Improved protocol for indoline synthesis via palladium-catalyzed intramolecular C(sp2)-H amination

Article abstract of DOI:10.1021/ol301352v

An efficient method has been developed for the synthesis of indoline compounds from picolinamide (PA)-protected β-arylethylamine substrates via palladium-catalyzed intramolecular amination of ortho-C(sp²)-H bonds. These reactions feature high efficiency, low catalyst loadings, mild operating conditions, and the use of inexpensive reagents.

Full text of DOI:10.1021/ol301352v

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Improved Protocol for Indoline Synthesis
via Palladium-Catalyzed Intramolecular
C(sp2)ꢀH Amination
Gang He, Chengxi Lu, Yingsheng Zhao, William A. Nack, and Gong Chen*
Department of Chemistry, The Pennsylvania State University, University Park,
Pennsylvania 16802, United States
guc11@psu.edu
Received May 16, 2012
ABSTRACT
An efficient method has been developed for the synthesis of indoline compounds from picolinamide (PA)-protected β-arylethylamine substrates
via palladium-catalyzed intramolecular amination of ortho-C(sp2)ꢀH bonds. These reactions feature high efficiency, low catalyst loadings, mild
operating conditions, and the use of inexpensive reagents.
Indolines are found in many natural products and
pharmaceuticals, and the chemical synthesis of indolines
has attracted the attention of generations of organic
chemists.1 For example, intramolecular CꢀN cross-cou-
pling reactions have been successfully applied for the
indoline synthesis.2 More recently, considerable effort
has been invested in obviating the prefunctionalization
step, required for indoline synthesis by conventional
coupling strategies, through direct functionalization of
CꢀH bonds of arenes or alkyl chains.3 A number of
indoline synthesis protocols based on CꢀH functionaliza-
tion strategies have emerged over the past few years.4,5
Despite conceptual innovation, the synthetic utility of
these CꢀH functionalization methods remains under-
developed, limiting application in organic synthesis.
Practical CꢀH functionalization protocols are still in
great demand.6 Herein, we report our latest develop-
ment on the palladium-catalyzed picolinamide-directed
(1) Selected examples of indoline synthesis: (a) Boger, D. L.;
Coleman, R. S. J. Org. Chem. 1984, 49, 2240–2245. (b) Overman,
L. E.; Wild, H. Tetrahedron Lett. 1989, 30, 647–650. (c) Uchiyama,
M.; Kameda, M.; Mishima, O.; Yokoyama, N.; Koike, M.; Kondo, Y.;
Sakamoto, T. J. Am. Chem. Soc. 1998, 120, 4934–4946. (d) Nicolaou,
K. C.; Roecker, A. J.; Pfefferkorn, J. A.; Cao, G.-Q. J. Am. Chem. Soc.
2000, 122, 2966–2967. (e) Bailey, W. F.; Mealy, M. J. J. Am. Chem. Soc.
2000, 122, 6787–6788. (f) Padwa, A.; Brodney, M. A.; Dimitroff, M.;
Liu, B.; Wu, T. J. Org. Chem. 2001, 66, 3119–3128. (g) Viswanathan, R.;
Prabhakaran, E. N.; Plotkin, M. A.; Johnston, J. N. J. Am. Chem. Soc.
2003, 125, 163–168. (h) Yamada, K.; Kurokawa, T.; Tokuyama, H.;
Fukuyama, T. J. Am. Chem. Soc. 2003, 125, 6630–6631. (i) Danheiser,
R. L.; Dunetz, J. R. J. Am. Chem. Soc. 2005, 127, 5776–5777. (j) Correa,
(3) For an excellent review on N-heterocycle synthesis via CꢀH
functionalization, see: Thansandote, P.; Lautens, M. Chem.;Eur. J.
2009, 15, 5874–5883.
(4) Selected examples of indoline synthesis via Pd-catalyzed
C(sp3)ꢀH functionalization: (a) Watanabe, T.; Oishi, S.; Fujii, N.;
Ohno, H. Org. Lett. 2008, 10, 1759–1762. (b) Nakanishi, M.; Katayev,
€
D.; Besnard, C.; Kundig, E. P. Angew. Chem., Int. Ed. 2011, 50, 7438–
7441. (c) Saget, T.; Lemouzy, S. J.; Cramer, N. Angew. Chem., Int. Ed.
