methylindole
1b furnished the C4 alkylated product 4b in 53% yield.
Likewise, 5-methoxy (1t), 7-methyl (1k), N-phenyl (1u), and
3-isovaleryl (1v) containing indoles converted to the alkylated
scaffolds 4d−g in 63−69% yields, whereas 5-bromoindole 1c
was an unsuccessful substrate, which may be due to steric
hindrance.
The reaction conditions were extended to the coupling of
substituted allyl alcohols 2j−p with indole 1a as a standard
substrate (Scheme 4). The reaction of pent-1-en-3-ol 2j gave
4h in 69% yield. Similarly, substitution of the phenyl ring at the
carbinol carbon with 4-methoxy (2k) and 4-phenyl (2l) groups
underwent reaction to afford 4i and 4j in 68 and 66% yields,
respectively. Remarkably, conjugated π-system based allyl
alcohols 2m−p efficiently conveyed the alkylation products
4k−n in 63−72% yields. These results displayed the
captivating potential of the method for C4 alkylation of
indoles to synthesize β-arylated ketones.
With these intriguing results, the alkenylation scope was
further explored using substituted allyl alcohols 2b−i with
indole 1a as a standard substrate (Scheme 3). 1-Phenylprop-2-
en-1-ol 2b underwent reaction to afford 3t in 64% yield. The
reaction of 3-trifluoromethyl analogue 2c produced 3u in 58%
yield, whereas 4-chloro (2d) and 4-fluoro (2e) derivatives
delivered the corresponding alkenylated product 3v and 3w in
63 and 51% yields, respectively. Similar results were perceived
with alkyl substitutions at the carbinol carbon of the allyl
alcohols 2f−h, delivering 3x−z in 53−68% yields. Naturally
To divulge the importance of carbonyl based coordinating
groups, the reaction of 2a was conducted with a series of C3-
carbonyl attached indole derivatives. Pivaloyl indole 1A
B
https://dx.doi.org/10.1021/acs.orglett.9b04612
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
a b
,
Scheme 3. Scope of C4 Alkenylation with Allyl Alcohols
Scheme 4. Scope of C4 Alkylation with Indoles and Allyl
Alcohols
a b
,
a
Reaction conditions: 1a (0.1 mmol), 2b−i (0.2 mmol),
[Cp*RhCl2]2 (2.5 mol %), AgSbF6 (20 mol %), Ag2CO3 (0.2
b
mmol), 1,4-dioxane (1.5 mL), 100 °C, 6 h, air. Isolated yields.
conveyed the C4 alkylated product 5a in 67% yield, whereas
formyl, 1a′, benzoyl 1b′, and trifluoromethylacetyl 1c′ were
unsuccessful substrates (Scheme S1). These results indicate
that, depending on the directing group a switch in product
distribution between C4-selective alkenylation and alkylation
can be achieved under identical reaction conditions.6b
a
Reaction conditions: 1 (0.1 mmol), 2j−p (0.2 mmol), [Cp*RhCl2]2
(2.5 mol %), AgOTf (20 mol %), NaOPiv·H2O (0.2 mmol), solvent
b
a
b
(1.5 mL), 120 °C, 12 h, air. Isolated yields. t-BuOH used. TFE
used.
