Decarboxylative Conjunctive Cross-coupling of Vinyl Boronic Esters using Metallaphotoredox Catalysis

Article abstract of DOI:10.1002/anie.201916340

The synthesis of complex alkyl boronic esters through conjunctive cross-coupling of vinyl boronic esters with carboxylic acids and aryl iodides is described. The reaction proceeds under mild metallaphotoredox conditions and involves an unprecedented decarboxylative radical addition/cross-coupling cascade of vinyl boronic esters. Excellent functional-group tolerance is displayed, and application of a range of carboxylic acids, including secondary α-amino acids, and aryl iodides provides efficient access to highly functionalized alkyl boronic esters. The decarboxylative conjunctive cross-coupling was also applied to the synthesis of sedum alkaloids.

Full text of DOI:10.1002/anie.201916340

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Accepted Article
Title: Decarboxylative Conjunctive Cross-coupling of Vinyl
Boronic Esters using Metallaphotoredox Catalysis
Authors: Riccardo S. Mega, Vincent K. Duong, Adam Noble, and
Varinder Kumar Aggarwal
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201916340
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10.1002/anie.201916340
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Decarboxylative Conjunctive Cross-coupling of Vinyl Boronic
Esters using Metallaphotoredox Catalysis
Riccardo S. Mega, Vincent K. Duong, Adam Noble* and Varinder K. Aggarwal*
Abstract: The synthesis of complex alkyl boronic esters via a
conjunctive cross-coupling of vinyl boronic esters with carboxylic
acids and aryl iodides is described. The reaction proceeds under mild
metallaphotoredox conditions and involves an unprecedented
decarboxylative radical addition/cross-coupling cascade of vinyl
boronic esters. Excellent functional group tolerance is displayed, and
application of a range of carboxylic acids, namely secondary α-amino
acids, and aryl iodides provides efficient access to highly
functionalized alkyl boronic esters. The decarboxylative conjunctive
cross-coupling was also applied to the synthesis of sedum alkaloids.
Reactions that can transform feedstock chemicals into
structurally complex and synthetically valuable products are
highly sought after in organic synthesis. An attractive approach to
achieving this goal is to use multicomponent reactions, wherein
three or more substrates are simultaneously coupled, thus rapidly
increasing molecular complexity.[1] A useful subset of these
reactions is three-component conjunctive cross-couplings of
carbon–carbon π-bonds, which extends the synthetic utility of
traditional cross-couplings by incorporating a conjunctive reagent
that is difunctionalized by reaction with both the nucleophilic and
electrophilic coupling partners (Scheme 1a).[2] Despite recent
advances in this area, these methods rely heavily on
organometallic reagents, prefunctionalized starting materials and
precious metal catalysts.
Carboxylic acids, which are abundant feedstock chemicals,
have recently emerged as unconventional alternatives to
traditional nucleophilic coupling partners in cross-coupling
reactions.[3] This is due to recent developments in
metallaphotoredox catalysis, where carboxylic acids undergo
single-electron transfer (SET)-mediated decarboxylative cross-
coupling in the presence of a nickel catalyst under mild
photocatalytic conditions.[4] Although metallaphotoredox catalysis
has found many applications in two-component decarboxylative
cross-coupling reactions,[5] extension to three-component
conjunctive cross-couplings of alkenes has not been reported.[6]
To date, examples of metallaphotoredox-catalyzed conjunctive
cross-couplings are limited to the use of preactivated substrates,
such as oxalate esters or alkyl silicates,[7] which must first be
synthesized.[8] As such, the development of related reactions that
utilize readily available carboxylic acids is highly desirable.
Scheme 1. Conjunctive cross-coupling reactions and decarboxylative radical
additions to vinyl boronic esters.
We
recently
reported
a
photoredox-catalyzed
decarboxylative Giese reaction between carboxylic acids 1 and
vinyl boronic esters 2 (Scheme 1b).[9] Key to the success of this
reaction was the formation of a stabilized α-boryl radical 3 upon
addition of an alkyl radical to 2. We demonstrated that radical 3
could be reduced by the photocatalyst to the corresponding anion
4, giving the Giese product 5 after protonation. This radical–polar
crossover methodology was also extended by intercepting α-boryl
anion 4 in an intramolecular alkylation to access a range of
boronic ester-substituted cyclopropanes 6.[10] Inspired by recent
reports of nickel catalyzed cross-couplings of α-boryl halides,[11]
we questioned whether the α-boryl radical intermediate 3 could
be intercepted in nickel-catalyzed cross-couplings with aryl
halides to generate benzylic boronic esters 7. This would extend
our strategy to a three-component decarboxylative conjunctive
cross-coupling reaction, allowing rapid, convergent build-up of
molecular complexity using abundant, readily available feedstock
materials. Furthermore, the incorporation of the versatile boronic
ester into the product would provide a valuable functional handle
for further manipulation.[12,13] Herein, we report the first example
of a metallaphotoredox-catalyzed decarboxylative conjunctive
cross-coupling reaction between carboxylic acids, vinyl boronic
esters and aryl iodides.
