Synthesis of 4,5,6,7-tetrahydro-1H-indole derivatives through successive sonogashira coupling/Pd-mediated 5-endo-dig cyclization

Article abstract of DOI:10.1002/ejoc.201201417

A one-pot Sonogashira cross-coupling/5-endo-dig cyclization procedure leading to 2-aryl-4,5,6,7-tetrahydroindoles was developed. This short (only two steps from commercially available compounds) sequence avoids harsh conditions and expensive catalysts. Our procedure is highly tolerant to a range of functional groups (amino, nitro, carboxy, cyano, hydroxy, and bromo). A family of 21 tetrahydroindoles was synthesized on a gram scale in a good to excellent yields, which is indicative of the general character and scalability of this reaction. This methodology allows access to indoles bearing miscellaneous substituents at the C2 position (by variation of ArI) and at the nitrogen atom (by variation of RNH₂, including chiral moieties). A one-pot sequence based on Sonogashira cross-coupling/Pd-mediated 5-endo-dig cyclization was developed and applied to the gram-scale synthesis of 2-aryl-4,5,6,7- tetrahydroindoles (21 examples). Copyright

Full text of DOI:10.1002/ejoc.201201417

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201201417
Synthesis of 4,5,6,7-Tetrahydro-1H-indole Derivatives Through Successive
Sonogashira Coupling/Pd-Mediated 5-endo-dig Cyclization
Ivan A. Andreev,[a] Dmitry S. Belov,[a] Alexander V. Kurkin,*[a] and Marina A. Yurovskaya[a]
Keywords: Nitrogen heterocycles / Cross-coupling / Amino propargylic alcohols / Cyclization / Palladium
A one-pot Sonogashira cross-coupling/5-endo-dig cycliza- thesized on a gram scale in a good to excellent yields, which
tion procedure leading to 2-aryl-4,5,6,7-tetrahydroindoles
was developed. This short (only two steps from commercially
available compounds) sequence avoids harsh conditions and
expensive catalysts. Our procedure is highly tolerant to a
range of functional groups (amino, nitro, carboxy, cyano, hy-
droxy, and bromo). A family of 21 tetrahydroindoles was syn-
is indicative of the general character and scalability of this
reaction. This methodology allows access to indoles bearing
miscellaneous substituents at the C2 position (by variation of
ArI) and at the nitrogen atom (by variation of RNH2, includ-
ing chiral moieties).
secoagroclavine, and chuangxinmycin, as well as synthetic
drugs[6c] pindolol) and highly functionalized indoles.[7]
The great majority of procedures employed in construc-
Introduction
Recent studies on the chemistry of indole derivatives have
focused on the development of efficient and convenient tion of both N-substituted and N-unsubstituted tetra-
methods for the synthesis of natural products and their ana- hydroindoles are based on metal-catalyzed cyclization stra-
logues possessing potent biological and physiological activi- tegies.[8] Synthetic research in the field of metal-catalyzed 5-
ties.[1] One of the urgent directions in this field is the cre- endo-dig cyclizations[9] has recently increased, and amino
ation of new pathways leading to substances possessing the propargylic alcohols are often utilized as the key starting
4,5,6,7-tetrahydro-1H-indole scaffold. This structural motif material. Pyrrole- and furan-derived compounds have been
is present in two members of the Stemona alkaloid family.[2] obtained by Hg, Au, Ag, Zn, Cu, and Pd catalysis.[10]
Moreover, tetrahydroindole derivatives display a wide spec-
Recently, we developed an enantioselective method for
trum of biological activities: anti-implantation, hypoglyce- the synthesis of 4,5,6,7-tetrahydro-2-phenyl-1H-indole de-
mic, anti-inflammatory, and analgesic;[3] potent neuro- rivatives bearing a chiral substituent at the nitrogen
leptic[4] (e.g., molindone); and antitumor.[5] Tetrahydroind- atom.[11] It is based on the nucleophilic opening of the ep-
oles are also valuable intermediates in the synthesis of nat- oxide moiety of 1-phenylethynyl-7-oxabicyclo[4.1.0]heptane
ural alkaloids[6] such as goniomitine, arcyriacyanin A, 6,7- (1a) with chiral amines and/or amino acid esters, followed
Scheme 1. Initial attempts towards 2-aryl-4,5,6,7-tetrahydroindoles.
[a] Department of Chemistry, Lomonosov Moscow State
University,
by intramolecular Pd-catalyzed cyclization, which was pre-
1/3 Leninsky Gory, Moscow, 119991, Russia
viously disclosed by Utimoto et al.[10f] According to this
procedure, we obtained N-benzyl-2-phenyl-4,5,6,7-tetra-
hydro-1H-indole (3a) in 63% yield through Pd(OAc)2-cata-
lyzed cyclization (Scheme 1).
