Vinylic MIDA boronates: New building blocks for the synthesis of aza-heterocycles

Article abstract of DOI:10.1002/chem.201406549

Abstract A two-step synthesis of structurally diverse pyrrole-containing bicyclic systems is reported. ortho-Nitro-haloarenes coupled with vinylic N-methyliminodiacetic acid (MIDA) boronates generate ortho-vinyl-nitroarenes, which undergo a "metal-free" nitrene insertion, resulting in a new pyrrole ring. This novel synthetic approach has a wide substrate tolerance and it is applicable in the preparation of more complex "drug-like" molecules. Interestingly, an ortho-nitro-allylarene derivative furnished a cyclic β-aminophosphonate motif. Old dog, new tricks: A two-step synthesis of structurally diverse pyrrole-containing bicyclic systems is reported. ortho-Nitro-haloarenes coupled with vinylic N-methyliminodiacetic acid (MIDA) boronates generate ortho-vinyl-nitroarenes, which undergo a "metal-free" nitrene insertion, resulting in a new pyrrole ring. This approach has a wide substrate tolerance and it is applicable in the preparation of more complex "drug-like" molecules. Interestingly, an ortho-nitro-allylarene derivative furnished a cyclic β-aminophosphonate motif.

Full text of DOI:10.1002/chem.201406549

DOI: 10.1002/chem.201406549
Communication
&
Heterocycles
Vinylic MIDA Boronates: New Building Blocks for the Synthesis of
Aza-Heterocycles
Sabin Llona-Minguez,*[a] Matthieu Desroses,[a] Artin Ghassemian,[a] Sylvain A. Jacques,[a]
Lars Eriksson,[b] Rebecka Isacksson,[a] Tobias Koolmeister,[a] Pꢀl Stenmark,[c] Martin Scobie,[a]
and Thomas Helleday[a]
Abstract: A two-step synthesis of structurally diverse pyr-
role-containing bicyclic systems is reported. ortho-Nitro-
haloarenes coupled with vinylic N-methyliminodiacetic
acid (MIDA) boronates generate ortho-vinyl-nitroarenes,
which undergo a “metal-free” nitrene insertion, resulting
in a new pyrrole ring. This novel synthetic approach has
a wide substrate tolerance and it is applicable in the prep-
aration of more complex “drug-like” molecules. Interest-
ingly, an ortho-nitro-allylarene derivative furnished a cyclic
b-aminophosphonate motif.
Pyrrole-containing bicyclic systems such as indoles,[1] azain-
doles,[2] and thienopyrroles[3] are privileged scaffolds in the me-
dicinal chemistry literature (Figure 1). As part of a fragment-
based drug discovery effort, we were interested in expanding
our existing fragment library with a diverse set of 3-substituted
pyrrole-containing heterocyclic systems. 3-Substituted indoles,
Figure 1. Pharmacologically active compounds displaying 3-substituted pyr-
role-containing bicyclic systems
bearing aryl substituents in particular, have been the focus of
intense research over the past decade, which has led to signifi-
cant advances in synthetic methods. Transition-metal-catalyzed
reactions using activated arene substrates, such as aryl halides
or boronates, allow the direct and selective N1-, C2-, or C3-ary-
lation of indoles,[4] although C3-regioselective arylation meth-
ods have not been reported for any other pyrrole-containing
bicyclic core, which are often prepared in four synthetic steps
from the 3-unsubstituted parent compounds.[5]
dure has been applied in the preparation of a wide range of
heterocyclic scaffolds, including carbazoles, indoles, indazoles,
and triazoles,[7] and is of considerable interest to the synthetic
community.[8] The true nature of the Cadogan reaction has not
been elucidated, although a nitrene-based mechanism is gen-
erally accepted.[7,9] The reductive cyclization of substituted
ortho-nitro-vinylarenes, also known as the Cadogan–Sundberg
indole synthesis, furnishes 2-substituted indole cores,[7] where-
as unsubstituted ortho-nitro-vinylarenes lead to 3-substituted
systems. This transformation has mainly been the subject of re-
ductive N-heterocyclizations catalyzed by transition metals
such as Pd,[10] Mo,[11] Sn,[12] Ru,[13] Rh,[14] and non-metals such as
Se,[15] often requiring the presence of carbon monoxide. To our
surprise, literature examples of phosphite-mediated deoxyge-
nations of primary ortho-nitro-vinylarenes are rare, low-yield-
ing, and the required vinyl intermediates are obtained from
rather inconvenient synthetic routes (Scheme 1).[16] We rea-
soned that an improved synthetic route to these substrates
was required to fully exploit the potential of this “extended”
Cadogan–Sundberg reaction and allow the rapid generation of
these interesting fragments.
