Synthesis of indolines and tetrahydroisoquinolines from arylethylamines by PdII-catalyzed C-H activation reactions

Article abstract of DOI:10.1002/anie.200802187

(Chemical Equation Presented) Hand in hand: A versatile C-H activation route for the synthesis of indolines, tetrahydroquinolines, and tetrahydroisoquinolines from simple arylethylamines relies on a one-pot iodination and amination reaction (see scheme, Tf=trifluoromethanesulfonyl). The natural amino acids phenylalanine, tyrosine, and tryptophan can be converted into various heterocycles by using this technology.

Full text of DOI:10.1002/anie.200802187

Communications
DOI: 10.1002/anie.200802187
Heterocycle Synthesis
Synthesis of Indolines and Tetrahydroisoquinolines from
II
À
Arylethylamines by Pd -Catalyzed C H Activation Reactions**
Jiao-Jie Li, Tian-Sheng Mei, and Jin-Quan Yu*
Owing to the prevalence of heterocyclic compounds in
medicinal chemistry, the development of new transition-
metal-catalyzed reactions for the formation of heterocycles
continues to be an active area of research.[1,2] Construction of
an unsolved problem owing to sluggish reactions proceeding
via six- and seven-membered palladacycles.[7]
À
Herein we report a tandem C Hbond iodination/
amination route for the preparation of indolines using PdII/
CuI catalysts [Eq. (4)]. This reaction can also be modified to
À
À
such ring systems by means of C Hactivation followed by C
N bond formation is a complementary approach to the
remarkably powerful Buchwald–Hartwig amination reac-
tion.[3] For instance, Orito et al. developed a C Hactiva-
À
tion/carbonylation process for the preparation of benzolac-
tams [Eq. (1)].[4] Buchwald and co-workers reported a Pd-
prepare tetrahydroquinolines [Eq. (4)] and tetrahydroisoqui-
nolines by using different substrates and reaction conditions
[Eq. (5)].
catalyzed formation of a carbazole ring from acetylated 2-
phenylaniline [Eq. (2)].[5] Hiroya, Inamoto, and co-workers
developed a protocol for making indazole rings from hydra-
Prompted by our recently developed iodination reaction
II
À
for compounds with unactivated C Hbonds using a Pd
catalyst and IOAc as the stoichiometric oxidant,[8] we
À
À
envisioned that a tandem C Hbond-iodination/C N bond-
forming reaction using a combination of PdII and CuI catalysts
could lead to an effective protocol for heterocycle synthesis.
Thus, our first challenge was to develop an effective
zones [Eq. (3), Ts = toluenesulfonyl].[6] Despite these impor-
tant pioneering studies, a method for making indolines and
À
iodination reaction of C Hbonds using an amine as the
directing group, which can subsequently react directly with
À
the iodide to form the C N bond. The aforementioned amino
groups[4–6] and phenylsulfonamides[9] employed as directing
À
groups for C Hactivation reactions illustrate the feasibility
of the proposed approach. However, none of these directing
groups were effective for the type of substrates shown in
Equations (4) and (5) owing to the reduced reactivity of six-
and seven-membered palladacycles. We began to study a wide
tetrahydroisoquinolines from readily available phenylethyl-
À
amines and phenylpropylamines by C Hactivation remains
À
range of amino functionalities as directing groups to assist C
Hactivation. In order to form indolines, acetyl-, trifluoroa-
cetyl-, Boc-, and Troc-protected 2-phenylethylamines were
selected as substrates to develop a tandem iodination/
amination reaction (Scheme 1). Substrates 1–4 were sub-
jected to our previously developed iodination conditions.[8]
The results are consistent with the hypothesis that the acidity
[*] J.-J. Li, T.-S. Mei, J.-Q. Yu
Department of Chemistry
The Scripps Research Institute
La Jolla, CA 92037 (USA)
Fax: (+1)858-784-2409
E-mail: yu200@scripps.edu
J.-J. Li
À
of the NHmoiety is crucial in promoting the C Hactivation,
Department of Chemistry
Brandeis University
Waltham, MA 02454 (USA)
À
presumably owing to formation of Pd N bond while sufficient
electrophilicity of PdII center is maintained. We therefore
tested other phenylsulfonamide substrates. Notably, while
benzenesulfonyl-protected 2-phenylaniline[9] was previously
observed to undergo C Hactivation/Heck coupling,
significant improvement was observed with substrates 5–7.