We then turned our attention to assess the generality of C4
alkylation with respect to pivaloyl indoles 1B−G with 2a as a
standard substrate (Scheme 5). 5-Bromo derivative 1B was an
unsuccessful substrate, which may be due to the steric
hindrance near coupling site. However, 5-methoxy (1C), 6-
bromo (1D), and 7-chloro (1E) indoles underwent reaction to
deliver the alkylated products 5c−e in 63−71% yields. The
structure of 5d was determined using single-crystal X-ray
analysis (see the SI). The reaction of a fused indole derivative
1F gave 5f in 65% yield. Interestingly, prop-2-en-1-ol 2q was
smoothly coupled with 1A to give the β-aryl aldehyde 5g in
67% yield. In addition, fibrate drug gemfibrozil derived indole
1G was alkylated to furnish 5h in 70% yield. This showcase the
remarkable potential of the method for the late-stage drug
modification and the chemoselectivity can be altered depend-
ing on the directing group.6b
To gain insight into the reaction pathway, control, H/D
exchange, and kinetic isotope experiments were conducted
(Scheme S2). The reaction of 1a and 2a was performed under
argon atmosphere. Alkenylation product 3a was obtained in
71% yield, whereas alkylation 4a was obtained albeit in lower
yield (Scheme S2a). These results suggest that air might be
playing as an oxidant in case of alkylation. Under standard
conditions, allyl alcohol 2b afforded isomerization products 1-
phenylprop-2-en-1-one 2b′ and propiophenone 2b′′ as
detected in NMR (Scheme S2b), which suggests that the
reaction may proceed through the isomerized enone
intermediate.12a,e In the absence of [Cp*RhCl2]2, no H/D
exchange was detected at both C4−H and C2−H bonds,
implying the essential role of the Rh-catalyst in C−H
activation. Whereas, H/D exchange experiments of 1a and
1A independently in the presence or absence of 2a using D2O
as a cosolvent revealed significant deuterium incorporation at
C4 site (Scheme S2c), signifying the reversibility of the C−H
activation step. The H/D exchange of 1A with 2a revealed
significant deuterium incorporation at the α-carbon of the
carbonyl group of [Dn]-5a, thereby indicating the formation of
a rhodium-oxa-π alllyl species.12f Further, kinetic isotope
experiment using 1a and [D2]-1a with 2a, yielded a kH/kD =
1.48 (Scheme S2d). This result indicates that the C4−H bond
cleavage might not be involved in the rate-determining step.12b
On the basis of mechanistic considerations and literature,8,12
a plausible mechanism is depicted in scheme S3. The catalytic
cycle commenced with the generation of a cationic rhodium
species a or a′ by the reaction of dimeric Rh(III)-catalyst in
the presence of Ag(I) salts (AgOTf or AgSbF6) and additives,
Ag2CO3 or NaOPiv. Allyl alcohols under basic condition may
give the isomerized enone f.12a,e The weak precoordination of
carbonyl oxygen of 1 with a may deliver rhodacycle b, whereas
coordination of 1 with a′ furnishes b along with the generation
C
https://dx.doi.org/10.1021/acs.orglett.9b04612
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
a b
,
Accession Codes
Scheme 5. Scope of C4 Alkylation with Pivaloyl Indoles
CCDC 1959139 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Author
■
Tharmalingam Punniyamurthy − Department of Chemistry,
Indian Institute of Technology Guwahati, Guwahati 781039,
India; orcid.org/0000-0003-4696-8896; Email: tpunni@
iitg.ac.in
Authors
Sourav Pradhan − Department of Chemistry, Indian Institute of
Technology Guwahati, Guwahati 781039, India
Manmath Mishra − Department of Chemistry, Indian Institute
of Technology Guwahati, Guwahati 781039, India
Pinaki Bhusan De − Department of Chemistry, Indian Institute
of Technology Guwahati, Guwahati 781039, India
Sonbidya Banerjee − Department of Chemistry, Indian Institute
a
Reaction conditions: 1B−G (0.1 mmol), 2 (0.2 mmol),
[Cp*RhCl2]2 (2.5 mol %), AgSbF6 (20 mol %), Ag2CO3 (0.2
of Technology Guwahati, Guwahati 781039, India
b
mmol), 1,4-dioxane (1.5 mL), 100 °C, 6 h, air. Isolated yield.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.9b04612
Notes
of PivOH. Subsequent reaction of b with f may lead to the
formation of c. The latter may undergo reaction in two distinct
pathways to provide the target products. When Ag2CO3 is
present as a base additive in the medium, the intermediate c
may undergo β-hydride elimination (path a) to deliver the
alkenylated indoles 3. On the other hand, the intermediate c
may undergo preferential protodemetalation in the presence of
PivOH (path b) to give the alkylated products 4.10a In case of
pivaloyl indoles 1A−G, the electron-rich and bulkier carbonyl
group may yield a rigid metalacycle c′ which can prevent the β-
H elimination and undergo isomerization to give the oxa-π allyl
species g.6b,12d,f Tautomerization can afford the alkylated
product 5. The active Rh-catalyst may regenerate with the help
of Ag(I) and air to complete the catalytic cycle.
