Constructions of tetrahydro-γ-carboline skeletons via intramolecular oxidative carbon-carbon bond formation of enamines

Article abstract of DOI:10.1039/c3ob00039g

The synthetically and biologically important 4-methyl and 4-methoxy tetrahydro-γ-carboline compounds were readily synthesized in high yields from an aryl amine and a 5-amino-3-oxopentanoate derivative through a series of reactions of enamination, oxidative annulation, deprotection/lactamization and the final reduction reaction of the carbonyl group. The underpinning strategy involves the oxidative C(sp²)-C(sp²) bond formation realized by either Pd(OAc)₂/Cu(OAc)₂ or a hypervalent iodine reagent.

Full text of DOI:10.1039/c3ob00039g

Organic &
Biomolecular Chemistry
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Constructions of tetrahydro-γ-carboline skeletons
via intramolecular oxidative carbon–carbon bond
Cite this: Org. Biomol. Chem., 2013, 11,
1929
formation of enamines†
Received 9th January 2013,
Accepted 3rd February 2013
Jinglei Lv, Ji Li, Daisy Zhang-Negrerie, Siyun Shang, Qingzhi Gao, Yunfei Du* and
Kang Zhao*
DOI: 10.1039/c3ob00039g
www.rsc.org/obc
The synthetically and biologically important 4-methyl and 4-
methoxy tetrahydro-γ-carboline compounds were readily syn-
thesized in high yields from an aryl amine and a 5-amino-3-oxo-
pentanoate derivative through
a
series of reactions of
enamination, oxidative annulation, deprotection/lactamization
and the final reduction reaction of the carbonyl group. The under-
pinning strategy involves the oxidative C(sp2)–C(sp2) bond for-
mation realized by either Pd(OAc)2/Cu(OAc)2 or a hypervalent
iodine reagent.
The tetrahydro-γ-carboline framework (A) occupies an increas-
ingly important position in organic synthesis because of its
frequent presence in many novel pharmaceutical agents as
well as natural products. Numerous designed medical agents,
especially those with specific effects on human cardiovascular
and nervous systems, e.g., dimebon (I),1 second-generation
histone deacetylase 6 inhibitors (II),2 pyridoindole benzo-
diazepine antipsychotic agents (III),3 potential c-met inhibitors
(IV),4 antagonists of the 5-HT6 and H1 receptors (V),5 novel
NO-mimetic neuroprotective and procognitive agents (VI),6 all
contain the tetrahydro-γ-carboline skeleton in their chemical
structures. Furthermore, some natural products, such as hors-
filine (VII), can also be synthesized starting from tetrahydro-
γ-carboline compounds by known methods (Fig. 1).7
Fig. 1 Pharmaceutical agents containing the tetrahydro-γ-carboline skeleton
or natural products that can be synthesized from tetrahydro-γ-carboline
compounds.
A literature survey indicates that there are only a few strat-
egies so far developed for the construction of the tetrahydro-
γ-carboline skeleton, among which the most commonly used
approach involves the reactions between a substituted phenyl-
hydrazine derivative and a 4-piperidinone derivative, a method
known as the Fischer indole synthesis (Fig. 2, path a).8
Besides, the skeleton can also be assembled via a conden-
sation reaction between an isotryptamine and an aldehyde
followed by a subsequent iso-Pictet–Spengler reaction (Fig. 2,
Fig. 2 Existing approaches for the construction of the tetrahydro-γ-carboline
skeleton.
Tianjin Key Laboratory for Modern Drug Delivery and High-Efficiency, School of
Pharmaceutical Science and Technology, Tianjin University, Tianjin, 300072,
P. R. China. E-mail: duyunfeier@tju.edu.cn, kangzhao@tju.edu.cn;
Fax: +86-22-27404031; Tel: +86-22-27404031
†Electronic supplementary information (ESI) available: NMR data. See DOI:
10.1039/c3ob00039g
path b).9 A third method is through the treatment of substi-
tuted 2-fluorophenyl imines with LDA possibly through a
benzyne intermediate (Fig. 2, path c), as reported by
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Scheme 1 Retrosynthetic analysis.