The reductive cyclization of nitro-compounds by organic
phosphites was first reported by Cadogan et al.[6] The proce-
[a] Dr. S. Llona-Minguez, Dr. M. Desroses, A. Ghassemian, Dr. S. A. Jacques,
R. Isacksson, T. Koolmeister, Dr. M. Scobie, Prof. T. Helleday
Science for Life Laboratory
Division of Translational, Medicine & Chemical Biology
Department of Medical Biochemistry & Biophysics
Karolinska Institutet, Stockholm, 171 21 (Sweden)
E-mail: sabin.llona.minguez@scilifelab.se
Homepage: http://www.helleday.org
[b] Dr. L. Eriksson
Department of Materials and Environmental Chemistry
Stockholm University, Stockholm, 106 91 (Sweden)
[c] Dr. P. Stenmark
Department of Biochemistry and Biophysics
Stockholm University, Stockholm, 106 91 (Sweden)
Vinyl-containing N-methyliminodiacetic acid boronate
(MIDA) reagents have recently become commercially available,
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201406549.
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Scheme 1. Phosphite-mediated reductive cyclization of primary ortho-nitro-
vinylarenes.
allowing direct Pd-catalyzed vinylation reactions.[17] MIDA boro-
nates are air- and chromatography-stable boronic acid surro-
gates,[18] compatible with a wide variety of reactions,[19] provid-
ing an improved alternative to unstable boron reagents. We
envisioned that Pd-catalyzed vinylation of a wide range of
ortho-nitro-haloarenes using this new class of building blocks,
followed by a reductive cyclization, would give access to di-
verse pyrrole-containing pharmacophores (Scheme 1).
Scheme 2. Cadogan–Sundberg cyclization: indoles. Reaction conditions:
vinyl arene (0.15 mmol), P(OEt)3 (0.5 mL). Percentage values show isolated
yields.
To explore the feasibility of this synthetic approach, we first
attempted synthesis of 3-phenyl-1H-indole 1b (Scheme 2),
a simple and odorless indole derivative. Initial investigations
using 1-bromo-2-nitrobenzene as the model substrate showed
that Pd(PPh3)4/K2CO3 in 1,4-dioxane/water is an effective
system for the vinylation step, and no further method develop-
ment was investigated. The reaction setup is rather simple,
without the need of solvent degassing or inert atmosphere.
The resulting ortho-nitro-vinylarene 1a (Scheme 3) was then
treated with P(OMe)3, P(OEt)3, or P(nBu)3 under conventional
heating or microwave irradiation. Heating in neat P(OEt)3 at
1808C delivered a clean, fast, and high-yielding conversion to
1b, with no traces of ethylated or ethoxylated side-products.