[**] We wish to thank The Scripps Research Institute, Brandeis
University, and the U.S. National Science Foundation (NSF CHE-
0615716) for financial support and the A. P. Sloan Foundation for a
fellowship (J.-Q.Y.).
[10]
À
no
To further increase the acidity of the NHmoiety and
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200802187.
À
hence facilitate formation of the Pd N bond, the trifluoro-
6452
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2008, 47, 6452 –6455

Angewandte
Chemie
methylsulfonamide (triflamide, NHTf) deriv-
ative 8 of 2-para-tolylethylamine was prepared
to test the iodination reaction. We found that
the diiodinated product was obtained in syn-
thetically useful yields (59% yield of isolated
product) along with the monoiodinated prod-
À
Scheme 2. Catalytic cycle for tandemC H iodination/amination.
1
ucts (10–20% by HNMR analysis) (Table 1). Gratifyingly,
triflamides of the natural amino acids phenylalanine and
tyrosine are reactive under the same conditions (entries 3 and
4, Table 1). These products are valuable chiral building blocks
for heterocycle synthesis. Iodination of triflamide 12 through
a seven-membered cyclopalladation process also occurs,
albeit giving lower yield (entry 5, Table 1). The iodination
products are obtained in excellent yield with the mono-ortho-
substituted substrates (entries 6 and 7, Table 1).
Next, we sought to develop conditions conducive for
subsequent intramolecular amination. Since the iodination
proceeds through PdII/PdIV catalysis,[8] a subsequent Pd0-
catalyzed Buchwald–Hartwig intramolecular amination
would not be compatible. However, a CuI-catalyzed intra-
molecular amination[11] could, in principle, be accomplished
À
under the same conditions if the C Hactivation step is not
adversely affected by CuI salts (Scheme 2). Thus, the diiodi-
nated products were treated with CuI and Cs2CO3 in the same
solvent (DMF) as that used for the iodination reaction. The
intramolecular amination reaction is extremely effective
affording the indolines (entries 1–4, Table 2) and tetrahydro-
quinoline (entry 5, Table 2) in excellent yields.[12] The remain-
ing 5-iodo group in the products is a versatile functional group
for further transformation, especially through Pd-catalyzed
coupling reactions. Removal of the iodide can also be
achieved by stirring with Pd/C under hydrogen atomosphere.
À
Scheme 1. C H activation directed by acidic amides for the iodination
of substrates 1–7. Boc=tert-butyloxycarbonyl, Troc=2,2,2-trichloroe-
thoxycarbonyl.
Table 1: Pd(OAc)2-catalyzed iodination.[a]
Entry
Substrate
Product
Yield [%]
59
1
Table 2: CuI-catalyzed intramolecular amination.[a]
2
3
4
5
6
7
56
Entry
Substrate
Product
Yield [%]
96
1
68
2
3
4
95
52
92[b]
91[b]
31[b]
91
5
92
85
[a] Reaction conditions: 10 mol% Pd(OAc)2, 2 equiv C6H5I(OAc)2,
2 equiv I2, 1 equiv NaHCO3, DMF, 1308C, 72 h. [b] 15 mol% Pd(OAc)2.
[a] Reaction conditions: 0.5 equiv CuI, 1 equiv Cs2CO3, DMF, 1308C,
24 h. [b] 1 equiv CuI, 1 equiv NaHCO3, DMF, 1308C, 24 h.
