Construction of azacycles by intramolecular amination of organoboronates and organobis(boronates)

Article abstract of DOI:10.1021/acs.orglett.1c00856

Intramolecular amination of organoboronates occurs with a 1,2-metalate shift of an aminoboron ate complex to form azetidines, pyrrolidines, and piperidines. Bis(boronates) undergo site-selective amination to form boronate-containing azacycles. Enantiomerically enriched azacycles are formed with high stereospecificity.

Full text of DOI:10.1021/acs.orglett.1c00856

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Letter
Construction of Azacycles by Intramolecular Amination of
Organoboronates and Organobis(boronates)
Peilin Xu, Mingkai Zhang, Bryan Ingoglia, Christophe Allais, Anne-Marie R. Dechert-Schmitt,
Robert A. Singer, and James P. Morken*
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ABSTRACT: Intramolecular amination of organoboronates occurs with a 1,2-metalate shift of an aminoboron “ate” complex to
form azetidines, pyrrolidines, and piperidines. Bis(boronates) undergo site-selective amination to form boronate-containing
azacycles. Enantiomerically enriched azacycles are formed with high stereospecificity.
aturated nitrogen-containing heterocycles, such as azeti-
dines, pyrrolidines, and piperidines, are important
the formation of an aminoboron “-ate” complex, followed by a
1,2-metalate shift to establish the C−N bond (Scheme 2a). To
affect such an amination, a range of reagents have been
developed, including hydroxylamine-O-sulfonic acid,6 organic
azides,7 methoxyamine,8 and aminoazanium ions.9 When the
electrophilic amine is tethered to the organoboron motif,
intramolecular amination can lead to azacyclic compounds.
This approach was first established by Evans10a for the
synthesis of substituted proline derivatives (Scheme 2b) and
subsequently adopted by a number of groups for construction
of pyrrolidine and piperidine ring systems.10 Notably, Aggarwal
and co-workers established that the intramolecular reaction
could be applied to tertiary boronic esters (Scheme 2c) by
employing a synthesis sequence that proceeds by way of an
intermediate trifluoroborate salt.7f The examples described,
however, remain largely limited to the reaction between alkyl
azides and highly electrophilic trialkyl- or dihaloborane
substrates, with the latter compounds often generated in situ
through the use of caustic reagents. Processes that directly
employ boronic esters and that can enable the synthesis of
strained ring systems have not been well developed.
S
structures in natural product alkaloids,1 in pharmaceutical
targets,2 and as catalysts in organocatalytic synthesis3 (Scheme
1). In this connection, C−N bond formation is one of the most
Scheme 1. Pharmaceutical Targets Containing Saturated
Azacycles
common strategies to prepare such heterocycles, and within
that framework a straightforward method employed is
nucleophilic displacement of a leaving group by a nitrogen
nucleophile.4 However, with challenging ring closures such as
those that involve the formation of strained rings or that
require substitution at hindered electrophilic carbons, com-
petitive β-elimination of the leaving group can pose a
problem.4a,b As an alternative route to the construction of
azacycles, and one that capitalizes on recent advances5 in the
construction of chiral enantiomerically enriched organoboronic
esters, we undertook a study of intramolecular boronate
amination.
To accomplish stereospecific amination of a range of
primary and secondary alkylboronic esters, without the use
of highly Lewis acidic reagents, the use of methoxyamine
pretreated with either n-BuLi or KOt-Bu is effective.8 The
scope of this amination has been found to include tertiary
Received: March 11, 2021
Published: April 14, 2021
Stereospecific amination of organoboron compounds with
electrophilic nitrogen-based reagents can be brought about by
https://doi.org/10.1021/acs.orglett.1c00856
© 2021 American Chemical Society
Org. Lett. 2021, 23, 3379−3383
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intramolecular amination between an organoboronic ester and
a tethered methoxyamine group. An appealing feature of this
process is that the methoxyamine functional group is readily
introduced by reaction of BocNH(OMe) and either alkyl
halides (base promotion) or aliphatic alcohols (Mitsunobu
reaction). Prior to amination, the Boc group is removed with
CF3CO2H, the residue evaporated to dryness, and the
intermediate then heated in THF/toluene in the presence of
potassium tert-butoxide. As shown in Scheme 3, the trans-
formation applies to the synthesis of substituted azetidines and
can tolerate the presence of several useful malleable functional
groups, including an alkene (2, 3), a furan ring (4), and a
boronic ester (5). The formation of pyrrolidines and
piperidines is also easily accomplished from appropriate
precursor boronic ester derivatives. As depicted in Scheme 3,
a range of 2- or 3-substituted pyrrolidine motifs (6−9) can be
prepared in an efficient and simple fashion from the
corresponding δ-methoxyamino boronate derivatives, whereas
the analogous 1,5-methoxyamino boronates deliver 2- or 3-
substitued chiral piperidines (10−13).
Scheme 2. Intramolecular Amination via a 1,2-Metalate
Shift of the Aminoboron “-Ate” Complex
Because vicinal diboron compounds are readily prepared by
diboration12 of alkenes, we considered whether sequential
diboration and site-selective amination might deliver boron-
containing azacycles that could be useful for the preparation of
diverse sets of heterocyclic building blocks (Scheme 4). The
requisite substrates are readily prepared by diboration of
olefins bearing a tethered Boc-protected methoxyamine
group.13 Subsequent deprotection with TFA does not perturb
boronates and, in one case, has been employed to prepare a
piperidine ring.11 Within this framework, we set out to explore