2012, 51, 2238–2242. With C(sp2)ꢀH functionalization: (d) Houlden,
ꢀ
C. E.; Bailey, C. D.; Ford, J. G.; Gagne, M. R.; Lloyd-Jones, G. C.;
A.; Tellitu, I.; Domı
´
nguez, E.; SanMartin, R. J. Org. Chem. 2006, 71,
Booker-Milburn, K. I. J. Am. Chem. Soc. 2008, 130, 10066–10067.
(5) Selected examples of Pd-catalyzed intramolecular aminations of
C(sp2)ꢀH bonds to synthesize indoles, oxindoles, carbozoles: (a) Tsang,
W. C. P.; Zheng, N.; Buchwald, S. L. J. Am. Chem. Soc. 2005, 127,
14560–14561. (b) Inamoto, K.; Saito, T.; Katsuno, M.; Sakamoto, T.;
Hiroya, K. Org. Lett. 2007, 9, 2931–2934. (c) Wasa, M.; Yu, J.-Q. J. Am.
Chem. Soc. 2008, 130, 14058–14059. (d) Jordan-Hore, J. A.; Johansson,
C. C. C.; Gulias, M.; Beck, E. M.; Gaunt, M. J. J. Am. Chem. Soc. 2008,
130, 16184–16186. (e) Tan, Y.; Hartwig, J. F. J. Am. Chem. Soc. 2010,
132, 3676–3677. (f) Hwan, S.; Yoon, J.; Chang, S. J. Am. Chem. Soc.
2011, 133, 5996–6005.
8316–8319. (k) Boal, B. W.; Schammel, A. W.; Garg, N. K. Org. Lett.
2009, 11, 3458–3461.
(2) Selected examples of indoline synthesis via metal-catalyzed cross-
coupling reactions: (a) Guram, A. S.; Rennels, R. A.; Buchwald, S. L.
Angew. Chem., Int. Ed. Engl. 1995, 34, 1348–1350. (b) Klapars, A.;
Huang, X.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 7421–7428.
(c) Yamada, K.; Kubo, T.; Tokuyama, H.; Fukuyama, T. Synlett 2002,
231–234. (d) Omar-Amrani, R.; Thomas, A.; Brenner, E.; Schneider, R.;
Fort, Y. Org. Lett. 2003, 5, 2311–2314. (e) Minatti, A.; Buchwald, S. L.
Org. Lett. 2008, 10, 2721–2724.
r
10.1021/ol301352v
XXXX American Chemical Society

intramolecular CꢀH amination reaction for the synthesis
of indolines.
Table 1. Indoline Synthesis via Pd-Catalyzed Intramolecular
Amination of C(sp2)ꢀH Bonds
The picolinamide (PA) group, first introduced by the
Daugulis laboratory in 2005,7 has demonstrated excellent
directing abilities for a number of CꢀH functionalization
reactions.8 Recently, our laboratory8d as well as that of
Daugulis9 independently reported that picolinamide sub-
strates can undergo intramolecular amination reactions at
the δ-CꢀH position to afford five-membered pyrrolidine
and indoline products under the catalysis of Pd(OAc)2. An
illustrative example is the cyclization of the β-phenylethy-
lamine substrate 1 at the δ-C(sp2)ꢀH bond to form the
indoline product 2 (Table 1). PhI(OAc)2 was found to be
the best oxidant for the reaction (entries 1ꢀ10).
yield (%)a
Pd(OAc)2
additives (equiv) /
atmosphere
In comparison with the Daugulis protocol9 and Yu’s
pioneering triflamide-mediated reaction system,10 the
cyclization of 1 to form 2 proceeds under notably mild
operating conditions and in good yield. Encouraged by
the promising synthetic utility of this indoline synthesis
method, we carried out a new round of study. Further
work on this reaction system led us to several notable
conclusions and optimizations.