To display the practicality of the protocol, scale-up synthesis
was carried out (Scheme S4). The scale-up (1 mmol) with 1a
and 2a as the representative example gave the target
alkenylated product 3a in 66% yield. The acetyl directing
group can be removed by a reverse Friedel−Crafts reaction.5b
It is notable to mention that, the α,β-unsaturated carbonyl
residue at the C4-site of indole can function as a versatile
functional handle for further synthetic modifications.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Science and Engineering Research Board (SERB)
(CRG/2018/000406) and Council of Industrial Research
(CSIR) (02(0255)/16/EMR-II) for the financial support. We
also thank Central Instrumentation Facility, Centre of
Excellence FAST and FIST-II, IIT Guwahati for NMR and
mass analyses.
REFERENCES
■
(1) (a) Bandini, M.; Eichholzer, A. Catalytic Functionalization of
Indoles in a New Dimension. Angew. Chem., Int. Ed. 2009, 48, 9608.
(b) Joucla, L.; Djakovitch, L. Transition Metal-Catalysed, Direct and
Site-Selective N1-, C2- or C3-Arylation of the Indole Nucleus: 20
Years of Improvements. Adv. Synth. Catal. 2009, 351, 673. (c) Chen,
J. B.; Jia, Y. X. Recent Progress in Transition-Metal-Catalyzed
Enantioselective Indole Functionalizations. Org. Biomol. Chem. 2017,
15, 3550. (d) Corsello, M. A.; Kim, J.; Garg, N. K. Indole Diterpenoid
Natural Products as The Inspiration for New Synthetic Methods and
Strategies. Chem. Sci. 2017, 8, 5836. (e) Festa, A. A.; Voskressensky,
L. G.; Van der Eycken, E. V. Visible Light-Mediated Chemistry of
Indoles and Related Heterocycles. Chem. Soc. Rev. 2019, 48, 4401.
(2) (a) Van Order, R. B.; Lindwall, H. G. Indole. Chem. Rev. 1942,
30, 69. (b) Somei, M.; Yamada, F. Simple Indole Alkaloids and Those
with A Non-Rearranged Monoterpenoid Unit. Nat. Prod. Rep. 2005,
22, 73. (c) Kochanowska-Karamyan, A. J.; Hamann, M. T. Marine
Indole Alkaloids: Potential New Drug Leads for the Control of
Depression and Anxiety. Chem. Rev. 2010, 110, 4489. (d) Taylor, R.
D.; MacCoss, M.; Lawson, A. D. G. Rings in Drugs. J. Med. Chem.
2014, 57, 5845. (e) Zhang, M.-Z.; Chen, Q.; Yang, G.-F. A Review
On Recent Developments of Indole-Containing Antiviral Agents. Eur.
J. Med. Chem. 2015, 89, 421.
In summary, we have demonstrated a robust Rh-catalyzed
tunable C4 alkenylation and alkylation of indoles engaging
allylic alcohols with high selectivity and functional group
diversity. The dichotomy in product distribution can be
achieved by switching the additives or directing group.
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.9b04612.
(3) For a review, see: (a) Sandtorv, A. H. Transition Metal-
Catalyzed C-H Activation of Indoles. Adv. Synth. Catal. 2015, 357,
2403. For key seminal publications, see: (b) Wang, X.; Lane, B. S.;
General procedures, characterization data, NMR spectra
(PDF)
D
https://dx.doi.org/10.1021/acs.orglett.9b04612
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
Sames, D. Direct C-Arylation of Free (NH)-Indoles and Pyrroles
Catalyzed by Ar−Rh(III) Complexes Assembled In Situ. J. Am. Chem.
Soc. 2005, 127, 4996. (c) Deprez, N. R.; Kalyani, D.; Krause, A.;
Sanford, M. S. Room Temperature Palladium-Catalyzed 2-Arylation
of Indoles. J. Am. Chem. Soc. 2006, 128, 4972. (d) Stuart, D. R.;
Fagnou, K. The Catalytic Cross-Coupling of Unactivated Arenes.
