Synthesis of indolines via Pd(II)-catalyzed amination of C-H bonds using PhI(OAc)2 as the bystanding oxidant

Article abstract of DOI:10.1021/ol401246u

The Pd(II)-catalyzed intramolecular C-H amination of 2-pyridinesulfonyl- protected phenethylamine derivatives has been achieved using PhI(OAc) ₂ as a bystanding oxidant, providing access to a variety of substituted indoline derivatives in good yields. The use of the 2-pyridinesulfonyl protecting group allows for facile deprotection following C-H functionalization.

Full text of DOI:10.1021/ol401246u

ORGANIC
LETTERS
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Vol. XX, No. XX
000–000
Synthesis of Indolines via Pd(II)-Catalyzed
Amination of CꢀH Bonds Using PhI(OAc)2
as the Bystanding Oxidant
Tian-Sheng Mei, Dasheng Leow, Han Xiao, Brian N. Laforteza, and Jin-Quan Yu*
Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines
Road, La Jolla, California 92037, United States
yu200@Scripps.edu
Received May 3, 2013
ABSTRACT
The Pd(II)-catalyzed intramolecular CꢀH amination of 2-pyridinesulfonyl-protected phenethylamine derivatives has been achieved using
PhI(OAc)2 as a bystanding oxidant, providing access to a variety of substituted indoline derivatives in good yields. The use of the 2-pyridinesulfonyl
protecting group allows for facile deprotection following CꢀH functionalization.
Because of their prevalence in agrochemicals, pharma-
ceuticals, and other biologically active molecular scaffolds,
the design of novel protocols to efficiently synthesize
heterocycles remains a major area of focus in synthetic
organic chemistry.1 Over the past few years, transition-
metal-catalyzed CꢀH activation/Cꢀheteroatom bond-
forming reactions have received substantial attention
because of their ability to construct these motifs in an
extremely rapid manner.2 In particular, palladium-cata-
lyzed CꢀH aminations have emerged as powerful tools for
the synthesis of a number of unique heterocycles.3 For
example, in 2005, Buchwald and co-workers disclosed an
early report detailing the expedient synthesis of carbazoles
via the tandem directed CꢀH activation/amide arylation
of 2-acetaminobiphenyl derivatives.4 Moreover, in 2007,
Inamoto and Hiroya developed a protocol for the forma-
tion of indazole rings from conjugated hydrazones via
Pd-catalyzed CꢀH amination.5 Since these seminal pub-
lications, the direct Pd-catalyzed intramolecularamination
of arenes has proven to be an attractive approach toward
the generation of nitrogen-containing polycycles, and a
number of new methods have been introduced to affect
these transformations.6,7
Because of their synthetic value, we sought to develop
a CꢀH activation/amination protocol directed toward
the preparation of indolines from simple phenethylamine
derivatives. Synthesis of these types of heterocycles
through directed CꢀH functionalizations via six-membered
(1) For selected reviews of methods for constructing heterocycles
€
using traditional cross-coupling reactions, see: (a) Brase, S.; de Meijere,
A. In Metal-Catalyzed, Cross-Coupling Reactions; de Meijere, A.,
Diederich, F., Eds.; Wiley-VCH: Weinheim, Germany, 2004; p 272. (b)
Nakamura, I.; Yamamoto, Y. Chem. Rev. 2004, 104, 2127. (c) Cacchi, S.;
Fabrizi, G. Chem. Rev. 2005, 105, 2873. (d) Zeni, G.; Larock, R. C.
Chem. Rev. 2006, 106, 4644. (e) Nicolaou, K. C.; Bulger, P. G.; Sarlah, D.
Angew. Chem., Int. Ed. 2008, 47, 6338.
(2) For selected reviews, see: (a) Thansandote, P.; Lautens, M.
Chem.;Eur. J. 2009, 15, 5874. (b) Zhang, M. Adv. Synth. Catal. 2009,
351, 2243. (d) Stokes, B. J.; Driver, T. G. Eur. J. Org. Chem. 2011, 4071.