entry (mol %)
T (°C)
2
3
1
2
5
AgOAc (2), air
100 <2
100 <2
100 <2
100 <2
100 <2
100 <2
<2
<2
<2
<2
<2
<2
<2
<2
8
5
Cu(OAc)2 (2), air
Ce(SO4)2 (2), air
K2S2O8 (2), air
3
5
4
5
5
5
oxone (2), air
6
5
F(þ)b, air
7
5
BQ (2), air
100
7
8
5
PhI(OCOCF3)2 (2), air
PhI(OPiv)2 (2), air
PhI(OAc)2 (2), air
PhI(OAc)2 (2), air
PhI(OAc)2 (2), air
PhI(OAc)2 (2), O2 (1 atm)
PhI(OAc)2 (2), Ar
100 <2
100 78
100 80
While the PA-directed intramolecular amination of
δ-C(sp3)ꢀH bonds requires a reaction temperature of
110 °C, we found that amination of δ-C(sp2)ꢀH bonds
could be performed at a considerably lowered reaction
temperature. Cyclization of substrate 1 proceeds smoothly
at 60 °C in toluene using 5 mol % of Pd(OAc)2 catalyst
under air to afford 2 in >80% yield; this yield is slightly
improved when compared with the same reaction per-
formed at 100 °C (entries 10 and 11). Compound 3 was
isolated as the major side product, presumably resulting
from cyclization of acetoxylated byproduct 4. While high
reaction temperature accelerates the reaction rate, it also
promotes undesired side reactions such as the competing
acetoxylation pathway and results in generally diminished
chemoselectivity. The cyclization reaction also proceeds at
room temperature at a slower rate; a comparable yield of 2
was obtained with 10 mol % of Pd(OAc)2 and extended
reaction time (6 days, Ar, entry 23).
9
5
10
11
12
13
14
15
16
17
18
19
20
21
22
23
5
10
7
5
60
60
60
60
85
64
37
90 (88c) 6
2
6
2
<2
2
2
PhI(OAc)2 (2) þ AcOH (2), air 60
PhI(OAc)2 (2) þ PivOH (2), air 60
PhI(OAc)2 (2) þ TFA (2), air 60
PhI(OAc)2 (2) þ AdOH (2), air 60
70
75
<2
79
<2
9
2
9
2
<2
6
2
2
PhI(OAc)2 (2) þ Py (2), air
PhI(OAc)2 (2), Ar
60
60
80
80
rt
<2
1
84 (2 d) 8
82 (80c) 16
0.5
0.1
10
PhI(OAc)2 (2), Ar
PhI(OAc)2 (2), Ar
47
10
PhI(OAc)2 (2), Ar
85 (6 d) 5
a All screening reactions were carried out in a 20 mL glass vial with a
PTFE-lined cap on a 0.4 mmol scale; yields are based on 1H NMR
analysis of the reaction mixture. b 1-Fluoro-2,4,6-trimethylpyridinium
triflate. c Isolated yield on a 1.0 mmol scale.
We observed that O2 has a pronounced inhibitory effect
on the cyclization reaction, particularly with lower catalyst
loading or at lower reaction temperatures (e.g., 2 mol % of
Pd(OAc)2, 60 °C, entries 12 and 13). This contrasts with
our previously reported PA-directed C(sp2)ꢀH alkylation
reaction with alkyl halides, where O2 demonstrated a
promoting effect.8c,11 The reaction proceeds most effi-
ciently under an argon atmosphere and without the use
of any additives (entry 14). Under an air atmosphere,
addition of carboxylic acid additives such as PivOH and
AdOH restores the desired reactivity to a useful level of
75ꢀ80% (entries 16 and 18).
(6) Selected reviews on practical CꢀH functionalization methods:
€
(a) Wencel-Delord, J.; Droge, T.; Liu, F.; Glorius, F. Chem. Soc. Rev.
2011, 40, 4740–4761. (b) McMurray, L.; O’Hara, F.; Gaunt, M. J. Chem.
Soc. Rev. 2011, 40, 1885–1898. (c) Chen, X.; Engle, K. M.; Wang, D.-H.;
Yu, J.-Q. Angew. Chem., Int. Ed. 2009, 48, 5094–5115.
(7) Zaitsev, V. G.; Shabashov, D.; Daugulis, O. J. Am. Chem. Soc.
2005, 127, 13154–13155.
(8) (a) Feng, Y.; Chen, G. Angew. Chem., Int. Ed. 2010, 49, 958–961.
(b) He, G.; Chen, G. Angew. Chem., Int. Ed. 2011, 50, 5192–5196.