[*]
R. S. Mega, V. K. Duong, Dr. A. Noble, Prof. Dr. V. K. Aggarwal
School of Chemistry, University of Bristol
Cantock’s Close, Bristol, BS8 1TS (UK)
E-mail: a.noble@bristol.ac.uk
During our studies, we focused on the use of secondary
α-amino acids as substrates because (i) they are readily available
and would provide access to structurally complex alkyl boronic
ester products; and (ii) we wished to address a limitation of
previously reported metallaphotoredox-catalyzed conjunctive
v.aggarwal@bristol.ac.uk
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201916340
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COMMUNICATION
cross-couplings, which are mainly limited to reactions of tertiary
alkyl radicals,[7] unless highly electrophilic conjunctive reagents
are employed.[7b] This is because tertiary radicals do not readily
undergo the competing nickel-catalyzed two-component coupling
coupled product in 79% yield, outcompeting direct two-
component coupling of 1a and 10a, Giese hydroalkylation and
protodehalogenation of the aryl iodide limiting reagent (entry 1).
The use of pinacol boronic ester (vinyl-Bpin) in place of 2a
resulted in lower yield of 7a and an increase in formation of Giese
product 5a (entry 2). The corresponding aryl bromide led to a
dramatic decrease in yield, with increased amounts of Giese
product 5a suggesting inefficient nickel catalysis (entry 3).
Lowering the equivalents of vinyl boronic ester 2a resulted in a
reduced yield of 7a due to competitive formation of two-
component coupling product 13a (entry 4); however we were
surprised to still see good selectivity for 7a (compare entries 1 and
4, 7a:13a = 6:1 vs. 3:1). Further evaluation of catalyst loading and
solvent provided no improvement in efficiency (entries 5–8).
Finally control experiments confirmed the necessity of the two
catalysts, base, and light (entries 9–12).
reactions whereas secondary radicals do.
A
proposed
mechanism for the decarboxylative conjunctive cross-coupling is
depicted in Scheme 2. Initial SET between the excited state
photocatalyst (PC*) and the conjugate base of carboxylic acid 1a
generates a carboxyl radical that decarboxylates to give α-amino
radical 8. The nucleophilic radical 8 then adds to vinyl boronic
ester 2 to form the stabilized α-boryl radical 3. Concurrently, the
nickel catalytic cycle begins by formation of aryl nickel(II) complex
9 by oxidative addition of aryl halide 10 to the Ni(0) catalyst.
Interception of radical 3 by 9, followed by reductive elimination of
the resulting nickel(III) species 11, provides the desired
conjunctive cross-coupled product 7. Final SET between the
reduced state of the photocatalyst (PC•–) and nickel(I) complex 12
completes the two catalytic cycles. We recognized two main
challenges associated with the successful development of this
conjunctive cross-coupling: (i) the rate of addition of radical 8 to
the vinyl boronic ester 2 must be faster than addition of 8 to the
nickel(II) complex 9 in order to avoid formation of the two-
component coupling product 13, which is challenging because
alkyl radicals add to vinyl boronic esters with a rate >20 times
lower than that for addition to acrylates;[14] and (ii) the rate of
reaction of α-boryl radical 3 with 9 must be faster than SET
between 3 and the reduced photocatalyst (PC•–), which is
necessary to prevent the formation of Giese product 5.[9]
Table 1. Optimization studies.
