Pd/PTABS: Catalyst for Room Temperature Amination of Heteroarenes

Article abstract of DOI:10.1021/acs.orglett.7b03854

A mild and highly efficient catalytic amination procedure for chloroheteroarenes at ambient temperature using the Pd/PTABS catalytic system is reported. The protocol is selective for the amination of chloroheteroarenes using secondary amines such as piperidine, pyrrolidine, and several others. The exceptional mildness of the developed protocol is beneficial for the synthesis of a crucial Buparlisib intermediate as well as the formal synthesis of Alogliptin in competitive yields.

Full text of DOI:10.1021/acs.orglett.7b03854

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Pd/PTABS: Catalyst for Room Temperature Amination of
Heteroarenes
Siva Sankar Murthy Bandaru,‡ Shatrughn Bhilare,† Nicolas Chrysochos,‡ Vijay Gayakhe,† Ivan Trentin,‡
Carola Schulzke,‡ and Anant R. Kapdi*,†
†Department of Chemistry, Institute of Chemical Technology, Nathalal Road, Matunga, Mumbai 400019, India
‡Institut fur Biochemie, Ernst-Moritz-Arndt-Universitat Greifswald, Felix-Hausdorff-Str. 4, 17489 Greifswald, Germany
̈
̈
S
* Supporting Information
ABSTRACT: A mild and highly efficient catalytic amination procedure for
chloroheteroarenes at ambient temperature using the Pd/PTABS catalytic system is
reported. The protocol is selective for the amination of chloroheteroarenes using
secondary amines such as piperidine, pyrrolidine, and several others. The exceptional
mildness of the developed protocol is beneficial for the synthesis of a crucial Buparlisib
intermediate as well as the formal synthesis of Alogliptin in competitive yields.
eteroaromatic compounds with substituted amine func-
H
tionalities have found wide applicability as molecules of
biological and pharmaceutical relevance.1 Their regular occur-
rence as structural motifs in commercially available drugs (Figure
1), suchas Buparlisib (1, anticancer),2 ZSTK474 (2),3 Uptravi (3,
hypertension),4 and BuSpar (4, antidepressants),5 further
substantiates their case for developing respective efficient
synthetic methodologies.
Palladium-catalyzed Buchwald−Hartwig amination of halo-
(hetero)arenes6 is a successful synthetic strategy for the
installation of amine functionalities via efficient activation of
C−X bonds (X = I, Br, and Cl). Notably, the introduction of the
commercially available Buchwald ligand series has brought about
an accelerated development in this area of research owing to
Buchwald and his research group.7 Several other catalyst systems
have been reported in recent years allowing the catalytic
amination of bromo- or iodo(hetero)arenes to be carried out
efficiently, even at ambient temperature.8 Given the abundant
commercial availability and inexpensive nature of the heteroaryl
chlorides, however, the development of efficient catalytic
amination protocols addressing such substrates is desired.
The amination of chloro arenes has been described by several
research groups such as Beller (diadamantylphosphine ligand
system),9 Buchwald(seriesofactivephosphineligandsystems),10
Plenio,11 Reetz (phosphoramidite ligand),12 Organ (Pd-PEPPSI
complexes),13 and many others in combination with common
palladium precursors. Most of these protocols provided the
amination products in competitive yields, but at relatively high
temperatures of 80−130 °C, with use of strong bases and high
catalyst concentration, rendering them synthetically less
attractive. Only a few protocols are known from the research
groups of Buchwald,14 Hartwig,15 Stradiotto,16 and Nolan,17
which have allowed only chloroarenes to be aminated at ambient
temperature. Given the deficiency in finding efficient coupling
protocols for chloroheteroarenes, we report a highly efficient
Figure 1. Aminated heteroarene bearing commercial drugs.
synthetic protocol for the palladium-catalyzed amination of
chloroheteroarenes with secondary amines using the Pd(OAc)2/
PTABS system at ambient temperature. At the outset of this
study, the screening of catalytic systems was performed involving
different activating phosphine ligands in combination with
Pd(OAc)2 (Table 1). Uncatalyzed amination protocols are not
uncommon. A recent study by Moody and co-workers18 into the
transition-metal-free amination of heteroaryl chlorides prompted
us to test the involvement of the SNAr reaction under the
conditions envisaged for obtaining the coupling at ambient
temperature. In the presence of 2.0 equiv of pyrrolidine (acting as
both, starting material and base), without added metal precursor,
in DMF as solvent, and at ambient temperature (23 °C), the
reaction failed to furnish the target product.
This result rules out a SNAr-type amination taking place under
these conditions. Addition of Pd(OAc)2 promotes the formation
of the desired product but in poor yields (up to 20% only). Next,
the role of activating ligands in the catalytic amination reaction
Received: December 10, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b03854
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Letter
cross-coupled product (75%). Finally, the PTABS and PTAPS
ligand systems were employed, which were recently reported by
our group as efficient water-soluble ligands for the palladium-
catalyzed coupling of halo nucleosides, and the conditions were
optimized.19 BestresultswereobtainedwhenPTABS(2.0mol%)
was employed as ligand in combination with Pd(OAc)2 (1.0 mol
%) in DMF as solvent and pyrrolidine as reactant and base (entry
13, 79%). It was also found that the removal of Pd(OAc)2 resulted
in the complete absence of catalytic activity (entry 14). It was also
observed that reduction in concentration of the catalyst had a
deteriorating impact on the catalytic activity. The choice of not
incorporating an exogenous base was intriguing, but the potential
dependence of the catalytic protocol on the pKa of the added
amine might be detrimental in further stages of the investigation.
We decided to incorporate an exogenous base, and triethyl-
amine was found to provide the coupled product in very good
yield(entry20, 88%). Thisallowedustoreducetheamountofthe
secondary amine to 1.2 equiv in the presence of 1.5 equiv of Et3N
for reaching optimum catalytic efficiency. DMF was found to be
the solvent of choice with other solvents including water
providing lower yields. With an efficient optimized catalytic
protocol in hand, we envisaged being able to couple a wide variety
of heteroaryl chlorides with secondary amines at ambient
temperature. 2-Chloropyrazine was initially coupled with three
different cyclicsecondary amines, namely, pyrrolidine, piperidine,
and morpholine (Scheme 1, 7a−7c). Although, a slightly lower
yield of the coupled product was obtained for morpholine, overall
the yields were very good. Similarly in the case of 2-
chloroquinoxaline, all three heterocyclic bases gave excellent
yields of the aminated product, which was also the case with N-
Boc protected piperazine (7d−7g). Notably, an acyclic amine
such as diethylamine also could be coupled in good yields (7h).
The initial success with simple heteroaryl chlorides gave
incentive to test the amination protocol for more challenging and
Table 1. Screening for Room Temperature Amination of
Chloroheteroarenes
a
a
Reaction conditions: 1.0 mmol of 5a, 1.0 mol % of Pd(OAC)2, 3 mL
of solvent, H2O/ACN (1:1), stirring at room temperature for 4 h.
b
c
Isolated yields. Without added Pd(OAc)2 and ligand. Without added
d
e
f
ligand. Without added Pd(OAc)2. 0.5 mol % of Pd(OAc)2. 0.1 mol
% of Pd(OAc)2.
was assessed. The addition of triphenylphosphine brought about
only a slight improvement in the catalytic activity, while strongly
activating SPhos or XPhos ligands provided good yields of the
amination product. Addition of electron-rich and sterically
demanding tBu3P, tBu3P·HBF4, and (Ad)2BuP (the Beller ligand)
was found to provide satisfactory yields, while the commercially
available PEPPSI-Ipr catalyst provided the highest yield of the
Scheme 1. Scope for Amination of Chloro(heteroarenes)
B
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Letter
synthetically useful substrates. 6-Chloropurine, for example, is an
important starting material for obtaining functionalized purine
nucleosides with a variety of synthetic and biological
applications.20 Catalytic amination of 6-chloropurine was
performed with the different amines with good yields obtained
except for diethylamine (showing slightly reduced activity as
more hydro-dehalogenation was observed; entries 7i−7m).
Bioactive pyrrolo[1,2-a]pyrazines21 are important structural
motifs exhibiting a wide variety of antifungal, antitumor, and
antioxidant properties. The introduction of an amine function-
ality on these moieties would further enhance their bioactivity.
With this in mind, different secondary amines were successfully
coupled to 1-chloropyrrolo[1,2-a]pyrazine in very good yields
(7n, 7o).
Scheme 3. Synthesis of 6-Amine (Secondary Amine)-
Functionalized Purine
Further functionalizing pteridines with secondary amines was
presumed to be beneficial regarding the enhancement of
fluorescent properties as well as biological activity. To achieve
this goal, 6-chloropteridine was submitted to the optimized
amination conditions as outlined above with different secondary
amines. We observed good to excellent yields of the coupled
products, further confirming the potential and broad applicability
of the developed amination protocol. The crystalline nature of
some of the coupled products (7c−e,q,t) allowed their molecular
structures to be confirmed by single crystal X-ray analysis (see the
SI). Achieving efficient regioselectivity constitutes one of the
challenges for further synthetic utilization in catalytic coupling
reactions. Polyhalogenated heteroarene functionalization in a
selective manner has been accomplished most effectively using
palladium-catalyzed cross-coupling reactions.22 We then inves-
tigated the selective monoamination of 2,4-dichloropyrimidine
with four different secondary amines, namely, pyrrolidine,
piperidine, morpholine, and piperazine derivatives (Scheme 2).
