Regioselective Radical Borylation of α,β-Unsaturated Esters and Related Compounds by Visible Light Irradiation with an Organic Photocatalyst

Article abstract of DOI:10.1021/acs.orglett.1c01270

Radical hydroboration reactions have only recently been reported and are still rare. Here we describe a photoredox radical hydroboration of α,β-unsaturated esters, amides, ketones, and nitriles with NHC-boranes that uses only an organocatalyst and visible light. The conditions are mild, the substrate scope is broad, and the α/β regioselectivity is high. The reaction requires only the organocatalyst; there is no costly metal, and there are no other additives (base, cocatalyst, initiator).

Full text of DOI:10.1021/acs.orglett.1c01270

pubs.acs.org/OrgLett
Letter
Regioselective Radical Borylation of α,β-Unsaturated Esters and
Related Compounds by Visible Light Irradiation with an Organic
Photocatalyst
Guosong Li,§ Guanwang Huang,§ Ruixia Sun, Dennis P. Curran,* and Wen Dai*
Cite This: Org. Lett. 2021, 23, 4353−4357
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ABSTRACT: Radical hydroboration reactions have only recently been
reported and are still rare. Here we describe a photoredox radical
hydroboration of α,β-unsaturated esters, amides, ketones, and nitriles
with NHC-boranes that uses only an organocatalyst and visible light.
The conditions are mild, the substrate scope is broad, and the α/β
regioselectivity is high. The reaction requires only the organocatalyst;
there is no costly metal, and there are no other additives (base,
cocatalyst, initiator).
Scheme 1. Methods for Synthesis of Stable Boryl Carbonyl
Compounds
igated α- and β-boryl carbonyl compounds are air stable
Land easily handled. In these molecules, the ligated boryl
group and the carbonyl group can be independently
manipulated, and this opens paths to selective transformations
that are useful in a variety of fields.1 Ligated boryl carbonyl
compounds are typically either boronate derivatives of N-
methyliminodiacetic acid (MIDA)1 or borane complexes with
amines, phosphines, or N-heterocyclic carbene (NHC).2−5
B−H bond insertion reactions of ligated boranes and α-
diazocarbonyl compounds provided the first straightforward
route to make ligated α-boryl carbonyl compounds in the
borane oxidation state, and these reactions can be catalyzed by
Rh, Cu, and even genetically engineered enzymes (Scheme
1a).2 Wang has made a-NHC-boryl carbonyl compounds by
regioselective radical hydroboration of α,β-unsaturated carbon-
yl compounds with NHC-boranes (Scheme 1b).3 This reaction
is initiated by AIBN and aided by a thiol hydrogen atom
transfer (HAT) catalyst. We have made various α-NHC-boryl
ketones by radical reactions of alkenyl triflates and NHC-
boranes in the presence of diisopropyl ethyl amine (Scheme
1c).4 Most recently, Zhu described a photoredox method to
construct β-NHC-boryl imides using an iridium-based photo-
catalyst and thiol as the HAT catalyst (Scheme 1d).5
β-boryl compounds (Scheme 1d) is currently limited to imides.
Accordingly, practical methods of broad scope are needed.
These valuable methods have attendant limitations. α-
Diazocarbonyl compounds and alkenyl triflates need to be
synthesized and can be unstable (triflates) and even hazardous
(diazo carbonyls). Methods require expensive metal catalysts
or combine high-energy initiators with large amounts (20−50
mol %) of a thiol to aid hydrogen atom transfer. Substrate
limitations also constrain applicability. For example, the alkenyl
triflate (Scheme 1c) only provides ketones, while the route to
Received: April 15, 2021
Published: May 18, 2021
https://doi.org/10.1021/acs.orglett.1c01270
© 2021 American Chemical Society
Org. Lett. 2021, 23, 4353−4357
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Other reactions of NHC-boranes that are induced by visible
light and a metal photocatalyst include 1,4-hydroborations of
electron-poor aromatic rings,6,7 homolytic substitutions of
fluorine atoms in various settings,6,8,9 arylboration and
hydroboration of fluorinated alkenes,8 and hydroboration of
imines.10 In addition to a metal catalyst, all these reactions
require other additives including bases and thiols.
We next studied the scope with respect to the alkene
compounds, and Scheme 3 shows results of reactions of
various β-aryl-α,β-unsaturated esters, lactones, amides, nitriles,
and ketones. A variety of β-phenyl-α,β-unsaturated esters