For selected reviews on synthetic application of CꢀH bond functiona-
lization, see: (e) Gutekunst, W. R.; Baran, P. S. Chem. Soc. Rev. 2011, 40,
1976. (f) Engle, K. M.; Yu, J.-Q. Transition MetalꢀCatalyzed CꢀH
Functionalization: Synthetically Enabling Reactions for Building Mole-
cular Complexity. In Organic Chemistry ꢀ Breakthroughs and Perspectives;
Ding, K.; Dai, L.-X., Eds.; Wiley-VCH: Weinheim, 2012.
(4) Tsang, W. C. P.; Zheng, N.; Buchwald, S. L. J. Am. Chem. Soc.
2005, 127, 14560.
(5) Inamoto, K.; Saito, T.; Katsuno, M.; Sakamoto, T.; Hiroya, K.
Org. Lett. 2007, 9, 2931.
(6) (a) Tsang, W. C. P.; Munday, R. H.; Brasche, G.; Zheng, N.;
Buchwald, S. L. J. Org. Chem. 2008, 73, 7603. (b) Jorden-Hore, J. A.;
Johansson, C. C. C.; Gulias, M.; Beck, E. M.; Gaunt, M. J. J. Am. Chem.
Soc. 2008, 130, 16184. (c) Inamoto, K.; Saito, T.; Hiroya, K.; Doi, T.
Synlett 2008, 20, 3157.
(7) (a) Wasa, M.; Yu, J.-Q. J. Am. Chem. Soc. 2008, 130, 14058.
(b) Miura, T.; Ito, Y.; Murakami, M. Chem. Lett. 2009, 38, 328.
(3) For selected reviews, see: (a) Song, J. J.; Reeves, J. T.; Fandrick,
D. R.; Tan, Z.; Yee, N. K.; Senanayake, C. H. Arkivoc 2010, 390.
(b) Beccalli, E. M.; Broggini, G.; Fasana, A.; Rigamonti, M. J. Orga-
nomet. Chem. 2011, 696, 277. (c) Taber, D. F.; Tirunahari, P. K.
Tetrahedron 2011, 67, 7195. (d) Mei, T.-S.; Kou, L.; Ma, S.; Engle,
K. M.; Yu, J.-Q. Synthesis 2012, 44, 1778.
r
10.1021/ol401246u
XXXX American Chemical Society

palladacycles have remained largely underdeveloped thus
far, with the notable exception being the synthesis of
carbazoles utilizing highly conjugated biphenyl systems.6
Recently, our laboratory has developed the cyclization of
N-protected arylethylamines to yield a variety substituted
indolines in good yield via a one-pot CꢀH iodination/
amination sequence, as well as the direct intramolecular
CꢀH amination of phenethylamines with the aide of single-
or two-electron bystanding oxidants.8ꢀ10 While these two
methods provide powerful means to synthesize a variety of
indolines in an extremely rapid manner, both of these
protocols require the use of a trifluoromethylsulfonyl-pro-
tected amine as the requisite directing group, which has
proven crucial to allow efficient CꢀH cleavage for amine-
directed CꢀH functionalization. Unfortunately, this neces-
sity potentially complicates further synthetic manipulations
due to the traditionally harsh conditions employed for
the deprotection of trifluoromethylsulfonamides, thus se-
verely limiting functional group tolerance.11 Additionally,
long reaction times and expensive reagents are typically
employed under these reaction conditions.
Table 1. Optimization of Reaction Conditions
a Yield determined by 1H NMR analysis of crude reaction mixture
using CH2Br2 as an internal standard. b Isolated yield in parentheses.
c N-Fluoro-2,4,6-trimethylpyridinium triflate used as oxidant.
variety of CꢀH functionalization reactions.12 In light
of recent developments using pyridine13 and pyridine-
containing auxiliaries14,15 as directing groups for CꢀH
functionalization, we envisioned that the 2-pyridylsulfonyl
protecting group could potentially address difficulties in its
subsequent removal while still maintaining high levels of
reactivity for the cyclization of phenethylamines.
We began our investigations by preparing several
N-protected phenethylamine derivatives and submitting
them to our previously developed intramolecular CꢀH
amination conditions (Table 1).9 We were delighted to
observe formation of the desired indoline in 20% yield
with use of the 2-pyridylsulfonyl protecting group and
Figure 1. New conditions for the synthesis of indolines via
Pd(II)-catalyzed CꢀH activation.
