Synthesis of Boronic Ester γ-Lactam Building Blocks

Article abstract of DOI:10.1002/adsc.202001339

Saturated heterocycles are found widely in biologically active compounds such as medicinal drugs and agrochemicals. However, boronic acid-derived building blocks for these structures have limited availability, particularly in comparison to heteroaromatic boronic acids. We report the preparation of boronic ester γ-lactams through a Cu-catalysed conjugate borylation-cyclisation protocol. Using a chiral catalyst, this can be performed in high enantioselectivity. Exploration of the further transformations of these reagents suggest that the boronic esters have much potential as chemical building blocks. (Figure presented.).

Full text of DOI:10.1002/adsc.202001339

Title: Synthesis of Boronic Ester γ-Lactam Building Blocks
Authors: George Rodgers, Ellen Wilson, Craig Robertson, Daniel Cox,
and Benjamin Partridge
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10.1002/adsc.202001339
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.202001339
Synthesis of Boronic Ester γ-Lactam Building Blocks
George Rodgers,a Ellen J. Wilson,a Craig C. Robertson,a Daniel J. Cox,b and Benjamin
M. Partridgea*
a
Department of Chemistry, University of Sheffield, Dainton Building, Sheffield, S3 7HF, United Kingdom
Email: b.m.partridge@sheffield.ac.uk
Redbrick Molecular Ltd., 217 Portobello, Sheffield, S1 4DP
b
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
lactam. Previous conjugate borylation-cyclisation
biologically active compounds such as medicinal drugs and strategies have instead involved C-C bond formation
Abstract. Saturated heterocycles are found widely in
agrochemicals. However, boronic acid-derived building
blocks for these structures have limited availability,
particularly in comparison to heteroaromatic boronic acids.
We report the preparation of boronic ester γ-lactams
through a Cu-catalysed conjugate borylation-cyclisation
protocol. Using a chiral catalyst, this can be performed in
high enantioselectivity. Exploration of the further
transformations of these reagents suggest that the boronic
esters have much potential as chemical building blocks.
through reaction of an in situ formed enolate with a
pendent electrophile.[9] This work complements
recent reports from Lautens and co-workers, who
have developed a borylation-acylation strategy of
styrene-containing carbamoyl chlorides to form
lactams.[10]
Keywords: boron; lactams; copper; building blocks; cross-
coupling.
Boronic acids are valuable chemical building blocks,
which are used in a broad range of disciplines from
medicinal chemistry to materials science.[1]
Heteroaromatic boronic acids, and their derivatives,
are particularly useful for the preparation of
biologically active molecules through reactions such
as the Suzuki-Miyaura cross-coupling[2] and the
Chan-lam reaction.[3] This is further enabled by the
wide commercial availability and ease of preparation
of a broad range of hetereoaromatic boronic acids and
derivatives. Conversely, the corresponding boronic
acid-containing saturated heterocycles have limited
availability, despite the prevalence of such
heterocycles in pharmaceutical drugs.[4] To illustrate
this, at the time of publication Merck Sigma-Aldrich
sold only 4 pyrrolidine- or piperidine-based boronic
acids and derivatives.[5] There are a growing number
of transformations of alkylboron reagents.[6] However,
in order for such methods to be taken up widely by
both academia and industry, access to a broader range
of alkylboron building blocks is required.
Scheme 1. Examples of borylation-cyclisation strategies to
form saturated carbo- and heterocyclic boronic esters.
We started this investigation by subjecting enoate
1a to a B2Pin2 in the presence of CuI as a catalyst
(scheme 2). It was found that borylation proceeded
smoothly to give boronic ester 2a in good yield.
Interestingly, the reaction was complete within 1 h,
whereas the borylation of ethyl cinammate under the
same reaction conditions requires >12 h reaction time.
Boronic ester 2a did not lactamize spontaneously,
As part of an ongoing research programme into the
chemistry of alkylboronic esters,[7] we envisaged that
beta-boronic ester γ-lactams could be prepared
through conjugate borylation[8] of an E-amino enoate
(scheme 1). Borylation would break the unsaturation
of the enoate, allowing the pendent amine to form the
1
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10.1002/adsc.202001339
Advanced Synthesis & Catalysis
presumably due to the relatively low nucleophilicity
of the aniline nitrogen. Attempts to induce cylisation
under mildly basic conditions were successful, but
was accompanied by a small amount of a degradation
product from protodeboronation of the boronic ester.
Instead, treatment of boronic ester 2a with acetic acid
gave the corresponding lactam 3a, without need for
further purification. While the process can be
telescoped, purification after conjugate borylation
was found to be more successful.
H2O2/NaOH was carried out. See the supporting
information for full details.
When N-benzyl enoate 1h was subjected to
conjugate borylation, the linear boronic ester
underwent cyclisation in situ. This is presumably due
to the higher nucleophilicity of alkyl amines versus
anilines. While the boronic ester was formed in good