whether more challenging strained rings might be prepared by
intramolecular amination and whether site selectivity and
stereospecificity might be possible when multiple boronic
esters are present in a substrate.
Scheme 4. Chemoselectivity in Intramolecular Amination of
Vicinal Bis(boronic) Esters
As shown in Scheme 3, initial experiments showed that a
variety of substituted azacycles can be prepared with ease by
Scheme 3. Synthesis of Azetidine, Pyrrolidine, and
Piperidine Rings by Intramolecular Amination of Boronic
a
Esters
a
Yields refer to isolated yields of purified material and are an average
of two experiments.
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the vicinal bis(boronate) motif. As depicted in eq 1, given a
choice between forming an azetidine or a pyrrolidine ring
during the course of amination, the five-membered ring is
preferred and provides 3-borylpyrrolidine 15.14 Because there
are unlikely to be significant differences in strain between the
five- and six-membered chelated structures A and B (inset,
Scheme 4), it is plausible that the selectivity in eq 1 arises from
the rate of 1,2-metalate shift, with the formation of the
pyrrolidine occurring faster. A homologous substrate provides
the opportunity to form either a pyrrolidine or piperidine
derivative, and as shown in eq 2, the pyrrolidine is again
favored. Presumably selectivity in this case arises from a more
favorable six-membered chelate size (D) that furnishes the five-
membered ring product. When the substrate is configured in a
way that either the six- or seven-membered rings are
prospective products, the reaction is site-selective and favors
formation of the piperidine derivative (eq 3), likely a result of
the favorable formation of the seven-membered chelate (E)
over the eight-membered complex (F).
As described above, the intramolecular amination can be
conducted with good chemoselectivity and enantiospecificity
for a range of substrates. Given the importance of proline
derivatives as catalysts, ligands, and building blocks for the
synthesis of alkaloids, it was of interest to learn whether
compounds bearing two contiguous stereocenters might be
available by the diboration/amination reaction sequence. As
depicted in Scheme 6, alcohol 28 was converted to protected
Scheme 6. Construction of a Pyrrolidine with an Exocyclic
Stereogenic Center by Selective Amination
Enantiomerically enriched vicinal diboron compounds can
be synthesized using platinum-catalyzed enantioselective
diboration, and this strategy provides an opportunity to
examine whether the amination can occur with stereo-
specificity even for strained ring systems.15 As depicted in
Scheme 5, diboration of 20 provides 21 with good yield and
Scheme 5. Intramolecular Amination of Enantiomerically
Enriched Boronic Esters
methoxyamine 29 by a Mitsunobu reaction. Subsequent
Cs2CO3-catalyzed diboration furnished 30, which was
subjected to nitrogen deprotection, amination, and Boc
protection, thereby furnishing 31 as a single stereoisomer.
Subsequent oxidation provides 32, a compound found in the
construction of a KRas G12C inhibitor.17
In conclusion, we have developed a method to synthesize
azacycles of ring sizes 4−6 via intramolecular amination
reaction of methoxyamine-containing boronic esters. Boronate-
containing azacycles can be formed with high regioselectivity
from bis(boronates). In addition, the method can be utilized to
deliver enantiomerically enriched azacyclic compounds with
excellent enantiospecificity.
ASSOCIATED CONTENT
* Supporting Information
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The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c00856.
Procedures, characterization, and spectral data (PDF)
AUTHOR INFORMATION
Corresponding Author
■
James P. Morken − Department of Chemistry, Merkert
Chemistry Center, Boston College, Massachusetts 02467,
United States; orcid.org/0000-0002-9123-9791;
Email: morken@bc.edu
enantiomeric excess. Direct chemoselective amination to give
22 was found to occur with complete preservation of the
enantiomeric purity of the substrate such that 22 is accessed
with high selectivity. In addition, site-selective Suzuki−Miyaura
coupling of 21 gives 23, and amination of 23 furnishes the
azetidine derivative 24 with complete enantiospecificity. Of
note, compound 24, in its Boc-free form, is a known bioactive
compound with good affinity toward the TAAR1 receptor.16
Lastly, enantioselective diboration of 25 furnishes 26, and this
vicinal bis(boronate) was also found to participate in
stereospecific amination to provide boron-containing pyrroli-
dine 27 with good enantiomeric purity.
Authors
Peilin Xu − Department of Chemistry, Merkert Chemistry
Center, Boston College, Massachusetts 02467, United States
Mingkai Zhang − Department of Chemistry, Merkert
Chemistry Center, Boston College, Massachusetts 02467,
United States
Bryan Ingoglia − Department of Chemistry, Merkert
Chemistry Center, Boston College, Massachusetts 02467,
United States
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Christophe Allais − Pfizer Worldwide Research and
Development, Groton, Connecticut 06340, United States;
orcid.org/0000-0002-3443-9391
Anne-Marie R. Dechert-Schmitt − Pfizer Worldwide
Research and Development, Groton, Connecticut 06340,
United States
Robert A. Singer − Pfizer Worldwide Research and
Development, Groton, Connecticut 06340, United States;
orcid.org/0000-0001-9730-1261
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c00856
Notes
The authors declare the following competing financial
interest(s): C.A., A.R.D., and R.A.S. are employees and
stockholders of Pfizer Inc.
Several of the boron-containing compounds reported in this
manuscript will be accessible from Enamine.
ACKNOWLEDGMENTS
Financial support was provided by Pfizer.
■
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