In an effort to address these challenges, we investigated
the use of alternative protecting groups that would not
only allow efficient CꢀH activation, but also be easily
removed under relatively mild conditions (Figure 1). Re-
cently, Carretero and co-workers introduced the use of the
2-pyridylsulfonyl moeity as a capable directing group for a
ꢀ
(12) (a) Garcıa-Rubia, A.; Arrayas, R. G.; Carretero, J. C. Angew.
Chem., Int. Ed. 2009, 48, 6511. (b) Garcıa-Rubia, A.; Urones, B.;
ꢀ
Arrayas, R. G.; Carretero, J. C. Angew. Chem., Int. Ed. 2011, 50,
ꢀ
10927. (c) Garcıa-Rubia, A.; Fernandez-Ibanez, M. A.; Arrayas,
ꢀ
ꢀ~
ꢀ
(8) (a) Li, J.-J.; Mei, T.-S.; Yu, J.-Q. Angew. Chem., Int. Ed. 2008, 47,
6452. (b) Mei, T.-S.; Wang, X.; Yu, J.-Q. J. Am. Chem. Soc. 2009, 131,
10806. (c) Vickers, C. J.; Mei, T.-S.; Yu, J.-Q. Org. Lett. 2010, 12, 2511.
(9) Indolines have also recently been prepared via an alternative
C(sp3)ꢀH activation/amination protocol using anilines as starting
R. G.; Carretero, J. C. Chem.ꢀEur. J. 2011, 17, 3567. (d) Rodrıguez,
ꢀ
N.; Romero-Revilla, J. A.; Fernandez-Ibanez, M. A.; Carretero, J. C.
ꢀ
ꢀ~
Chem. Sci. 2013, 4, 175.
(13) Lyons, T. W.; Sanford, M. S. Chem. Rev. 2010, 110, 1147.
(14) Daugulis, O.; Zaitsev, V. G.; Shabashov, D.; Daugulis, O. J. Am.
Chem. Soc. 2005, 127, 13154.
(15) (a) Haffemayer, B.; Gulias, M.; Gaunt, M. J. Chem. Sci. 2011, 2,
312. (b) He, G.; Zhao, Y.; Zhang, S.; Lu, C.; Chen, G. J. Am. Chem. Soc.
2012, 134, 3. (c) Nadres, E. T.; Daugulis, O. J. Am. Chem. Soc. 2012, 134,
7. (d) He, G.; Lu, C.; Zhao, Y.; Nack, W. A..; Chen, G. Org. Lett. 2012,
14, 2944.
€
materials: Neumann, J. L.; Rakshit, S.; Droge, T.; Glorius, F. Angew.
Chem., Int. Ed. 2009, 48, 6892.
(10) For a review on bystanding oxidants, see: Engle, K. M.; Mei,
T.-S.; Wang, X.; Yu, J.-Q. Angew. Chem., Int. Ed. 2011, 50, 1478.
(11) Hendrickson, J. B.; Bergeron, R. Tetrahedron Lett. 1973, 14,
3839.
B
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Scheme 1. Pd-Catalyzed CꢀH Activation/Amination Scope
Scheme 2. Removal of 2-Pyridylsulfonyl Protecting Group
Scheme 3. Plausible Catalytic Cycle
N-fluoro-2,4,6-trimethylpyridinium triflate (Fþ) as the
oxidant (entry 3); however, attempts to modify the pyr-
idine ring proved detrimental and resulted in a significant
drop in reactivity (entries 1 and 2). Gratifyingly, by sub-
stituting Fþ with PhI(OAc)2 as the requisite oxidant,
we were able to discern a noticeable increase in reaction
efficiency (34% yield, entry 4). Interestingly, use of PhI-
(OAc)2 as the oxidant resulted in exclusive formation of
the cyclized product. This lies in stark contrast to when
the trifluorosulfonyl protecting group is employed, which
results in acetoxylation of the aromatic ring under other-
wise similar conditions.8c,16 Although the origin of this
phenomenon is still currently being investigated, these
observations highlight the importance of controlling the
selectivity of multiple competitive reductive elimination
pathways from Pd(IV) centers.17 Choice of reaction med-
ium had the most significant impact on cyclization, with
aromatic solvents proving to be most efficient for the
desired transformation (entries 5ꢀ7, 54ꢀ88% yield). It
should be noted that when either the quinolyl or 2-methyl-
pyridyl directing group is utilized under these optimal
conditions, <50% desired product is observed.