% yield[a]
5a[b]
variation from above
Entry
conditions
7a
13a
14a
10a
1
2
none
79
69
5
13
7
8
17
52
8
7
0
0
vinyl-Bpin instead of 2a
ArBr instead of 10a
1.5 equiv of 2a
10 mol% NiCl2•dtbbpy
DMF as solvent
DMSO as solvent
MeCN as solvent
no photocatalyst
no nickel/dtbbpy
no base
17
11
11
12
16
27
20
7
3
2
58
0
4
67
75
70
23
38
0
22
13
13
5
5
8
0
6
11
15
17
0
0
7
18
19
69
0
8
12
0
9
10
11
12
0
0
11
0
58
2
0
0
75
89
no light
0
0
0
0
All reactions were carried out with 1a (0.12 mmol), 2a (0.30 mmol), 10a
(0.10 mmol), NiCl2•glyme (5 mol%), dtbbpy (6 mol%), and Cs2CO3 (1.3
equiv) in DMA (4 mL). [a] Determined by 19F NMR using hexafluorobenzene
as an internal standard. [b] Determined by GC using 1,2,4-
trimethoxybenzene as an internal standard. DMA
dimethylacetamide.
=
N,N-
Scheme 2. Proposed mechanism.
With the optimal reaction conditions in hand we next
explored the scope of the conjunctive cross-coupling reaction with
respect to the carboxylic acid substrate (Table 2, top). For
isolation of the products, we found that partial instability of the
benzylic hexylene glycol boronic esters resulted in diminished
yields (64% for 7a) and that in situ oxidation with H2O2 allowed
isolation of the corresponding alcohols in high yield (76% for 7a).
A range of cyclic secondary α-amino acids, including those with
different ring sizes and carbamate protecting groups, gave the
corresponding three-component coupled products in moderate to
Our investigations began with the reaction of Boc-Pro-OH
1a, hexylene glycol vinyl boronic ester 2a, and 4-
fluoroiodobenzene (10a) (Table 1). We were delighted to find that
using
2
mol% of the organic photocatalyst, 1,2,3,5-
tetrakis(carbazol-9-yl)-4,6-dicyanobenzene (4CzIPN), 5 mol%
NiCl2•glyme and 6 mol% 4,4′-di-tert-butyl-2,2′-dipyridyl (dtbbpy) in
combination with Cs2CO3 gave the desired conjunctive cross-
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10.1002/anie.201916340
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high yields (15−18). A cyclic tertiary amino acid also reacted with
good efficiency (19). In addition, primary, secondary and tertiary
acyclic α-amino acids were found to be suitable substrates (21–
30), and a range of functional groups were tolerated under the
mild conditions. In general, we found that lower yields were
obtained with substrates containing an NH group, however, N-
Boc-N-Me-Gly-OH) resulted in an 11% yield of product 21,
increasing the selectivity for conjunctive cross-coupling from
<5:95 to 24:76. Selectivity was switched in favor of conjunctive
cross-coupling upon changing to secondary α-amino acids due to
increased steric hindrance around the putative carbon-centered
radical, with Boc-Ala-OH providing a 67:33 ratio of 22:22′. The
beneficial effect of N-methylation was also observed with alanine
as Boc-N-Me-Ala-OH provided 23 with >95:5 selectivity over the
methylation resulted in improved yields. Alternatively,
phthalimide protecting group could be used, providing 26 in
a
moderate yield. The reaction was not only limited to α-amino acids, direct coupling product 23′ (entry 4). As expected, the tertiary
as α-oxy acids also gave the corresponding products in modest
to high yield, including Trolox (31), a vitamin E analogue,
bezafibrate (32), a fibrate-drug, and clofibric acid (33), a herbicide.
The successful application of these substrates exemplifies the
potential to rapidly incorporate molecular complexity at a late
stage into biologically important molecules.
Given the known application of α-amino acids in
metallaphotoredox-catalyzed two-compound cross-couplings,[5a]
and the previous reliance on tertiary alkyl radical precursors in
conjunctive cross-couplings,[7,13] we were intrigued by the
unexpected high selectivity for conjunctive cross-coupling in our
system so proceeded to investigate the effect of sterics on the
reaction outcome (Scheme 3). The use of the primary α-amino
acid, Boc-Gly-OH gave none of the desired product 20, instead
forming only the two-component cross-coupled product 20′.
Interestingly, methylating the nitrogen of Boc-Gly-OH (forming
Scheme 3. Effect of sterics on product selectivity.
Table 2. Decarboxylative conjunctive cross-coupling scope.[a]
[a] Reactions were carried out on a 0.30 mmol scale with irradiation times of between 16 and 48 h. See Supporting Information for exact experimental procedures.
Yields are of isolated products after oxidation with urea hydrogen peroxide (3.0 equiv). Products 7a, 15–19, 22–31, and 34–43 were formed as mixtures of
diastereomers with diastereomeric ratios of between 50:50 and 66:34. [b] Yield of isolated boronic ester on 0.10 mmol scale.