Fax: +7-495-939-2288
E-mail: kurkin@direction.chem.msu.ru
Homepage: www.chem.msu.ru
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201201417.
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I. A. Andreev, D. S. Belov, A. V. Kurkin, M. A. Yurovskaya
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Table 1. Synthesis of 2-aryl-4,5,6,7-tetrahydroindoles 3.[a]
[a] Reaction conditions: Method A: (1) ArI, Pd(dba)2 (5 mol-%), CuI (10 mol-%), Ph3P (10 mol-%), Et2NH, 25 °C, 10 h, N2 (atm), one
pot. (2) Reflux, 8 h. Method B: (1) ArI, Pd(dba)2 (5 mol-%), CuI (10 mol-%), Ph3P (10 mol-%), pyrrolidine, 25 °C, 10 h, N2 (atm), isolation
of intermediate amino propargylic alcohol. Method C: Pd(OAc)2 (1 mol-%), MeCN, reflux, 1–2 h, N2 (atm). [b] The starting amino
propargylic alcohol employed in the cyclization by using method B was 2a or 2aЈ. [c] Yield in parentheses is given for analytically
pure sample. [d] Vacuum distillation of excessive aryl iodide was required. [e] Tetrahydroindole 3n was isolated in a mixture with 3b.
[f] Tetrahydroindole 3aЈ was formed by method C without isolation of the intermediate amino propargylic alcohol.
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Eur. J. Org. Chem. 2013, 649–652

Synthesis of 4,5,6,7-Tetrahydro-1H-indole Derivatives
We have suggested that this procedure could be applied of an efficient purification approach for 3d is most likely
to the synthesis of N-alkyltetrahydroindoles 3. The trans- associated with the chemical properties of the aryl iodide
stereoselective and highly regioselective nucleophilic open- and the generated tetrahydroindole bearing a free carboxyl
ing[12] of epoxide 1a with different amines (including op- moiety.
tically pure derivatives) with subsequent cyclization allows
In the vast majority of the cross-couplings, steric factors
variation of the substituent at the nitrogen atom of the pyr- compared to electronic factors have a greater influence on
role ring. However, a significant disadvantage of this the final results (Table 1, entries 8–13). In the case of 3k,
method is that derivatization at the C2 position of the re- the yield is comparable to para-substituted 2-aryltetrahyd-
sultant tetrahydroindole requires a multistep synthesis of roindoles and can be attributed to specific coordination be-
alkynyl oxiranes 1, which generally have poor stability.
tween the palladium catalyst and the corresponding aryl
iodide. Tetrahydroindole 3i was obtained by method A with
a significant amount (20 mol-%) of chromatographically in-
separable admixture 3b. This fact provided an excellent op-
portunity to test the two-step approach (methods B + C).
Results and Discussion
Therefore, we decided to alter the aryl function by mod- Thus, 3i was acquired in 49% yield from 2b. The synthesis
ifying the C–H bond of commercially available alkynyl oxir- of tetrahydroindole 3n is the most striking example of the
ane 1b. Sonogashira coupling[13] (a ubiquitous method for relationship between the reaction outcome and steric fac-
2
creating of Csp–Csp bonds) of epoxide 1b or derived ter- tors. Thus, we were only able to obtain 3n in a 1:2 ratio
minal amino propargylic alcohols with the corresponding with 3b.
aryl iodide followed by Pd-mediated 5-endo-dig cyclization
were envisioned as the key transformations. However, at- ology, we modified the substituent at the nitrogen atom of
tempted Sonogashira coupling of 1b was unsuccessful.[14]
the propargylic amino alcohol (Scheme 2). 2-Phenyl-substi-
To improve the synthetic scope of the proposed method-
Thus, we decided to employ the Sonogashira coupling of tuted tetrahydroindoles 3aЈ, 3o, and 3p were synthesized un-
amino propargylic alcohols with aryl iodides and to find der typical conditions (method A, Table 1, entries 14–16).
the optimal reaction conditions in terms of the cross-cou- Allyl and benzyl groups were tolerated under the reaction
pling of 2b with iodobenzene. Pd(dba)2 was chosen as a conditions, which allowed the synthesis of a wide range of
stable form of palladium(0), Ph3P (2 equiv. with respect to substrates. However, the yield of tetrahydroindole 3p was
Pd) as a ligand, and diethylamine as a mild base. Given that low, and the proposed conditions are not suitable for the
the Sonogashira coupling and 5-endo-dig cyclization are synthesis of NH compounds.
both Pd-catalyzed, we attempted to conduct a one-pot pro-
cedure. To put our assumption into practice, after comple-
tion of the Sonogashira coupling, the reaction mixture was
heated at reflux. To our great relief, this one-pot methodol-
ogy furnished 3a in a 78% yield after flash chromatography.