Angew. Chem. Int. Ed. 2008, 47, 6452 –6455
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
6453

Communications
precursor for the preparation of 5-substituted analogues. The
triflamide group can be readily removed by Hendricksonꢀs
procedure (Scheme 4).[13] The obtained indolines can also be
oxidized to indoles by treating with MnO2 at 408C.[14]
À
We envisioned that the triflamide-directed C Hactiva-
tion could also be combined with a Heck coupling to give
precursors from which tetrahydroisoquinolines could be
prepared by an intramolecular metal-catalyzed addition of
the sulfonamide to the olefin using recently reported proce-
dures.[15] A wide range of substrates were subjected to
conditions similar to those of the iodination reactions. The
monoalkenylated products were obtained in 50–65% yield
along with dialkenylated products in 10–20% yield (Table 4).
À
Scheme 3. One-pot iodination–amination of C H bonds.
With the triflamide-directed iodination and amination
procedures in hand, we subjected substrate 8 to reaction
conditions for both of these transformations simultaneously.
The tandem iodination/amination reaction proceeded to give
a mixture of products 8b and 8c (Scheme 3). We reasoned
that formation of 8b from the diiodinated precursor could be
minimized by using more CuI to accelerate the amination
reaction of the monoiodinated precursor. Indeed, the use of
1 equiv of CuI significantly improved the selectivity in favor
of the formation of indolines from the monoiodinated
precursors (Table 3). Although the ester groups in substrates
10 and 11 are partially hydrolyzed in the presence of Cs2CO3,
the tolerance of halides, benzylic methoxyl and acid-labile
ketal groups (entries 3–5 and 7, Table 3) illustrates the
potential utility of this new route for the preparation of
indolines. Notably, the 5-chloroindoline 14b is a valuable
Scheme 4. Deprotection of trifluorosulfonamide.
Table 4: Pd(OAc)2-catalyzed alkenylation reactions.[a]
Entry Substrate
Olefin
Product
Yield
[%][b]
1
2
50
61[c]
Table 3: One-pot intramolecular amination catalyzed by Pd(OAc)2 and
CuI.[a]
3
4
65[c]
39
Entry
1
Substrate
Product
Yield [%]
59[b]
2
3
58[b]
50[b]
5
58[d]
4
5
6
7
49[b]
46[b]
81[c]
82[c]
6
7
87
51[e]
8
56[e]
[a] Reaction conditions: 10 mol% Pd(OAc)2, 2.5 equiv AgOAc, 4 equiv
olefin, 0.1 mL DMF, 2 mL dichloroethane, 1308C, 72 h. [b] Dialkenylated
products also formed in 10–20% yield. [c] 1 equiv NaH2PO4 was added to
decrease the formation of the dialkenylated products. [d] Reaction was
stopped after 85 h. [e] Reaction was stopped after 48 h.
[a] Reaction conditions: 10 mol% Pd(OAc)2, 2 equiv C6H5I(OAc)2,
2 equiv I2, 1 equiv Cs2CO3, 1 equiv CuI, DMF, 1308C, 96 h. [b] 5-
Iodoindolines were isolated in 7—10% yield . [c] 0.5 equiv CuI.
6454 www.angewandte.org
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2008, 47, 6452 –6455

Angewandte
Chemie
[2] For an early application of Pd0 mediated stoichiometric C N
À
Both electron-deficient and electron-rich olefins are reactive.
While the formation of dialkenylated products reduced the
efficiency of this reaction, the alkenylation of the ortho-
substituted substrate 13 afforded 13c in exceedingly high
yield (entry 6, Table 4).
bond formation in heterocycle synthesis see: D. L. Boger, J. S.
Panek, Tetrahedron Lett. 1984, 25, 3175.
[3] J. M. Janey, Name Reactions for Functional Group Transforma-
tions (Eds.: J. J. Li, E. J. Corey), Wiley, New York, 2007, pp. 564 –
609.
[4] K. Orito, A. Horibata, T. Nakamura, H. Ushito, H. Nagasaki, M.
Yuguchi, S. Yamashita, M. Tokuda, J. Am. Chem. Soc. 2004, 126,
14342.