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10.1002/anie.201916340
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carboxylic acid, Boc-Aib-OH provided complete selectivity for
conjunctive cross-coupled product 24. The importance of sterics
for promoting conjunctive cross-coupling was further highlighted
by the unsuccessful reaction of simple unhindered secondary
aliphatic carboxylic acids.[15]
In
conclusion,
a
metallaphotoredox-catalyzed
decarboxylative conjunctive cross-coupling of vinyl boronic esters
with carboxylic acids and aryl iodides has been developed for the
synthesis of complex alkyl boronic esters from feedstock
materials. The unexpectedly high selectivity for conjunctive cross-
coupling over direct two-component coupling in reactions of
secondary α-amino acids is distinct from many previously
reported radical-mediated conjunctive cross-couplings, which rely
heavily on the use of tertiary alkyl radical precursors.[7,13] This
allowed the reaction to be applied to a wide range α-amino acids,
and the synthetic utility of the method was highlighted in concise
syntheses of four sedum alkaloids.
Next, we explored the use of different aryl iodides (Table 2,
bottom). A wide range of electron-rich aryl iodides could be
effectively coupled to give the desired conjunctive cross-coupled
products (34–43). In addition to alkyl substituents, ortho-fluoro
(35) and para-methoxy (36) groups were tolerated. Various
iodoaniline derivatives also reacted in good yields, providing para-
and meta-carbamates 38 and 39, and pyrrole 40. Heterocyclic
iodides were also successful coupling partners, including
pyridines,[16] indoles and benzodihydrofurans, giving products 41–
43 in good to excellent yields. Unfortunately, although electron-
deficient aryl iodides were competent coupling partners, the
boronic ester products proved unstable to protodeboronation
under the reaction conditions.[15] Furthermore, extension of this
decarboxylative conjunctive cross-coupling to other Michael
acceptors, such as acrylates, proved unsuccessful due to the
facile generation of Giese hydroalkylation products.[15]
Presumably, the success of the vinyl boronic esters is due to a
slower rate of reduction of the α-boryl radical 3 by the reduced
photocatalyst (PC•–), compared to the corresponding α-carboxyl
radical (–1.25 V[9] vs. –0.6 V[17] respectively), which allows it to be
intercepted by the nickel(II) complex 9.
Acknowledgements
We thank H2020 ERC (670668) for financial support. V.K.D
thanks the National University of Ireland for a Travelling
Studentship Award.
Keywords: metallaphotoredox catalysis • decarboxylative cross-
coupling • conjunctive cross-coupling • alkyl boronic esters •
carboxylic acids
[1]
For selected reviews on multicomponent reactions, see: a) J. E. Biggs-
Houck, A. Younai, J. T. Shaw, Curr. Opin. Chem. Biol. 2010, 14, 371; b)
R. C. Cioc, E. Ruijter, R. V. A. Orru, Green Chem. 2014, 16, 2958; c) S.
Zhi, X. Ma, W. Zhang, Org. Biomol. Chem. 2019, 17, 7632.
J. Derosa, V. T. Tran, V. A. van der Puyl, K. M. Engle, Aldrichimica Acta
2018, 51, 21.
In order to demonstrate the utility of this methodology, we
applied it in two-step syntheses of several sedum alkaloids,
including sedamine (46), which shows potential in the treatment
of cognitive disorders, and allosedamine (47), which is used in the
treatment of respiratory illnesses (Scheme 4).[18] These alkaloids
contain the ubiquitous 1,3-aminoalcohol motif, which is easily
[2]
[3]
[4]
T. Patra, D. Maiti, Chem. Eur. J. 2017, 23, 7382.
a) J. Twilton, C. Le, P. Zhang, M. H. Shaw, R. W. Evans, D. W. C.
MacMillan, Nat. Rev. Chem. 2017, 1, 0052; b) J. A. Milligan, J. P. Phelan,
S. O. Badir, G. A. Molander, Angew. Chem. Int. Ed. 2019, 58, 6152;
Angew. Chem. 2019, 131, 6212.
generated
using
this
methodology.
Conducting
the
decarboxylative conjunctive cross-coupling with Boc-Pip-OH,
vinyl boronic ester 2a and iodobenzene 10b, followed by in situ
oxidation with H2O2 provided the separable diastereomeric γ-
amino alcohols 44 and 45 in 70% combined yield. Subsequent
reduction of the Boc-group with LiAlH4 provided (±)-sedamine (46)
and (±)-allosedamine (47) in 84% and 71% yield from 44 and 45,
respectively. Alternatively, Boc-deprotection with methanolic HCl
gave (±)-norsedamine (48) and (±)-norallosedamine (49) in
excellent yields.