In each investigated case, monoamination was observed to take
place selectively at the 4-position, thus leaving the 2-chloro
position to be subjected to further synthetic modification (single
crystal X-ray was obtained for 9a and 9c).
It is important to note that this selectivity was achieved by
performing the catalytic amination at ambient temperature while
increasing the reaction temperature to 80 °C allowed for efficient
diamination (in the presence of 2.0 equiv of added amine). Such a
protocol also provides the possibility of synthesizing the
Buparlisib2 drug intermediate 10a (Buparlisib is a pan-class 1
phosphoinositide 3-kinase inhibitor) in very good yields.
Another synthetic challenge involves the amination of a ribose
nucleoside, 6-chloro-9-β-D-ribofuranosylpurine. In the literature,
Koomen,23a Schmalz,23b and Lakshman23c,d reported on the
amination of silyl-protected ribose nucleosides in decent yields.
The mild nature of the optimized catalytic system, when used for
the amination of the ribose nucleoside, provided the coupled
product inexcellentyieldswithouttherequirementforprotection
of the hydroxyl groups on the sugar moiety (Scheme 3).
Finally, todemonstrate thesyntheticpotentialofthedeveloped
protocol toward the synthesis of a commercially important drug,
we investigated the possibility of preparing Alogliptin (Scheme
4).24 Beinganorallyadministeredantidiabeticdrug, Alogliptinisa
uracil based molecule that could be accessed by the protection of
amidic N−H followed by a subsequent amination.24 Accordingly,
we first synthesized a structural mimic of Alogliptin involving the
methyl protection of both its precursor’s N−H groups.
Scheme 2. Monoselective Amination
The resultant 6-chloro derivative was subjected to the Pd-
catalyzed amination with N-Boc protected 3-aminopiperidine to
provide the coupled product in very good yield (13d). To achieve
the actual synthesis ofAlogliptin, the N−H protection was carried
out using methyl iodide and 2-cyanobenzyl bromide. These two
reactions proceeded with essentially quantitative conversions to
furnish the protected 6-chlorouracil. The Pd-catalyzed amination
with the Pd/PTABS system of the protected 6-chloro uracil with
NH-Boc protected 3-aminopiperidine furnished the desired
product in very high conversion under milder reaction conditions
than those previously reported.24 An acid-mediated deprotection
of the NH-Boc group in the cross-coupled intermediate obtained
in the previous step furnished Alogliptin (14) in excellent yield.
Thesuccessofthisapproach wasconfirmedbysinglecrystalX-ray
analysis of Alogliptin’s ammonium derivative with trifluoroace-
tate counterion.
In conclusion, a novel, mild, and highly efficient Pd-catalyzed
amination protocol for chloroheteroarenes using the Pd(OAc)2/
PTABS catalytic system, with secondary amines performed at
ambient temperature, is reported. The powerful nature of the
developed protocol allowed the coupling of a large variety of
heteroaryl chlorides, besides providing access to commercially
successful drugs, e.g., a Buparilsib intermediate and Alogliptin.
C
DOI: 10.1021/acs.orglett.7b03854
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Organic Letters
Letter
Scheme 4. Actual Synthesis of Alogliptin
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ASSOCIATED CONTENT
* Supporting Information
TheSupportingInformationisavailablefreeofchargeontheACS
Publications website at DOI: 10.1021/acs.orglett.7b03854.
■
S
Syntheses and spectral data (PDF)
Accession Codes
CCDC 1585321−1585328 contain the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge CB2
1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
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Corresponding Author
*E-mail: ar.kapdi@ictmumbai.edu.in.
ORCID
Anant R. Kapdi: 0000-0001-9710-8146
Notes
(24) Feng, J.; Zhang, Z.; Wallace, M. B.; Stafford, J. A.; Kaldor, S. W.;
Kassel, D. B.; Navre, M.; Shi, L.; Skene, R. J.; Asakawa, T.; Takeuchi, K.;
Xu, R.; Webb, D. R.; Gwaltney, S. L., II J. Med. Chem. 2007, 50, 2297.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
A.R.K. and C.S. acknowledge The Alexander von Humboldt
Foundation for the research cooperation programme, which is
also thanked for the equipment grant to A.R.K. We also thank the
University Grants Commission India for a UGC-SAP fellowship
for S.B.
D
DOI: 10.1021/acs.orglett.7b03854
Org. Lett. XXXX, XXX, XXX−XXX