prepared in good yield through this CꢀH functionaliza-
tion protocol. Both electron-donating (2bꢀe) and elec-
tron-withdrawing (2fꢀl) groups are tolerated at a variety
of positions on the aromatic ring. Substrates incorporating
Br and Cl at the ortho- and meta-positions allowed access
to indolines well suited for future synthetic manipulations
(in particular, metal-catalyzed cross-coupling reactions).18
Moreover, substitution on the alkyl tether provided 2- and
3-substituted cyclized products in good yield (2mꢀo),
highlighting the versatility of this CꢀH activation protocol.
It is worth noting that the reaction described above typi-
cally reached completion within 4 h, which is a substantial
improvement over previous protocols, which required up
to 72 h to achieve satisfactory yields.9b
As mentioned previously, a major concern regarding
N-protected directed CꢀH activation reactions is removal
of the protecting group following successful functionali-
zation. To demonstrate the advantages of utilizing the
2-pyridylsulfonyl directing group, we sought to deprotect
phenylalanine-derived indoline 2o, which contain both
a readily reduced ester moeity and an easily racemizable
R-stereocenter. To our delight, by treating the cyclized
product with excess magnesium in methanol at 0 °C,19 we
were able to isolate the free indoline in 86% yield with no
Having thus identified optimal conditions for the intra-
molecular amination of phenethylamine, we next exam-
ined the scope of the cyclization reaction. As illustrated in
Scheme 1, a variety of substituted indolines are readily
(16) No acetoxylation from Pd(OAc)2 is observed when N-fluoro-
2,4,6-trimethylpyridinium triflate is utilized as the oxidant (Table 1,
entry 3).
(17) Racowski, J. M.; Sanford, M. S. Top. Organomet. Chem. 2011,
35, 61.
(18) (a) Littke, A. F.; Dai, C.; Fu, G. C. J. Am. Chem. Soc. 2000, 122,
4020. (b) Hama, T.; Culkin, D. A.; Hartwig, J. F. J. Am. Chem. Soc.
2006, 128, 4976.
(19) Pak, C. S.; Lim, D. S. Synth. Commun. 2001, 31, 2209.
Org. Lett., Vol. XX, No. XX, XXXX
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observed racemization of the sensitive stereocenter
(Scheme 2).
its facile removal postcyclization under relatively mild
conditions.
A plausible mechanism for this Pd-catalyzed intra-
molecular amination protocol is depicted in Scheme 3.
Coordination of Pd by the amine and pyridine functional
units allows selective o-CꢀH cleavage resulting in an
organopalladium(II) complex. At this stage, oxidation by
PhI(OAc)2 provides an intermediate Pd(IV) species, which
could then undergo selective CꢀN reductive elimination
to forge the new carbonꢀheteroatom bond, thus yielding
the desired indoline and regenerating the active palladium
catalyst.
In summary, we have developed a new protocol for
the synthesis of indolines via a palladium-catalyzed CꢀH
activation/cyclization sequence utilizing the 2-pyridylsul-
fonyl directing group and PhI(OAc)2 as a bystanding
oxidant. Use of this novel amine protecting group allows
Acknowledgment. We gratefully acknowledge The
Scripps Research Institute and the U.S. National Science
Foundation (NSF CHE-1011898) for financial support,
the Camille and Henry Dreyfus Foundation for a New
Faculty Award and A. P. Sloan Foundation for a Fellowship
(J.-Q. Y.). We thank China Scholarship Council for Ous-
tanding Self-Financed Students Abroad Award (T.-S. Mei).
Supporting Information Available. Experimental proce-
dure and characterization of all new compounds (PDF). This
material is available free of charge via the Internet at http://
pubs.acs.org
The authors declare no competing financial interest.
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Org. Lett., Vol. XX, No. XX, XXXX