(c) Zhao, Y.; Chen, G. Org. Lett. 2011, 13, 4850–4853. (d) He, G.; Zhao, Y.;
Zhang, S.; Lu, C.; Chen, G. J. Am. Chem. Soc. 2012, 134, 3–6. (e) Zhang,
S. Y.; He, G.; Zhao, Y.; Wright, K.; Nack, W. A.; Chen, G. J. Am. Chem.
Soc. 2012, 134, 7313–7316. (f) Zhao, Y.; He, G.;Nack, W. A.; Chen, G. Org.
Lett. 2012, DOI: 10.1021/ol301214u. (g) Gou, F. R.; Wang, X. C.; Huo, P. F.; Bi,
H. P.; Guan, Z. H.; Liang, Y. M. Org. Lett. 2009, 11, 5726.
In comparison with many of the known CꢀH functio-
nalization protocols, low catalyst loading was required for
this cyclization reaction to proceed. Excellent results were
obtained with 2 mol % of Pd(OAc)2 at 60 °C for 24 h
(general condition A, entry 14) or with 0.5 mol % of
Pd(OAc)2 at 80 °C for 24 h (general condition B, entry
21). We reason that, unlike the secondary amide starting
(11) One possible explanation for this observed inhibition involves
O2 reversibly binding the PdII palladacycle intermediate. Such an
interaction would presumably hamper the subsequent PdII/IV oxidation
by PhI(OAc)2. More detailed studies will be published in the future.
(9) Nadres, E. T.; Daugulis, O. J. Am. Chem. Soc. 2012, 134, 7–9.
(10) Mei, T.-S.; Wang, X.; Yu, J.-Q. J. Am. Chem. Soc. 2009, 131,
10806.
B
Org. Lett., Vol. XX, No. XX, XXXX

observe that OTf, halogen groups including Br and even
ortho-I12 groups of arenes were preserved under these
reaction conditions (7ꢀ9 and 18). This unique blend of
reactivity and functional group compatibility may be due
to suppressed formation of undesired Pd0 species under the
optimized reaction conditions with low catalyst loading
and relatively low reaction temperature. Finally, R- and
β-substituted arylethylamine substrates could provide
densely functionalized indoline products in variably di-
minished yield (15ꢀ18).13
Table 2. Substrate Scope of β-Arylethylamine Substratesa
The PA group used in this indoline synthesis can be
considered a protecting group as it can be readily removed
under mild conditions from the cyclized product. For
example, treatment of compound 2 with 1.5 equiv of
NaOH in MeOH/THF/H2O at 50 °C gave indoline 19 in
excellent yield (Scheme 1). PA-protected indoline 2 was
also readily oxidized by DDQ to form the indole product
20 in high yield. The cyclization and oxidation steps can be
carried out sequentially in one pot. The PA group of the
resulting indole 20 was easily removed under mildly basic
conditions to give free indole 21.
Scheme 1. Further Transformations
a Yields based on isolated products on a 1.0 mmol scale. Acetoxy-
lated product yields are shown in parentheses. b The remaining mass
balance consisted mainly of starting material.
material, the tertiary amide product has little affinity for
the catalytic PdII species, lessening competition for the
catalytic pathway. We also noted the reaction mixture
remained a transparent yellow solution during the course
of the reaction; Pd black precipitate was rarely observed.
A range of β-arylethylamine substrates were then cy-
clized under the newly optimized conditions (Table 2). In
general, electron-deficient substrates (5, 6, 8, and 10) were
cyclized in excellent yield along with small amounts
(<10%) of undesired acetoxylated products. The reac-
tions of substrates bearing electron-donating functional
groups like OBn (11) and OMe (12) were found to be
slightly less selective. In particular, we noted that sub-
strates bearing electron-donating groups para to the tar-
geted CꢀH bond (e.g., 13) gave considerably diminished
yield of cyclized product, with increased amounts of
acetoxylated side products. This acetoxylation side reac-
tion is much less prominent with electron-deficient sub-
trates (e.g., 5 and 6)
The PA-directed intramolecular C(sp2)ꢀH amination
reaction likely proceeds through a PdII/IV catalytic cycle by
a sequence of CꢀH palladation, PdII/IV oxidation, and
CꢀN reductive elimination (Scheme 2A).14,15 However,
our efforts to obtain a palladacycle intermediate have been
unsuccessful. The ortho-CꢀH bond of substrate 22 was
readily deuterated under the catalysis of Pd(OAc)2 by
AcOD, providing 23. A primary kinetic isotope effect
(∼3.1) was observed in the cyclization of 22 and 23 under
general condition A.