Science 2007, 316, 1172. (e) Phipps, R. J.; Grimster, N. P.; Gaunt, M.
J. Cu(II)-Catalyzed Direct and Site-Selective Arylation of Indoles
Under Mild Conditions. J. Am. Chem. Soc. 2008, 130, 8172.
(f) Lebrasseur, N.; Larrosa, I. Room Temperature and Phosphine
Free Palladium Catalyzed Direct C-2 Arylation of Indoles. J. Am.
Chem. Soc. 2008, 130, 2926. (g) Toutov, A. A.; Liu, W.-B.; Betz, K.
N.; Fedorov, A.; Stoltz, B. M.; Grubbs, R. H. Silylation of C−H Bonds
in Aromatic Heterocycles by an Earth-Abundant Metal Catalyst.
Nature 2015, 518, 80.
Catalyzed Switchable Cyclization to Quinolines and Indoles. ACS
Catal. 2016, 6, 2352. (d) Zell, D.; Bursch, M.; Muller, V.; Grimme, S.;
Ackermann, L. Switch of C-H Activation Mechanism for Full
Selectivity Control in Cobalt(III)-Catalyzed C-H Alkylations.
Angew. Chem., Int. Ed. 2017, 56, 10378. (e) Ping, L.; Chung, D. S.;
Bouffard, J.; Lee, S. Transition Metal-Catalyzed Site- And Regio-
Divergent C−H Bond Functionalization. Chem. Soc. Rev. 2017, 46,
4299. (f) Tran, G.; Hesp, K. D.; Mascitti, V.; Ellman, J. A. Base-
Controlled Completely Selective Linear or Branched Rhodium(I)-
Catalyzed C-H ortho-Alkylation of Azines without Preactivation.
̈
́
Angew. Chem., Int. Ed. 2017, 56, 5899. (g) Najera, C.; Beletskaya, I. P.;
Yus, M. Metal-Catalyzed Regiodivergent Organic Reactions. Chem.
Soc. Rev. 2019, 48, 4515.
(7) (a) Werner, E. W.; Mei, T.-S.; Burckle, A. J.; Sigman, M. S.
Enantioselective Heck Arylations of Acyclic Alkenyl Alcohols Using a
Redox-Relay Strategy. Science 2012, 338, 1455. (b) Sundararaju, B.;
Achard, M.; Bruneau, C. Transition Metal Catalyzed Nucleophilic
Allylic Substitution: Activation of Allylic Alcohols Via Π-Allylic
Species. Chem. Soc. Rev. 2012, 41, 4467. (c) Larionov, E.; Lin, L.;
(4) (a) Yang, G.; Lindovska, P.; Zhu, D.; Kim, J.; Wang, P.; Tang,
R.-Y.; Movassaghi, M.; Yu, J.-Q. Pd(II)-Catalyzed meta-C−H
Olefination, Arylation, and Acetoxylation of Indolines Using a U-
Shaped Template. J. Am. Chem. Soc. 2014, 136, 10807. (b) Yang, Y.;
Li, R.; Zhao, Y.; Zhao, D.; Shi, Z. Cu-Catalyzed Direct C6-Arylation
of Indoles. J. Am. Chem. Soc. 2016, 138, 8734. (c) Leitch, J. A.;
Bhonoah, Y.; Frost, C. G. Beyond C2 and C3: Transition-Metal-
Catalyzed C−H Functionalization of Indole. ACS Catal. 2017, 7,
5618. (d) Yang, Y.; Shi, Z. Regioselective Direct Arylation of Indoles
On the Benzenoid Moiety. Chem. Commun. 2018, 54, 1676.
(e) Borah, A. J.; Shi, Z. Rhodium-Catalyzed, Remote Terminal
Hydroarylation of Activated Olefins through a Long-Range
Deconjugative Isomerization. J. Am. Chem. Soc. 2018, 140, 6062.
(f) Shah, T. A.; De, P. B.; Pradhan, S.; Punniyamurthy, T. Transition-
Metal-Catalyzed Site-Selective C7-Functionalization of Indoles:
Advancement and Future Prospects. Chem. Commun. 2019, 55, 572.