Scheme 3 Synthesis of tetrahydro-γ-carbolines from aryl amines and 5-amino-
3-oxopentanoate 5. aReagents and conditions: (a) 5, CH3CO2H, 95% (7a), 94%
(7b); (b) Method A: Pd(OAc)2 (10%), Cu(OAc)2, K2CO3, DMF, 80 °C, 89% (8a),
90% (8b); Method B: PhI(OAc)2, DCE, 60 °C, 52% (8a), 50% (8b); (c) (1) TFA,
DCM; (2) NaHCO3, H2O; (3) NaOH, MeOH, reflux, 92% (9a), 95% (9b); (d)
LiAlH4, THF, reflux, 85% (10a), 88% (10b).
aqueous hydroxide solution.15 Intermediate 4 then undergoes
a condensation reaction, according to the method described
by Challenger,16 with potassium monomethyl malonate salt in
the presence of CDI and magnesium chloride, to afford β-keto
ester 5 in 92% yield. Consisting of simple reaction steps of
Scheme 2 Preparation of intermediate 5. aReagents and conditions: (a)
MeNH2, EtOH, −10 °C, 86%; (b) (Boc)2O, TEA, CH2Cl2, 94%; (c) (1) NaOH, EtOH–
H2O; (2) HCl (1 M); 95%; (d) CDI, MgCl2, KOCOCH2CO2Et, MeCN, 92%.
Kudzma.10 However, with this method, the ortho-fluoro substi- extremely high yields, the above synthetic procedures afford
tuent in the imine substrates is essential for the cyclization to the key β-keto ester compound 5 in an overall 71% yield, and
occur. In this communication, we report a new strategy for the can be applied to the preparation of this class of compounds
construction of the tetrahydro-γ-carboline framework from the as a straightforward and efficient approach.
readily available arylamine and 5-amino-3-oxopentanoate
With the key intermediate 5 prepared, the construction of
derivatives.
the tetrahydro-γ-carboline skeleton was tested by using the syn-
Our synthetic strategy of the target tetrahydro-γ-carboline thetic protocol shown in Scheme 3. Two particular substituted
(A) was designed based on the retrosynthetic analysis shown in anilines, namely 6a and 6b, were chosen as the arylamine
Scheme 1. We envisaged that the tetrahydro-γ-carboline skele- since the corresponding tetrahydro-γ-carboline compounds
ton could be obtained by the reduction of the carbonyl group have been widely used for the synthesis of important pharma-
in lactam B, which was expected to be easily prepared from the ceutical agents1–3 and natural products.7 As a first step,
indole intermediate C through deprotection and the sub- solvent-free acid-catalyzed enamination of 5-amino-3-oxopen-
sequent lactamization. The construction of the key indole skele- tanoate 5 with the N-aryl-enamine (6a or 6b) gave the enamine
ton of C was foreseen to be realized through C(sp2)–C(sp2) intermediates 7, a mixture of trans and cis isomers, in excellent
bond formation in the enamine D by either the palladium- yields (95% for 7a and 94% for 7b).11a,b,12,17 Then the oxidative
catalyzed oxidative annulation,11 such as the method devel- annulation of N-aryl-enamine compound 7 was attempted by
oped by Glorius,11a,b or the hypervalent iodine reagent- two established methods, with the first one being the appli-
mediated direct oxidative carbon–carbon bond formation, cation of Glorius’s method11a,b for indole synthesis through
developed in our laboratory.12 The synthesis of the enamine palladium(II)-catalyzed oxidative cyclization of N-aryl enam-
intermediate D was expected from the reaction of arylamine ines. This method proved to be an ideal approach since the
E and an N-protected 5-amino-3-oxopentanoate F through a desired indole intermediates 8a and 8b were obtained in 89%
condensation reaction.
and 90% yields, respectively. We also applied our own tran-
Scheme 2 shows the synthesis of compound 5, a specific sition metal-free approach, i.e., the hypervalent iodine reagent
example of intermediate F where the protecting group is tert- as the oxidant, to test the feasibility of this transformation.