The synthetic utility of this CꢀH amination chemistry
was then explored in our effort toward the total synthe-
sis of the natural product betanin (32, Scheme 3).16
(13) Ring strain associated with the CꢀN reductive elimination from
the six-membered palladacycle intermediate to form the more densely
substituted five-membered indoline product might promote the produc-
tion of the less strained acyclic acetoxylated side products.
(14) For selected reviews on PdIV chemistry, see: (a) Canty, A. J. Acc.
Chem. Res. 1992, 25, 83–90. (b) Xu, L.; Li, B.; Yang, Z.; Shi, Z. Chem.
Soc. Rev. 2010, 39, 712–733. (c) Racowski, J.; Sanford, M. S. Top.
Organomet. Chem. 2011, 53, 61–84.
(15) For related mechanistic studies on Pd-catalyzed PhI(OAc)2-
mediated CꢀOAc forming reactions, see: (a) Racowski, J. M.; Dick,
A. R.; Sanford, M. S. J. Am. Chem. Soc. 2009, 131, 10974–10983.
(b) Gary, J. B.; Sanford, M. S. Organometallics 2011, 30, 6143–6149.
(16) Strack, D.; Vogt, T.; Schliemann, W. Phytochemistry 2003, 62,
247–269.
Excellent regioselectivity at the least sterically hindered
position was observed in substrates bearing two inequiva-
lent ortho-CꢀH bonds (18). Common functional groups
such as esters, acetyls, and TBS protecting groups were
tolerated (15ꢀ18). Furthermore, we were pleased to
(12) Excellent tolerance for iodo groups on arene substrates is rare in
related Pd-catalyzed CꢀH functionalization literature.
Org. Lett., Vol. XX, No. XX, XXXX
C

Scheme 2. Preliminary Mechanistic Studies
Scheme 3. Application of Our Effort toward the Synthesis of
Betanin
We envisioned that the indoline core of 30 could be
constructed via the PA-directed intramolecular CꢀH ami-
nation reaction in the late stages of synthesis. Dopamine
intermediate 25 can be readily prepared from free tyrosine
in good yield in three steps based on a known procedure.17
The Boc group of 25 was then replaced with PA group by
standard deprotection and amide coupling. Upon removal
of the OAc group, the phenol intermediate 26 was reacted
with Bn- and Ac-protected glucosyl bromo donor 27 under
a biphasic glycosylation conditions to give glucosylated
product 28 in good yield and excellent stereoselectivity.18
The CꢀN cyclization reaction provided the desired indo-
line core 29 in 59% yield under general reaction condition
A with extended time (2 mol % of Pd(OAc)2, 60 °C,
3 days).19 Global deprotection of the protecting groups
and final condensation with a suitable betalamic acid
partner 31 to furnish the target product is currently under
investigation.20
group for the indoline products and can be easily removed
under mildly basic conditions. Finally, the PA group of
the indoline product could potentially enable further
structural transformation via directed functionalization
of neighboring CꢀH bonds. Development along these
lines will be reported in due course.
In summary, we have developed a practical protocol for
the synthesis of indoline compounds from picolinamide-
protected β-arylethylamine substrates. This method fea-
tures high efficiency and functional group tolerance
and operates under mild and economical conditions. The
PA group serves as a well-behaved amine protecting
Acknowledgment. We gratefully acknowledge financial
support from The Pennsylvania State University, the
U.S. National Science Foundation (CHE-1055795), and
ACS-PFR (51705-DNI1).
(17) Chen, C.; Zhu, Y.-F.; Wilcoxen, K. J. Org. Chem. 2000, 65,
2574–2576.
(18) Zhu, C.; Peng, W.; Li, Y.; Han, X.; Biao, Y. Carbohydr. Res.
2006, 341, 1047–1051.
(19) An acetoxylated compound was isolated as the major side
product. The observed moderate cyclization yield was anticipated due
to the para-O substitutent of 28.
(20) A cloesly related condensation strategy has been successfully
demonstrated in Herrmann’s synthesis of betalaine using a deglycosy-
lated indoline substrate: Herrmann, K.; Dreiding, A. S. Helv. Chim. Acta
1975, 58, 1805–1808.
Supporting Information Available. Experimental pro-
cedures and spectroscopic data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX