Chemoselective One-Pot Synthesis of Functionalized Amino-azaheterocycles Enabled by COware

Article abstract of DOI:10.1021/acs.orglett.7b03214

Functionalized bicyclic amino-azaheterocycles are rapidly accessed in a one-pot cross-coupling/reduction sequence enabled by the use of COware. Incompatible reagents are physically separated in a single reaction vessel to effect two chemoselective transformations - Suzuki-Miyaura cross-coupling and heteroarene reduction. The developed method allows access to novel heterocyclic templates, including semisaturated Hedgehog and dual PI3K/mTOR inhibitors, which show enhanced physicochemical properties compared to their unsaturated counterparts.

Full text of DOI:10.1021/acs.orglett.7b03214

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX-XXX
Chemoselective One-Pot Synthesis of Functionalized Amino-
azaheterocycles Enabled by COware
Thomas A. Clohessy,†,‡ Alastair Roberts,‡ Eric S. Manas,§ Vipulkumar K. Patel,‡ Niall A. Anderson,‡
and Allan J. B. Watson*,†
†WestCHEM, Department of Pure and Applied Chemistry, University of Strathclyde, 295 Cathedral Street, Glasgow G1 1XL, U.K.
‡GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, U.K.
§GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, United States
S
* Supporting Information
ABSTRACT: Functionalized bicyclic amino-azaheterocycles are rapidly accessed in a one-pot cross-coupling/reduction
sequence enabled by the use of COware. Incompatible reagents are physically separated in a single reaction vessel to effect two
chemoselective transformationsSuzuki−Miyaura cross-coupling and heteroarene reduction. The developed method allows
access to novel heterocyclic templates, including semisaturated Hedgehog and dual PI3K/mTOR inhibitors, which show
enhanced physicochemical properties compared to their unsaturated counterparts.
he use of multistep, one-pot reactions has been widely
Tadopted as a strategy for increasing the efficiency of
chemical synthesis.1 These approaches can be significantly less
time- and resource-intensive due to the removal of intermediate
isolation steps and subsequent reaction setup. A caveat to this
strategy is potential incompatibilities of chemical reagents
within the same reaction vessel. Consequently, methods to
avoid reagent incompatibilities are desirable. One such solution
is via the physical separation of mismatched reagents: an
engineering solution to a chemical problem.
Here we report the use of COware to enable a one-pot
chemoselective Suzuki−Miyaura cross-coupling/heteroarene
reduction sequence for the synthesis of novel heteroaromatic
tetrahydropyridopyrimidine (THPP) derivatives (Scheme 1).
We also show how the generated products align with medicinal
chemistry design principles through the preparation of
semisaturated Hedgehog and dual PI3K/mTOR inhibitors,
which show improved physicochemical properties compared to
their unsaturated counterparts.
Encapsulated reagents have allowed separation of incompat-
ible or sensitive reactants, rendering air-sensitive processes
more achievable, as well as enabling the development of
sequential one-pot processes. For example, seminal work on
encapsulation from Taber allowed safer use of KH,2 while
catalytic processes using encapsulation of organometallic
transition-metal catalysts from Taber,3 Buchwald,4 and Wu5
have allowed olefin metathesis, C−X cross-couplings, and one-
pot cross-coupling/thiophene ring annulations, respectively,
avoiding catalyst degradation/poisoning.
Scheme 1. (a) Pyridopyrimidines and the Unexplored THPP
Template. (b) COware Approach to the THPP Scaffold
A recent physical separation approach using reaction
chambering has been developed through COware.6 COware
was initially developed for the in situ generation and use of low
molecular weight gases such as carbon monoxide, ethene, and
hydrogen.7 Due to the safety issues associated with the use and
storage of hydrogen, especially on discovery scale in industry,
the ability to generate and use hydrogen in small volumes at a
specific time point over the course of a reaction is an attractive
concept.
Received: October 14, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b03214
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 1. Reaction Development
b
b
yield 2a/3a
yield 4a
(%)
entry
conditions a
PdCl2dppf (4 mol %), K3PO4 (3 equiv), H2O (5 equiv), THF, 80 °C, 1 h
PdCl2dppf (4 mol %), K3PO4 (3 equiv), H2O (5 equiv), THF, 40 °C, 1 h
PdCl2dppf (4 mol %) K3PO4 (2 equiv) H2O (5 equiv) CPME, 40 °C, 16 h
conditions b
(%)
c
1
2
3
4
5
6
52:48
d
60:4
89:9
H2, Pd/Al2O3 (5 mol %), THF, rt
H2, PtO2 (5 mol %), THF, rt
0
e
39
e
H2, Pd/Al2O3 (5 mol %), CPME,
rt
34
e
7
8
H2, PtO2 (5 mol %), CPME, rt
95
e
PdCl2dppf (4 mol %), PtO2 (10 mol %), K3PO4 (2 equiv), H2O (5 equiv), CPME, HCl, Zn, rt
78
40 °C
a
Conditions a: 1 (1 equiv, 0.125 mmol), PhB(OH)2 (1.05 equiv), PdCl2dppf (4 mol %), K3PO4, H2O, solvent, N2. Conditions b: catalyst, H2, rt. See
b
c
d
the Supporting Information for full details. Determined by HPLC analysis using an internal standard. Using PhB(OH)2 (1.5 equiv). Mass balance
is starting material. Isolated yield.
e
Substituted pyridopyrimidine derivatives are important
scaffolds in drug discovery.8 However, there has been relatively
little research into the biological activity of the related
semisaturated tetrahydropyridopyrimidine (THPP) systems.9
As a benchmark reaction for the synthesis of functional
THPPs, we envisioned the chemoselective cross-coupling of
dichloropyridinopyrimidine 1 to generate 2a,10 which would
then undergo a one-pot chemoselective hydrogenation to
deliver 4a (Table 1). Compound 4a is an attractive product
from a medicinal chemistry perspective due to the functional
group handles embedded: the 2-chloropyrimidine is readily
modifiable by cross-coupling or SNAr strategies, and the newly
formed piperidine ring nitrogen provides a second flexible
vector. Important to our objectives was the generation of both a
practical as well as accessible method, with inexpensive catalysts
and solvents more aligned with sustainable chemistry preferred.
Before undertaking the one-pot process, we first assessed the
cross-coupling and hydrogenation reactions independently.
Under conditions employed for similar processes using 2,4-
dichloropyrimidine, chemoselective Suzuki−Miyaura cross-
coupling of 1 with PhB(OH)2 was poor at ca. 1:1 in favor of
the desired product 2a, with significant over-reaction observed
producing 3a (entry 1). Lowering the reaction temperature
improved the 2a:3a ratio but conversion was only moderate
(entry 2). However, optimization of this step (see the
Supporting Information for full details) delivered an effective
set of reaction conditions where a good yield of 2a was
recorded (89%) while 3a was minimized (entry 3).
Chemoselective hydrogenation of the pyridine ring while
retaining the chloropyrimidine was then explored using a range
of catalysts and solvents (entries 3−7; see the SI for full
details). Low reactivity and issues with hydrogenation of the C-
Cl bond (to deliver 5a) were observed when Pd catalysts were
used (entries 4 and 6). Poor conversion was also seen with
PtO2 when THF was used as the solvent (entry 5); however,
full conversion and 95% isolated yield of 4a were observed
when PtO2 in CPME was used (entry 7).
Combining the Suzuki−Miyaura and hydrogenation pro-
cesses into the COware setup proceeded smoothly: chamber A
contained 1, PhB(OH)2, PdCl2dppf, PtO2, K3PO4, H2O, and
CPME, while chamber B contained Zn. Heating the mixture at
40 °C allowed chemoselective Suzuki−Miyaura cross-coupling.
Upon completion of the cross-coupling, H2 was generated in
chamber B using Zn/HCl and allowed chemoselective
hydrogenation of the pyridine ring. This ultimately provided
78% isolated yield of the desired product 3a (entry 8).
Several points relating to the overall optimization are worth
noting. Other catalyst types were effective (for example,
PEPPSI-IPr; see the SI); however, PdCl2dppf was selected as
the more economical choice. Similarly, CPME offered both
improved reactivity/selectivity at lower temperatures (entry 2
vs entry 3) and sustainability credentials over THF and was
more economical vs competitor green solvents, such as 2-
MeTHF.
With effective conditions for the benchmark reaction in
place, we proceeded to assess the generality of the COware
process by generation of a small collection of functionalized
aza-heterocycle products accessed by variation of both the
organoboron and chloroheterocycle components (Scheme 2).
Variation of the organoboron component was readily
accommodated (Scheme 2a). Electron-rich and electron-
deficient aryl groups, with varying regiochemistry, delivered
the functionalized THPPs in generally good yield (4a−j).
Similarly, heterocyclic organoboron components operated
effectively (4k−m). The use of alkenyl organoborons resulted
in hydrogenation of both the pyridine ring as well as the olefin
to provide the products of formal sp2−sp3 cross-coupling in
moderate overall yield (4n, 4o).
Variation of the heterocyclic core was also possible to deliver
both regioisomeric THPPs (4a vs 6e, 6f) as well as a series of
analogues including regioisomeric tetrahydroquinolines (6a, 6c,
6d, 6g, 6h, 6i, 6j), piperazinopyrimidines (6b), and
piperidinopyridines (6k, 6l) in good yield (Scheme 2b).
The chemoselective hydrogenation step retains the 2-
chloropyrimidine, allowing for subsequent functionalization.
For example, a three-component process was developed where
an additional SNAr event was coupled with the COware process
to allow the one-pot synthesis of the semisaturated analogue of
both a Hedgehog inhibitor 811 and dual PI3K/mTOR inhibitor
912 (Scheme 3).
The increased fsp3 of 8 and 9 vs the parent compounds
containing the pyridine ring (10 and 11, respectively) results in
B
DOI: 10.1021/acs.orglett.7b03214
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Letter
a
Scheme 2. Scope of the COware Process
Scheme 3. Synthesis of Semisaturated Analogues of
Hedgehog and PI3K/mTOR Inhibitors
Figure 1. Physicochemical property comparison of semisaturated
derivatives of Hedgehog and PI3K/mTOR inhibitors. Ar = 2,6-
Me2C6H3. fsp3, fraction sp3 atoms; HSA PPB, human serum albumin
plasma protein binding; PFI, property forecast index.
chloropyrimidine motif. This allows access to semisaturated
derivatives of patented drug molecules that display enhanced
physicochemical properties vs the parent compounds.
a
b
Isolated yields. Pd(OAc)2 (4 mol %), XPhos (8 mol %) catalyst
ASSOCIATED CONTENT
system used.
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b03214.
significant improvements in physicochemical properties of
these compounds, in alignment with medicinal chemistry
strategy (Figure 1).13 For example, the solubility, permeability,
human serum albumin plasma protein binding (HSA PPB), and
property forecast index (PFI)14 are all markedly improved in
comparison to the progenitor compounds.
Experimental procedures, characterization data, and
NMR spectra (PDF)
AUTHOR INFORMATION
In summary, we have developed a one-pot chemoselective
cross-coupling/hydrogenation protocol using COware for the
expedient preparation of a diverse set of pharmaceutically
relevant aza-heterocycles. The utility of both the COware
process and the generated products can be expanded by
inclusion of an additional functionalization event using the
■
Corresponding Author
*E-mail: allan.watson.100@strath.ac.uk.
ORCID
Allan J. B. Watson: 0000-0002-1582-4286
C
DOI: 10.1021/acs.orglett.7b03214
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank GSK for financial and material support.
■
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