Encouraged by the initial results, we decided to apply the
Suzuki protocol to generate a set of ortho-nitrovinyl deriva-
tives, including diverse-substituted benzene (Scheme 3; 2a to
13a), pyridine (14a, 15a, 16a, and 17a), thiophene (18a), pyr-
azole (19a), imidazole (20a and 21a), benzimidazole (22a),
and quinoxaline (23a) systems (Scheme 4). The protocol
proved to be robust and consistently delivered fast and clean
conversions across the set, irrespective of halide (Cl- for 7a,
13a, 15a, 17a, 18a, 19a, 20a, 21a, and 22a;[20] Br- for the
rest of the examples), neighboring functional groups (sulfone
12a and sulfonamide 13a were isolated in lower yields) or het-
erocyclic core with the exception of 3a, where milder condi-
tions were required for a satisfactory conversion (see Support-
ing Information, Suzuki–Miyaura coupling reaction conditions
B, adapted from Burke et al.).[18] The resulting ortho-nitro-vinyl-
arenes were subjected to the phosphite-mediated reductive
cyclizations (Scheme 2). The nature of the substituent adjacent
to the alkene moiety plays an important role in the nitrene in-
sertion step as seen in 1b, 2b, and 3b, which followed the re-
activity order: Ph>Me>H. Electron-donating (6b and 9b) or
-withdrawing substituents (7b, 8b, 11 b, 12b, and 13b) in the
benzene did not influence the reaction efficiency, with the ex-
ception of methyl substitution ortho- to the nitro- (4b) or the
vinyl- (5b) group, which required longer reaction times. It is
worth noting that aniline 10b rapidly decomposed to black tar
upon heating in P(OEt)3. As expected by this broad functional
group tolerance, the cyclization step was also applicable to the
more complex and “drug-like” compound 13b[20] (Scheme 2).
The method also fared well with most heterocyclic cores
(Scheme 5), with clean conversions by LC-MS analysis in gener-
al. Reaction speed was greatly decreased in the case of azain-
dole 14b and pyrrolopyrazole 19b, without significant forma-
tion of side-products after several hours of heating. In the case
of pyridine 16b, the reaction proceeded rapidly and longer re-
action times led to the formation of a bis-alkylated side-prod-
uct. Unfortunately, imidazole-containing substrates such as
20b, 21b, and 22b rapidly decomposed, even after 5 min of
heating in P(OEt)3.
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Scheme 4. Suzuki cross-coupling: heterocyclic core scope. Reaction condi-
tions: haloarene (0.3 mmol, 1 equiv), MIDA boronate (1.1 equiv), K2CO3
(2 equiv), and Pd(PPh3)4 (0.1 equiv). Percentage values show isolated yields.
Table 1. Optimization of the Cadogan–Sundberg reaction conditions.
Entry Heating method
Reducing agent Temp [8C] Time 1b [%][a]
1
2
3
4
5
microwave heating[b] P(OEt)3
microwave heating[b] P(OMe)3
180
150
180
180
80
30 min 45
30 min 36
30 min 95
30 min 29
Scheme 3. Suzuki cross-coupling: MIDA boronate and functional group
scope. Reaction conditions: Haloarene (0.3 mmol, 1 equiv), MIDA boronate
(1.1 equiv), K2CO3 (2 equiv), and Pd(PPh3)4 (0.1 equiv). Percentage values
show isolated yields. [a] Reaction conditions: haloarene (0.3 mmol, 1 equiv),
heating block[b]
heating block[b]
heating block[c]
P(OEt)3
P(OMe)3
P(nBu)3
16 h
0
.
MIDA boronate (1.1 equiv), K3PO4 (7 equiv), and Pd(dppf)Cl2 CH2Cl2
[a] Conversions were determined by LC-MS, based on area under the
curve integration at 254 nm of 1a vs. 1b. [b] Vinyl arene (0.15 mmol),
phosphite (0.5 mL). [c] See Genung et al.[8c]
(0.1 equiv).
The pyrrolopyrazole scaffold is a rare motif in the chemical
literature,[21] and the substitution pattern present in 19b
(Scheme 5) has not been previously reported. Intrigued by this
unusual 5–5 bicyclic system, we decided to confirm its struc-
ture by means of single-crystal X-ray diffraction. Careful re-crys-
tallization of the trifluoroacetate salt of 19b from ethanol al-
lowed us to obtain material suitable for the study (Figure S3 in
the Supporting Information). The crystals diffracted to 1 ꢂ reso-
lution and the electron density for 19b was of very good quali-
ty (Figure S1 in the Supporting Information). 19b crystallized
in the space group P21 (Table 1 in the Supporting Information).