(5) For recent examples, see: (a) Lanke, V.; Ramaiah Prabhu, K.
Regioselective Synthesis of 4-Substituted Indoles via C−H Activation:
A Ruthenium Catalyzed Novel Directing Group Strategy. Org. Lett.
2013, 15, 6262. (b) Lv, J.; Wang, B.; Yuan, K.; Wang, Y.; Jia, Y.
Regioselective Direct C-4 Functionalization of Indole: Total
Synthesese of (−)-Agroclavine and (−)-Elymoclavine. Org. Lett.
2017, 19, 3664. (c) Yang, Y.; Gao, P.; Zhao, Y.; Shi, Z.
Regiocontrolled Direct C−H Arylation of Indoles at the C4 and C5
Positions. Angew. Chem., Int. Ed. 2017, 56, 3966. (d) Liu, X.-H.; Park,
H.; Hu, J.-H.; Hu, Y.; Zhang, Q.-L.; Wang, B.-L.; Sun, B.; Yeung, K.-
S.; Zhang, F.-L.; Yu, J.-Q. Diverse ortho-C(sp2)-H Functionalization
of Benzaldehydes using Transient Directing Groups. J. Am. Chem. Soc.
2017, 139, 888. (e) Chen, S.; Feng, B.; Zheng, X.; Yin, J.; Yang, S.;
You, J. Iridium-Catalyzed Direct Regioselective C4-Amidation of
Indoles under Mild Conditions. Org. Lett. 2017, 19, 2502. (f) Borah,
A. J.; Shi, Z. Palladium-Catalyzed Regioselective C-H Fluoroalkylation
of Indoles at the C-4-Position. Chem. Commun. 2017, 53, 3945.
(g) Lv, J.; Chen, X.; Xue, X.-S.; Zhao, B.; Liang, Y.; Wang, M.; Jin, L.;
Yuan, Y.; Han, Y.; Zhao, Y.; Lu, Y.; Zhao, J.; Sun, W.-Y.; Houk, K. N.;
Shi, Z. Metal-Free Directed sp2 C-H Borylation. Nature 2019, 575,
336. (h) Pradhan, S.; De, P. B.; Punniyamurthy, T. Weak
Coordination-Guided Regioselective Direct Redox-Neutral C4
Allylation of Indoles with Morita−Baylis−Hillman Adducts. Org.
Lett. 2019, 21, 9898. (i) Chen, S.; Zhang, M.; Su, R.; Chen, X.; Feng,
B.; Yang, Y.; You, J. C2/C4 regioselective Heteroarylation of Indoles
by Tuning C-H Metalation Modes. ACS Catal. 2019, 9, 6372. For a
review, see: (j) Kalepu, J.; Gandeepan, P.; Ackermann, L.; Pilarski, L.
T. C4−H Indole Functionalisation: Precedent and Prospects. Chem.
Sci. 2018, 9, 4203.
́
́
́
Guenee, L.; Mazet, C. Scope and Mechanism in Palladium-Catalyzed
Isomerizations of Highly Substituted Allylic, Homoallylic, and Alkenyl
Alcohols. J. Am. Chem. Soc. 2014, 136, 16882. (d) Butt, N. A.; Zhang,
W. Transition Metal-Catalyzed Allylic Substitution Reactions with
Unactivated Allylic Substrates. Chem. Soc. Rev. 2015, 44, 7929.
(e) Mishra, N. K.; Sharma, S.; Park, J.; Han, S.; Kim, I. S. Recent
Advances in Catalytic C(sp2)−H Allylation Reactions. ACS Catal.
2017, 7, 2821.
(8) (a) Shi, Z.; Boultadakis-Arapinisa, M.; Glorius, F. Rh(III)-
Catalyzed Dehydrogenative Alkylation of (Hetero)Arenes with Allylic
Alcohols, Allowing Aldol Condensation to Indenes. Chem. Commun.