Irregular results were observed for Sonogashira coupling by
Scheme 2. Synthesis of amino propargylic alcohols 2f–h. Reaction
conditions: [a] 4-Fluoroaniline, LiClO4, MeCN, 70 °C, 24 h.
employing pyrrolidine instead of Et2NH. Thus, arylated
amino propargylic alcohol 2a was obtained as a major
product in 90% yield under analogous conditions. However,
heating the reaction mixture at reflux afforded incomplete
conversion of 2a into 3a, and pyrrolidine possibly inhibited
the cyclization step.
Considering the above-mentioned model experiments
and the enhanced methodology based on tandem Sonoga-
shira coupling followed by Pd-mediated 5-endo-dig cycliza-
tion, we proposed three distinct approaches (methods A, B,
and C) for the synthesis of 4,5,6,7-tetrahydroindole deriva-
tives. Representative examples of these approaches are visu-
alized in Table 1.
To evaluate the electronic/steric contributions to the reac-
tion outcome, we subjected aryl iodides of a miscellaneous
nature to the reaction with amino propargylic alcohol 2b as
a model substrate. In the case of para- and meta-substituted
aryl iodides, the yields of tetrahydroindoles 3a,c–h (Table 1,
entries 1–7) exceeded 70%, which indicates that electronic
effects have little impact on the reaction progress. It is well
[b] MeOH sat. with NH3, 60 °C, 10 h. [c] R*NH2, LiClO4, MeCN,
60 °C, 8–24 h; 2e and 2f were obtained as a 1:1 diastereomeric mix-
ture.
At the final stage of our investigation, we attempted to
synthesize tetrahydroindoles 3q–v (Table 1, entries 17–22)
possessing a chiral substituent at the nitrogen atom. Amino
propargylic alcohols 2e and 2f were obtained as a mixture
of diastereomers in a 1:1 molar ratio and subjected to the
cross-coupling/cyclization sequence without separation
(Scheme 2).
Despite this, further formation of tetrahydroindoles 3q–
v (method A) proceeded in high yields (Table 1). Racemiza-
tion was observed only for alanine-substituted tetrahydroin-
doles 3t–v, whereas (S)-(1-phenyl)ethylamine derivatives 3q–
s were obtained with Ͼ99%ee.[15]
Conclusions
Although the literature contains dozens of examples of
known that aryl iodides with electron-withdrawing groups one-pot Sonogashira couplings accompanied by further cy-
provide higher yields because of facilitated C–I bond inser- clization,[16] to the best of our knowledge, the above-de-
tion of Pd0; the yield of 3c is above average (93%). The lack scribed method is the first example of such cross-couplings
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I. A. Andreev, D. S. Belov, A. V. Kurkin, M. A. Yurovskaya
SHORT COMMUNICATION
followed by 5-endo-dig cyclization applied to the synthesis
of 4,5,6,7-tetrahydroindoles. Moreover, any of the 21 tetra-
hydroindoles could be obtained in gram-scale quantities,
which extends the synthetic value of our methodology. This
methodology allows access to indoles with diverse substitu-
ents not only at the C2 position but also at the nitrogen
atom, including chiral moieties. Studies towards retention
of the enantioselectivity of amino acid derivatives are cur-
rently underway.
[1] a) M. Hesse, Alkaloids, Nature’s Curse or Blessing?, Wiley-
VCH, Weinheim, Germany, 2002, p. 316; b) D. S. Seigler, Plant
Secondary Metabolism, Springer, Berlin, 2001, pp. 628–776.
[2] a) P. Wipf, S. R. Spencer, J. Am. Chem. Soc. 2005, 127, 225–
235; b) R. A. Pilli, G. B. Rosso, M. d. C. Ferreira de Oliveira,
Nat. Prod. Rep. 2010, 27, 1908–1937.
[3] a) K. Nagarajan, J. Chem. Sci. 2006, 118, 291–309; b) K. Naga-
rajan, P. K. Talwalker, R. K. Shah, S. R. Mehta, G. V. Nayak,
Ind. J. Chem. Sect. B: Org. Chem. Incl. Med. Chem. 1985, 24,
98–111.
[4] A. A. Rubin, H. C. Yen, M. Pfeffer, Nature 1967, 216, 578–579.
[5] R. Martínez, A. Clara-Sosa, M. T. Ramírez Apan, Bioorg.
Med. Chem. 2007, 15, 3912–3918.