The unit cell contained two molecules of 19b and two mole-
cules of trifluoroacetic acid (TFA) (Figure 2b). Nitrogen N1 of
19b is likely to be protonated and thereby positively charged
with the negatively charged TFA molecule as counter ion. The
crystal lattice was built up by a network of hydrogen bonds
between 19b and TFA (S2 in the Supporting Information). 19b
was well-ordered and agreed with the expected chemical
structure (Figure 2a). The position of the three fluorine atoms
of the TFA molecule was not clearly defined, as shown by their
anisotropic ellipsoids (Figure 2b).
Unexpectedly, during the course of these investigations we
discovered that allyl quinoxaline 24a was cyclized to amino-
phosphonate 24b (Scheme 6). Although the nature of this
transformation has not been studied in detail, we suggest
a plausible mechanism that involves insertion of nitrene A into
the vicinal alkene bond to generate aziridine B,[22] followed by
ring opening at the less sterically hindered end by a P(OEt)3
and a subsequent Arbuzov reaction (C, see Scheme 6). We are
currently investigating the scope of this new reaction, and re-
sults will be reported in due course.
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Scheme 5. Cadogan–Sundberg cyclization: pyrrole-containing heterocycles.
Reaction conditions: Vinyl arene (0.15 mmol), P(OEt)3 (0.5 mL). Percentage
values show isolated yields.
ment library. Both synthetic steps follow a straight forward
setup, are amenable to parallel synthesis, and have a broad
functional-group tolerability/heterocyclic-core scope. Addition-
ally, we have reported on the unusual formation of a cyclic b-
aminophosphonate upon reductive cyclization of an ortho-
nitro-allylarene.
Figure 2. A) Anisotropic ellipsoids representing the crystal structure of 19b.
B) The unit cell, containing two molecules of 19b and two molecules of TFA.
In summary, we have developed a simple protocol to access
diverse 3-substituted pyrrole-containing bicyclic systems:
a robust vinylation reaction using commercially available MIDA
boronates generates ortho-nitro-vinylarenes, which are subse-
quently cyclized under phosphite-mediated conditions to fur-
nish the desired heterocyclic cores as part of an internal frag-
Experimental Section
The Supporting Information contains experimental procedures, an-
alytical data, copies of 1H and 13C NMR spectra for novel com-
pounds, and X-ray crystal structure coordinates and data files for
compound 19b. CCDC 1038003
contains the supplementary crys-
tallographic data for this paper.
These data can be obtained free of
charge from The Cambridge Crys-
tallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/
cif.
Acknowledgements
We would like to acknowledge
Dr. Cynthia Paulin and Dr. Olov
Wallner for useful discussions on
NMR spectroscopy, Dr. Pawel
Baranczewski (UDOPP, Uppsala
Scheme 6. Suggested mechanism for the formation of cyclic b-aminophosphonate 24b from ortho-nitro-allylarene
24a. Percentage values show isolated yields.
University) for HR-MS determina-
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heterocycles · MIDA · nitrene
· boronate · cyclization ·
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Received: December 18, 2014
Published online on && &&, 0000
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COMMUNICATION
&
Heterocycles
S. Llona-Minguez,* M. Desroses,
A. Ghassemian, S. A. Jacques, L. Eriksson,
R. Isacksson, T. Koolmeister, P. Stenmark,
M. Scobie, T. Helleday
&& – &&
Vinylic MIDA Boronates: New Building
Blocks for the Synthesis of Aza-
Heterocycles
Old dog, new tricks: A two-step syn-
thesis of structurally diverse pyrrole-
containing bicyclic systems is reported.
ortho-Nitro-haloarenes coupled with vi-
nylic N-methyliminodiacetic acid (MIDA)
boronates generate ortho-vinyl-nitroar-
enes, which undergo a “metal-free” ni-
trene insertion, resulting in a new pyr-
role ring. This approach has a wide sub-
strate tolerance and it is applicable in
the preparation of more complex “drug-
like” molecules. Interestingly, an ortho-
nitro-allylarene derivative furnished
a cyclic b-aminophosphonate motif.
&
&
Chem. Eur. J. 2015, 21, 1 – 6
www.chemeurj.org
6
ꢁ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!