butoxy carbonyl (Boc). Although a new compound, compound The desired indole products 8a and 8b were found to be
5 can be prepared from the readily available starting materials achieved in 52% and 50% yields, respectively.18
through a series of well-known reactions. The synthesis starts
Removal of the Boc protective group in 8, prior to the intra-
with an aza-Michael addition13 of methylamine to methyl acry- molecular lactamization reaction (step c), was realized by
late at low temperature, affording N-methyl-β-alanine ester 2 in using TFA with the subsequent neutralization with aqueous
86% yield. Treatment of intermediate 2 with Boc2O in the pres- NaHCO3. After unsuccessful attempts to obtain the desired
ence of TEA14 conveniently furnishes the N-Boc protected lactam products of 9 by using the published procedures in pre-
N-methyl-β-alanine ester 3, which yields its corresponding car- vious literature,19,20 specifically, through treating
8
with
boxylic acid 4 in an excellent yield of 95% after hydrolysis in NaHCO3 in DCM at room temperature, we conducted a series
1930 | Org. Biomol. Chem., 2013, 11, 1929–1932
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In conclusion, we have demonstrated a new approach to
construct the synthetically and biologically important 4-methyl
and 4-methoxy tetrahydro-γ-carboline compounds from the
readily available 5-amino-3-oxopentanoate derivatives and sub-
stituted anilines. The most crucial step is the oxidative annula-
tion, which can be realized by either Pd-catalyzed or PhI(OAc)2-
mediated C–C bond oxidative formation, with the former
method furnishing the cyclized product in better yields. It can
be envisaged that by starting off with different arylamines, this
method provides convenient access to a variety of tetrahydro-
γ-carboline derivatives containing different substituents on the
phenyl ring.
Scheme 4 An alternative synthetic protocol. aReagents and conditions: (a) 2,
DCC, CH2Cl2, rt, 91%; (b) EtONa, EtOH, 80 °C, 84%; (c) 5% HCl (aq.), 80 °C, 58%;
(d) 6a, AcOH, rt 92%; (e) Method A: Pd(OAc)2 (10%), Cu(OAc)2, K2CO3, DMF,
80 °C, 66%; Method B: PhI(OAc)2, DCE, −20 °C to −60 °C, 0%.
of screening tests of the various conditions/parameters includ-
ing the types of bases, the reaction temperature and the
Acknowledgements
solvent. To our delight, we found that the use of sodium Y. Du acknowledges the National Natural Science Foundation
hydroxide in methanol at reflux temperature could furnish the of China (#21072148) and the Cultivation Foundation (B) for
desired lactam 9a or 9b in 92% or 95% yields, respectively. Young Faculty of Tianjin University (TJU-YFF-08B68) for finan-
Finally, lactams 9a and 9b underwent smooth carbonyl cial support.
reduction by using LiAlH4 in THF to give the target compound,
tetrahydro-γ-carboline 10a and 10b, respectively, in satisfactory
yield.21
Notes and references
We also tested an alternative synthetic protocol in which
the lactamization occurs before the formation of the indole
ring (Scheme 4). The enamination of 14 with arylamine 6a
afforded the enamine intermediate 15 in 92% yield,17 and the
oxidative C(sp2)–C(sp2) bond formation in 15 was again
realized by using Glorius’s method, but with a lower yield of 66%
in comparison to the case of intermediate 7.11a,b However, this
method suffers a significant disadvantage as the crucial inter-
mediate, 1-methylpiperidine-2,4-dione (14), is not readily avail-
able and its preparation by the known methods22 proved to be
less efficient with an overall yield of only 38% starting from
methylamine and methyl acrylate. Furthermore, the oxidative
annulation of 15 was also tested by our own transition metal-
free approach,12 but afforded an inseparable complex mixture
even at lower temperature.
Both methods of the transition metal and the hypervalent
iodine reagent can convert various N-aryl enamine substrates
into their corresponding indole products through oxidative
C–C bond formation, with the requirement that the N-aryl
enamine compound bear one or more electron-withdrawing
groups such as cyano, ester or acyl groups, as their presence is
essential for keeping the enamine configuration of the sub-
strates. However, the hypervalent iodine reagent was also
found to be applicable to the synthesis of 3-nitroindole from
the N-aryl β-nitroenamine compound. On comparing the two
methods, the transition metal method offers the advantage of
tolerating a variety of substituents on the aromatic ring of the
N-aryl enamine reactant, including nitro, cyano, amide,
hydroxyl and trifluoromethyl groups. Furthermore, the oxi-
dative annulation of cyclic N-aryl enamines was found to be
achieved exclusively by the former method while our metal-
free approach proved to be ineffective for this class of cyclic
substrates.23
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