[5] a) W. C. P. Tsang, N. Zheng, S. L. Buchwald, J. Am. Chem. Soc.
2005, 127, 14560; b) For related copper catalyzed C-Hactivation
reactions see: G. Brasche, S. L. Buchwald, Angew. Chem. 2008,
120, 1958; Angew. Chem. Int. Ed. 2008, 47, 1932, and references
therein.
À
Notably, a tandem C Halkenylation and aza-Michael
addition proceeds to give the desired tetrahydroisoquinolines
in high diastereoselectivity when vinyl ketones are used.
Among the strategies for constructing isoquinoline rings, the
Pictet–Spengler condensation and the Bischler–Napieralski
cyclization are most widely used.[16] However, both of these
methods often require two electron-donating groups on the
aryl rings. The results in Scheme 5 show that our cyclization
[6] K. Inamoto, T. Saito, M. Katsuno, T. Sakamoto, K. Hiroya, Org.
Lett. 2007, 9, 2931.
[7] a) For an intramolecular radical amidation onto aryl rings see:
H. Togo, Y. Hoshina, T. Muraki, H. Nakayama, M. Yokoyama, J.
À
Org. Chem. 1998, 63, 5193; b) For arylation of ortho-C Hbonds
in benzylamines see: A. Lazareva, O. Daugulis, Org. Lett. 2006,
À
8, 5211; c) For Pd-catalyzed allylic amination of C Hbonds see:
S. A. Reed, M. C. White, J. Am. Chem. Soc. 2008, 130, 3316.
[8] a) R. Giri, X. Chen, J.-Q. Yu, Angew. Chem. 2005, 117, 2150;
Angew. Chem. Int. Ed. 2005, 44, 2112; b) R. Giri, M. Wasa, S. P.
Breazzano, J.-Q. Yu, Org. Lett. 2006, 8, 5685; c) D.-H. Wang, X.-
S. Hao, D.-F. Wu, J.-Q. Yu, Org. Lett. 2006, 8, 3387.
[9] M. Miura, T. Tsuda, T. Satoh, S. Pivsa-Art, M. Nomura, J. Org.
Chem. 1998, 63, 5211.
Scheme 5. One-pot synthesis of tetrahydroisoquinoline.
[10] For examples of Pd-catalyzed C-Hactivation/Heck-coupling
reactions see: a) C. Jia, D. Piao, J. Oyamada, W. Lu, T. Kitamura,
Y. Fujiwara, Science 2000, 287, 1992; b) M. D. K. Boele, G. P. F.
van Strijdonck, A. H. M. de Vries, P. C. J. Kamer, J. G. de Vries,
P. W. N. M. Van Leevuwen, J. Am. Chem. Soc. 2002, 124, 1586;
c) E. M. Ferreira, B. M. Stoltz, J. Am. Chem. Soc. 2003, 125,
9578; d) M. Dams, D. E. De Vos, S. Celen, P. A. Jacobs, Angew.
Chem. 2003, 115, 3636; Angew. Chem. Int. Ed. 2003, 42, 3512;
e) V. G. Zaitsev, O. Daugulis, J. Am. Chem. Soc. 2005, 127, 4156;
f) N. P. Grimster, C. D. Godfrey, M. J. Gaunt, Angew. Chem.
2005, 117, 3185; Angew. Chem. Int. Ed. 2005, 44, 3125; g) E.
Capito, J. M. Brown, A. Recci, Chem. Commun. 2005, 1854;
h) G. Cai, Y. Fu, Y. Li, X. Wan, Z. Shi, J. Am. Chem. Soc. 2007,
129, 7666; i) J.-R. Wang, C.-T. Yang, L. Liu, Q.-X. Guo,
Tetrahedron Lett. 2007, 48, 5449.
[11] a) J.-F. Marcoux, S. Doyle, S. L. Buchwald, J. Am. Chem. Soc.
1997, 119, 10539; b) D. Ma, Y. Zhang, J. Yao, S. Wu, F. Tao, J.