2013, 49, 6489. (b) Huang, L.; Wang, Q.; Qi, J.; Wu, X.; Huang, K.;
Jiang, H. Rh(III)-Catalyzed Ortho-Oxidative Alkylation of Unac-
tivated Arenes with Allylic Alcohols. Chem. Sci. 2013, 4, 2665.
(c) Suzuki, Y.; Sun, B.; Sakata, K.; Yoshino, T.; Matsunaga, S.; Kanai,
M. Dehydrative Direct C-H Allylation with Allylic Alcohols under
[Cp*Co(III)] Catalysis. Angew. Chem., Int. Ed. 2015, 54, 9944.
(d) Manoharan, R.; Jeganmohan, M. Synthesis of Isoindolinones Via a
Ruthenium-Catalyzed Cyclization of N-Substituted Benzamides with
Allylic Alcohols. Chem. Commun. 2015, 51, 2929. (e) Hu, X.-Q.; Hu,
Z.; Trita, A. S.; Zhang, G.; Gooßen, L. J. Carboxylate-Directed C−H
Allylation with Allyl Alcohols or Ethers. Chem. Sci. 2018, 9, 5289.
(9) (a) Engle, K. M.; Mei, T.-S.; Wasa, M.; Yu, J.-Q. Weak
Coordination as a Powerful Means for Developing Broadly Useful C−
H Functionalization Reactions. Acc. Chem. Res. 2012, 45, 788. (b) De
Sarkar, S.; Liu, W.; Kozhushkov, S. I.; Ackermann, L. Weakly
Coordinating Directing Groups for Ruthenium(II)- Catalyzed C-H
Activation. Adv. Synth. Catal. 2014, 356, 1461. (c) Li, G.; Wan, L.;
Zhang, G.; Leow, D.; Spangler, J.; Yu, J.-Q. Pd(II)-Catalyzed C-H
Functionalizations Directed by Distal Weakly Coordinating Func-
tional Groups. J. Am. Chem. Soc. 2015, 137, 4391. (d) Zhang, B.;
Wang, H.-W.; Kang, Y.-S.; Zhang, P.; Xu, H.-J.; Lu, Y.; Sun, W.-Y.
Rhodium-Catalyzed Direct Ortho C−H Arylation Using Ketone as
Directing Group with Boron Reagent. Org. Lett. 2017, 19, 5940.
(e) Zhou, B.; Hu, Y.; Liu, T.; Wang, C. Aromatic C-H Addition of
Ketones to Imines Enabled by Manganese Catalysis. Nat. Commun.
2017, 8, 1169. (f) Hu, Y.; Zhou, B.; Chen, H.; Wang, C. Manganese-
Catalyzed Redox-Neutral C−H Olefination of Ketones with
Unactivated Alkenes. Angew. Chem., Int. Ed. 2018, 57, 12071.
(g) Tan, E.; Quinonero, O.; Elena de Orbe, M.; Echavarren, A. M.
Broad-Scope Rh-Catalyzed Inverse-Sonogashira Reaction Directed by
Weakly Coordinating Groups. ACS Catal. 2018, 8, 2166. (h) da Silva
(6) (a) Beck, E. M.; Grimster, N. P.; Hatley, R.; Gaunt, M. J. Mild
Aerobic Oxidative Palladium (II) Catalyzed C−H Bond Functional-
ization: Regioselective and Switchable C−H Alkenylation and
Annulation of Pyrroles. J. Am. Chem. Soc. 2006, 128, 2528.
(b) Kim, J.; Park, S.-W.; Baik, M.-H.; Chang, S. Complete Switch
of Selectivity in the C−H Alkenylation and Hydroarylation Catalyzed
by Iridium: The Role of Directing Groups. J. Am. Chem. Soc. 2015,
́
Junior, E. N.; Jardim, G. A. M.; Gomes, R. S.; Liang, Y.-F.;
Ackermann, L. Weakly-Coordinating N-Oxide and Carbonyl Groups
for Metal-Catalyzed C−H Activation: The Case of A-Ring
Functionalization. Chem. Commun. 2018, 54, 7398. (i) Jia, B.; Yang,
Y.; Jin, X.; Mao, G.; Wang, C. Rhenium-Catalyzed Phthalide Synthesis
from Benzamides and Aldehydes via C−H Bond Activation. Org. Lett.