[6] a) C. L. Morales, B. L. Pagenkopf, Org. Lett. 2008, 10, 157–
159; b) H. Ishibashi, S. Akamatsu, H. Iriyama, K. Hanaoka,
T. Tabata, M. Ikeda, Chem. Pharm. Bull. 1994, 42, 271–276;
c) H. Ishibashi, S. Akamatsu, H. Iriyama, K. Hanaoka, T. Tab-
ata, M. Ikeda, Chem. Pharm. Bull. 1994, 42, 271–276.
[7] a) N. Hatanaka, N. Watanabe, M. Matsumoto, Heterocycles
1986, 24, 3157–3162; b) W. A. Remers, R. H. Roth, G. J. Gibs,
M. J. Weiss, J. Org. Chem. 1971, 36, 1232–1240.
[8] a) A. Fürstner, H. Weintritt, A. Huppets, J. Org. Chem. 1995,
60, 6637–6641; b) D. J. Gorin, N. R. Davis, F. D. Toste, J. Am.
Chem. Soc. 2005, 127, 11260–11261.
[9] a) B. M. Trost, J.-P. Lumb, J. M. Azzarelli, J. Am. Chem. Soc.
2011, 133, 740–743; b) K. Stevens, A. Tyrrell, S. Skerratt, J.
Robertson, Org. Lett. 2011, 13, 5964–5967.
Experimental Section
General Procedure for the Synthesis of 4,5,6,7-Tetrahydro-1H-ind-
oles (Method A): Amino propargylic alcohol 2a–f (1.00 g, 1 equiv.),
the aryl iodide (1 equiv.), and triphenylphosphane (0.1 equiv.) were
placed in a 50 mL oven-dried Schlenk flask equipped with a mag-
netic stirring bar and a condenser. The reaction vessel was charged
with diethylamine (20 equiv.), and after complete dissolution of the
starting material, a strong flow of nitrogen was introduced for a
period of 2–3 min. The pressure of the inert gas was decreased and
Pd(dba)2 (0.05 equiv.) and CuI (0.1 equiv.) were added. The reac-
tion mixture was stirred under a slow stream of nitrogen at ambient
temperature overnight (10 to 20 h) and then heated at reflux for 8–
12 h (TLC control was possible with the general use of petroleum
ether/EtOAc, 3:1). The reaction mixture was cooled to ambient
temperature and poured into a saturated solution of NH4Cl
(50 mL). The resulting mixture was extracted with CH2Cl2 (3–4 ϫ
50 mL). The combined organic extracts were dried with anhydrous
Na2SO4 and concentrated under reduced pressure. The resulting
crude mixture was subjected to flash chromatography (petroleum
ether/EtOAc, 100:1 to 50:1) to obtain an analytically pure com-
pound.
[10] a) D. W. Knight, C. M. Sharland, Synlett 2004, 119–121; b) A.
Aponick, C.-Y. Li, J. Malinge, E. F. Marques, Org. Lett. 2009,
11, 4624–4627; c) J. H. Kim, S. B. Lee, W. K. Lee, D.-H. Yoon,
H.-J. Ha, Tetrahedron 2011, 67, 3553–3558; d) Y. Yin, W. Ma,
Z. Chai, G. Zhao, J. Org. Chem. 2007, 72, 5731–5736; e) B.
Gabriele, P. Plastina, M. V. Vetere, L. Veltri, R. Mancuso, G.
Salerno, Tetrahedron Lett. 2010, 51, 3565–3567; f) K. Utimoto,
H. Miwa, H. Nozaki, Tetrahedron Lett. 1981, 22, 4277–4278.
[11] I. A. Andreev, I. O. Ryzhkov, A. V. Kurkin, M. A. Yurovskaya,
Chem. Heterocycl. Compd. 2012, 48, 715–719.
[12] M. Chini, P. Crotti, F. Macchia, Tetrahedron Lett. 1990, 31,
4661–4664.
[13] K. Sonogashira, in: Comprehensive Organometallic Synthesis
(Eds.: B. M. Trost, I. Fleming), Pergamon Press, New York,
1991, vol. 3, pp. 521–549.
[14] For initial attempts on the preparation of 4,5,6,7-tetrahydro-
indoles 3, see the Supporting Information.
Supporting Information (see footnote on the first page of this arti-
cle): Experimental procedures, product characterization data, and
1
copies of the H NMR and 13C NMR spectra.
[15] The ee value for alanine ethyl ester exceeded 99% and was
measured on N-benzoyl derivatives. It remains unknown
whether racemization occurs during nucleophilic ring opening
or during the final Pd-catalyzed cyclization step.
Acknowledgments
[16] M. M. Heravi, S. Sadjadi, Tetrahedron 2009, 65, 7761–7775.
This study was supported by the Russian Foundation for Basic
Research (RFBR), Russia (grant number 11-03-00444a).
Received: October 24, 2012
Published Online: December 17, 2012
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