yield, attempts at purification led to significant
decomposition of the product. Instead, to give an
indication of the efficiency of the reaction, oxidation
of the boronic ester was performed to give alcohol 4.
Access to enantiomerically enriched boronic ester
(S)-2a was achieved using a catalyst derived from
CuCl and (R,S)-Josiphos as a ligand[12] to give (S)-2a
in 56% yield. Cyclisation followed by oxidation of
the C-B bond gave alcohol (S)-5 in 90% e.e.. The
absolute configuration of (S)-5 was confirmed
through X-ray crystallography.[11,13]
Scheme 2. Borylation and cyclisation of enoate 1a.
We next subjected our protocol to the formation of
a range of boronic ester-containing lactams (scheme
3). The method is tolerant to functional groups
including esters, nitriles and aryl bromides.
Lactamisation of anilines substituted with electron
withdrawing groups required longer reaction times
(3d, 3e, 3g). Both steps of the protocol could be
performed on multigram scale.[11]
Scheme 4. Enantioselective borylation-cyclisation and
oxidation. e.e. determined by HPLC analysis of (S)-5.
To demonstrate the utility of boronic ester lactams,
we explored their further reactivity. Oxidation of the
boronic ester to alcohol 6, using NaBO3·H2O, and
fluoride 7, using AgNO3 and Selectfluor,[14]
proceeded smoothly. Zweifel olefination and
Aggarwal arylation[15] were both successful, despite
the presence of enolizable protons from the lactam.
Suzuki-Miyaura cross coupling could be carried out
using the corresponding trifluoroborate salt 8, albeit
in moderate yield.[16]
Scheme 3. Scope of boronic ester lactams. Yields are of
isolated material unless otherwise state. a) 24 h reaction
time for step 2. b) 9 h reaction time for step 2. c) 5 h
reaction time for step 2. d) isolated as a 1:1 mixture with
pinacol. e) oxidation of the crude material using
2
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10.1002/adsc.202001339
Advanced Synthesis & Catalysis
References
[1]
D. G. Hall, Editor, Boronic Acids, Volume 1:
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Scheme 5. Transformations of boronic ester lactams. a)
NaBO3·H2O, THF/H2O. b) AgNO3 Selectfluor, TFA,
CH2Cl2/H2O, 60 °C. c) KHF2, MeOH. d) PhBr, cataCXium
A Pd G3 (5 mol%), Cs2CO3, PhMe/H2O, 110 °C. e) i)
furan, nBuLi, THF, −78 °C ii) 3c, iii) NBS, THF, −78 °C-
RT. f) i) vinyl MgBr, THF, −78 °C, ii) I2, MeOH, −78 °C,
iii) NaOMe, MeOH, −78 °C-RT.
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2019, 9, 4296–4301; (b) F. M. Dennis, C. C.
Robertson, B. M. Partridge, Synthesis 2020, 52,
1903–1914.
In summary, we have developed a protocol for the
preparation of γ-lactams containing an alkylboronic
ester handle. These boronic esters have much
potential as heterocyclic chemical building blocks,
demonstrated by a range of further transformations of
the boronic ester moeity. Further methods to produce
boronic ester heterocycles are underdevelopment and
will be reported in due course.
[8]
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3861.
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Experimental Section
General procedure for the preparation of γ-lactam boronic
esters (3):
An oven dried Schlenk flask was charged with B2pin2
(0.305 g, 1.20 mmol), CuI (4.0 mg, 0.020 mmol), K2CO3
(0.235 g, 1.70 mmol) and backfilled with Ar. Anhydrous
THF (2 mL) was added, and the mixture was stirred for 10
mins. A solution of the enoate 1 (1.00 mmol) in anhydrous
THF (1.3 ml) and methanol (0.08 ml, 2 mmol) was added,
and the mixture stirred for 1 h. The mixture was passed
through a plug of celite, and the solution was concentrated
in vacuo. The crude material was purified by either
chromatography or recrystallisation to give boronic ester 2.
[10]
(a) A. Torelli, A. Whyte, I. Polishchuk, J. Bajohr,
M. Lautens, Org. Lett. 2020, DOI
10.1021/acs.orglett.0c02837; (b) A. Whyte, K. I.
Burton, J. Zhang, M. Lautens, Angew. Chem. Int.
Ed. 2018, 57, 13927–13930.
Boronic ester 2 (0.5 mmol) was stirred in AcOH (1 ml,
0.5 M) at 50 °C for 4 h. The mixture was quenched with
saturated aqueous Na2CO3 (10.0 ml), and extracted with
CH2Cl2 (3 × 15.0 ml). The combined organic phases were
dried (MgSO4), filtered, and concentrated in vacuo to give
lactam 3.
[11]
[12]
For full details, see the supporting information.
J.-E. Lee, J. Yun, Angew. Chem. Int. Ed. 2008, 47,
145–147.
Acknowledgements
[13]
CCDC 2041142 ((S)-5) contains the
supplementary crystallographic data for this paper.
These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre.
This work was supported by EPSRC (EP/T009292/1) and the
University of Sheffield. We thank Redbrick Molecular Ltd. for a
CASE studentship for GR. We acknowledge Dr Antonio Romero-
Arenas for performing the HPLC analysis.
3
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10.1002/adsc.202001339
Advanced Synthesis & Catalysis
[14]
Z. Li, Z. Wang, L. Zhu, X. Tan, C. Li, J. Am.
Chem. Soc. 2014, 136, 16439–16443.
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4
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10.1002/adsc.202001339
Advanced Synthesis & Catalysis
COMMUNICATION
Synthesis of Boronic Ester γ-Lactam Building
Blocks
Adv. Synth. Catal. Year, Volume, Page – Page
George Rodgers, Ellen Wilson, Daniel Cox, Craig
C. Robertson, and Benjamin M. Partridge*
5
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