[5]
For selected examples, see: a) Z. Zuo, D. T. Ahneman, L. Chu, J. A.
Terrett, A. G. Doyle, D. W. C. MacMillan, Science 2014, 345, 437; b) A.
Noble, S. J. McCarver, D. W. C. MacMillan, J. Am. Chem. Soc. 2015,
137, 624; c) Z. Zuo, H. Cong, W. Li, J. Choi, G. C. Fu, D. W. C. MacMillan,
J. Am. Chem. Soc. 2016, 138, 1832; d) C. P. Johnston, R. T. Smith, S.
Allmendinger, D. W. C. MacMillan, Nature 2016, 536, 322.
[6]
[7]
A single report of decarboxylative three-component conjunctive cross-
coupling of alkynes was recently reported, see: C. Zhu, H. Yue, B. Maity,
I. Atodiresei, L. Cavallo, M. Rueping, Nat. Catal. 2019, 2, 678.
a) L. Guo, H.-Y. Tu, S. Zhu, L. Chu, Org. Lett. 2019, 21, 4771; b) A.
García-Domínguez, R. Mondal, C. Nevado, Angew. Chem. Int. Ed. 2019,
58, 12286; Angew. Chem. 2019, 131, 12414; For a metallaphotoredox-
catalyzed conjunctive cross-coupling of alkynes, see: c) L. Guo, F. Song,
S. Zhu, H. Li, L. Chu, Nat. Commun. 2018, 9, 4543.
[8]
[9]
During the preparation of this manuscript, Molander reported a
metallaphotoredox-catalyzed conjunctive cross-coupling of vinyl boronic
esters using readily available potassium alkyl trifluoroborate salts, see:
M. W. Campbell, J. S. Compton, C. B. Kelly, G. A. Molander, J. Am.
Chem. Soc. 2019, 141, 20069.
a) A. Noble, R. S. Mega, D. Pflästerer, E. L. Myers, V. K. Aggarwal,
Angew. Chem. Int. Ed. 2018, 57, 2155; Angew. Chem. 2018, 130, 2177;
For a review of radical additions to alkenylboron compounds, see: b) G.
J. Lovinger, J. P. Morken, Eur. J. Org. Chem. 2019, DOI:
10.1002/ejoc.201901600.
[10] C. Shu, R. S. Mega, B. J. Andreassen, A. Noble, V. K. Aggarwal, Angew.
Chem. Int. Ed. 2018, 57, 15430; Angew. Chem. 2018, 130, 15656.
[11] a) J. Schmidt, J. Choi, A. T. Liu, M. Slusarczyk, G. C. Fu, Science 2016,
354, 1265; b) S.-Z. Sun, R. Martin, Angew. Chem. Int. Ed. 2018, 57,
3622; Angew. Chem. 2018, 130, 3684.
[12] C. Sandford, V. K. Aggarwal, Chem. Commun. 2017, 53, 5481.
Scheme 4. Application to the synthesis of sedum alkaloids.
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[13] For a conjunctive cross-coupling of vinyl boronic esters using organozinc
reagents, see: M. Chierchia, P. Xu, G. J. Lovinger, J. P. Morken, Angew.
Chem. Int. Ed. 2019, 58, 14245; Angew. Chem. 2019, 131, 14383.
[14] N. Guennouni, L. Lhermitte, S. Cochard, B. Carboni, Tetrahedron 1995,
51, 6999.
[15] See Supporting Information for details.
[16] For the formation of product 41, the electron-donating 2-methoxy
substituent on the pyridine ring was required to avoid protodeboronation
of the boronic ester product.
[17] N. Bortolamei, A. A. Isse, A. Gennaro, Electrochim. Acta 2010, 55, 8312.
[18] S. G. Davies, A. M. Fletcher, P. M. Roberts, A. D. Smith, Tetrahedron
2009, 65, 10192.
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Entry for the Table of Contents
One-step to molecular complexity: A decarboxylative conjunctive cross-coupling of carboxylic acids, vinyl boronic esters and aryl
iodides is described. The reaction proceeds under mild metallaphotoredox conditions and utilizes readily available feedstock materials,
namely secondary α-amino acids, to access highly functionalized benzylic boronic esters in a single step.
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