Am. Chem. Soc. 1998, 120, 12459; c) A. Kiyomori, J.-F. Marcoux,
S. L. Buchwald, Tetrahedron Lett. 1999, 40, 2657; d) A. Klapars,
X. Huang, S. L. Buchwald, J. Am. Chem. Soc. 2002, 124, 7421.
[12] For Pd0-catalyzed intra-molecular amination using sulfonamides
and aryl bromides see: J. P. Wolfe, R. A. Rennels, S. L. Buch-
wald, Tetrahedron 1996, 52, 7525.
reaction does not require electron-donating groups on the
aryl rings. Trifluoromethylsulfonate at the para position does
not retard the reaction (entry 3, Table 4). As shown in the
tandem iodination and amination reaction, the electron-
withdrawing chloro group is also tolerated (entries 3, 7,
Table 3). In addition, various olefins are inexpensive reagents
for introducing diversified substitutions at C1.
À
In summary, we have developed a promising C H
activation route for the preparation of indolines and tetrahy-
droisoquinolines from arylethylamines. The natural amino
acids phenylalanine, tyrosine, and tryptophan can be con-
verted into various heterocycles using this method.[17] We are
currently exploiting this method to access medicinally rele-
vant heterocycle libraries.
Received: May 9, 2008
Published online: July 15, 2008
[13] J. B. Hendrickson, R. Bergeron, Tetrahedron Lett. 1973, 14, 3839.
[14] T. Chandra, S. Zhou, K. L. Brown, Tetrahedron Lett. 2004, 45,
7783.
[15] a) J. Zhang, C.-G. Yang, C. He, J. Am. Chem. Soc. 2006, 128,
1798; b) K. Komeyama, T. Morimoto, K. Takaki, Angew. Chem.
2006, 118, 3004; Angew. Chem. Int. Ed. 2006, 45, 2938; c) C. F.
Bender, R. A. Widenhoefer, Chem. Commun. 2006, 4143;
d) G. L. Hamilton, E. J. Kang, M. Mba, F. D. Toste, Science
2007, 317, 496; e) W. Zeng, S. R. Chemler, J. Am. Chem. Soc.
2007, 129, 12948.
[16] M. Chrzanowska, M. Rozwadowska, Chem. Rev. 2004, 104, 3341.
[17] For iodination of phenylalanine side chains of peptides using
IPy2BF4 see: G. Espuꢁa, G. Arsequell, G. Valencia, J. Barluenga,
J. M. Alvarez-Gutierrez, A. Ballesteros, J. M. Gonzalez, Angew.
Chem. 2004, 116, 329; Angew. Chem. Int. Ed. 2004, 43, 325.
À
Keywords: amination · C H activation · indolines ·
tetrahydroisoquinolines
.
[1] a) K. R. Roesch, R. C. Larock, J. Org. Chem. 1998, 63, 5306;
b) A. M. Kearney, C. D. Vanderwal, Angew. Chem. 2006, 118,
7967; Angew. Chem. Int. Ed. 2006, 45, 7803; c) L. Ackermann, A.
Althammer, Angew. Chem. 2007, 119, 1652; Angew. Chem. Int.
Ed. 2007, 46, 1627; d) I. V. Seregin, V. Ryabova, V. Gevorgyan, J.
Am. Chem. Soc. 2007, 129, 7742; e) S. Chuprakov, V. Gevogyan,
Org. Lett. 2007, 9, 4463; f) M. Nagamochi, Y.-Q. Fang, M.
Lautens, Org. Lett. 2007, 9, 2955; g) X.-Y. Liu, P. Ding, J.-S.
Huang, C.-M. Che, Org. Lett. 2007, 9, 2645; h) T. Pei, C.-Y. Chen,
P. G. Dormer, I. W. Davies, Angew. Chem. 2008, 120, 4299;
Angew. Chem. Int. Ed. 2008, 47, 4231.
Angew. Chem. Int. Ed. 2008, 47, 6452 –6455
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
6455