2019, 21, 6259.
́
́
137, 13448. (c) Lu, Q.; Vasquez-Cespedes, S.; Gensch, T.; Glorius, F.
Control over Organometallic Intermediate Enables Cp*Co(III)
E
https://dx.doi.org/10.1021/acs.orglett.9b04612
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
(10) For selected reviews, see: (a) Schipper, D. J.; Hutchinson, M.;
Fagnou, K. Rhodium(III)-Catalyzed Intermolecular Hydroarylation of
Alkynes. J. Am. Chem. Soc. 2010, 132, 6910. (b) Colby, D. A.; Tsai, A.
S.; Bergman, R. G.; Ellman, J. A. Rhodium Catalyzed Chelation-
Assisted C−H Bond Functionalization Reactions. Acc. Chem. Res.
̈
2012, 45, 814. (c) Kuhl, N.; Schroder, N.; Glorius, F. Formal SN-Type
Reactions in Rhodium(III)-Catalyzed C-H Bond Activation. Adv.
Synth. Catal. 2014, 356, 1443. (d) Gensch, T.; Hopkinson, M. N.;
Glorius, F.; Wencel-Delord, J. Mild Metal-Catalyzed C−H Activation:
Examples and Concepts. Chem. Soc. Rev. 2016, 45, 2900. (e) Rej, S.;
Chatani, N. Rhodium-Catalyzed C(sp2)- or C(sp3)−H Bond
Functionalization Assisted by Removable Directing Groups. Angew.
Chem., Int. Ed. 2019, 58, 8304.
(11) (a) Lotz, M. D.; Camasso, N. M.; Canty, A. J.; Sanford, M. S.
Role of Silver Salts in Palladium-Catalyzed Arene and Heteroarene
C−H Functionalization Reactions. Organometallics 2017, 36, 165.
(b) Bay, K. L.; Yang, Y.-F.; Houk, K. N. Multiple Roles of Silver Salts
in Palladium-Catalyzed C−H Activations. J. Organomet. Chem. 2018,
864, 19.
́
́
(12) (a) Uma, R.; Davies, M.; Crevisy, C.; Gree, R. Efficient
Isomerization of Allylic Alcohols to Saturated Carbonyl Compounds
by Activated Rhodium and Ruthenium Complexes. Eur. J. Org. Chem.
2001, 2001, 3141. (b) Patureau, F. W.; Glorius, F. Rh Catalyzed
Olefination and Vinylation of Unactivated Acetanilides. J. Am. Chem.
Soc. 2010, 132, 9982. (c) Simmons, E. M.; Hartwig, J. F. On The
Interpretation of Deuterium Kinetic Isotope Effects in C-H Bond
Functionalizations by Transition-Metal Complexes. Angew. Chem., Int.
Ed. 2012, 51, 3066. (d) Boerth, J. A.; Ellman, J. A. Rh(III)-Catalyzed
Diastereoselective C−H Bond Addition/Cyclization Cascade of
Enone Tethered Aldehydes. Chem. Sci. 2016, 7, 1474. (e) Liu, T.-
L.; Ng, T. W.; Zhao, Y. Rhodium-Catalyzed Enantioselective
Isomerization of Secondary Allylic Alcohols. J. Am. Chem. Soc.
2017, 139, 3643. (f) Kumar, G. S.; Chand, T.; Singh, D.; Kapur, M.
Ruthenium-Catalyzed C−H Functionalization of Benzoic Acids with
Allyl Alcohols: A Controlled Reactivity Switch between C−H
Alkenylation and C−H Alkylation Pathways. Org. Lett. 2018, 20,
4934. (g) Jambu, S.; Sivasakthikumaran, R.; Jeganmohan, M. Aerobic
Oxidative Alkenylation of Weak O-Coordinating Arylacetamides with
Alkenes via a Rh(III)-Catalyzed C−H Activation. Org. Lett. 2019, 21,
1320.
F
https://dx.doi.org/10.1021/acs.orglett.9b04612
Org. Lett. XXXX, XXX, XXX−XXX