smoothly underwent regioselective hydroboration to afford α-
boryl-β-phenyl esters, regardless of the electronic nature of the
substituents on the aromatic ring (see 3b−3k). β-Heteroaryl-
α,β-unsaturated esters with pyridine, thiophene, or quinoline
rings were also viable substrates, delivering the corresponding
α-addition products in moderate yields (3l−3n). Hydro-
boration of two cumarins worked well to give a-boryl lactones
3o and 3p.
In contrast, α,β-unsaturated esters bearing an additional
ester or cyano group at α-position led exclusively to β-addition
products in excellent yield (3q−3t). When α,β-unsaturated
esters containing an additional methyl group at α-position
were subjected to this protocol, the β-addition pathway
continued to predominate, giving stereoisomeric β-addition
products 3u-β and 3u-β′ in 62% combined yield with an 8%
yield of α-addition product 3u-α. The change in regioselec-
tivity is probably caused by synergistic steric and electronic
effects of the added substituent. The steric effect disfavors α-
addition. When a second electron-withdrawing group is added
at the α-position, the nucleophilicity of the NHC-boryl radical
takes over and β-selectivity is favorable.
̂
́
Predating all this recent work, Lacote and Lalevee reported
in 2012 the first examples of generation of NHC-boryl radicals
by visible light.11 They described soft polymerization of
acylates with NHC-boranes and acridine orange. Since then,
organic photocatalysts (dyes) have seen little use in small
molecule reactions of NHC-boranes. The hydroboration
reactions of Zhu succeeded with an iridium photocatalyst
but failed with eosin Y and 4-CzIPN (see Table S1 for
structure).5 Wu reported a few successful defluoroborylation
reactions with 4-CzIPN, but conditions with Ir photocatalysts
were much preferred.6
We have discovered that visible-light irradiation of
unsaturated carbonyl compounds or nitriles, NHC-boranes,
and a small amount of photocatalyst 2,4,5,6-tetrakis(diphenyl-
amino)isophthalonitrile (4-DPAIPN) regioselectively delivers
either α- or β-NHC-boryl functionalized compounds, depend-
ing on the substrate structure (Scheme 2). The starting
Scheme 2. Strategy for the Synthesis of Boryl
Functionalized Molecules
All the reactions in the scope study were conducted on 0.2
mmol scale. To test the scalability, we conducted a reaction
with 1.00 g (5.8 mmol) of 1a and 2 (674 mg, 1.1 equiv) under
the standard conditions. This provided 1.26 g of 3a, and the
yield (78%) is comparable to the small-scale experiment (83%,
Table S1, entry 14) (see the SI).
Next, we examined alternatives to esters as activating groups.
Pleasingly, representative α,β-unsaturated amides gave α-boryl
amides in good yields (3v−3z). Notably, several β-aryl-α,β-
unsaturated nitriles and a ketone also underwent the α-
additions affording the α-NHC-boryl products (3aa−3af).
However, cinnamic acid and cinnamaldehyde were inert to the
hydroboration process and did not provide the boryl carbonyl
compounds.
materials are structurally diverse and readily accessible, and the
scope is broad. The conditions are mild and metal-free, and no
base, cocatalyst, or other additive is needed.
The β-aryl group in these substrates stabilizes the adduct
radical by resonance, thereby promoting α-addition. In
contrast, β-addition might be favored due to the strong
nucleophilicity of NHC-boryl radical if this group is absent. To
test this notion, we next studied the reactions to β-alkyl-α,β-
unsaturated carbonyl compounds (Scheme 4). Indeed, a wide
range of β-alkyl-α,β-unsaturated esters and lactones were
suitable substrates and underwent β-addition, giving solely β-
boryl esters and lactones in generally good yields (3ag−3an).
Increasing the steric effect on the β-carbon, such as ethyl 3-
methylcrotonate, failed to give the desired hydroboration
product. Interestingly, ethyl acrylate, which is easily poly-
merized by NHC-boryl radicals,11 was hydroborated to provide
the β-NHC-boryl ester 3ao in good yield. Reactions of β-alkyl-
α,β-unsaturated amides were also highly β-selective, albeit with
moderate yields (3ap−3ar). Finally, a β-alkyl-α,β-unsaturated
nitrile also afforded the β-boryl nitrile in good yield (3as).
Scheme 5 summarizes experiments aimed at providing
mechanistic information. In radical-blocking experiments,
reactions of 1a and 2 were conducted under standard
conditions in the presence of 2,2,6,6-tetramethyl-1-piperidinyl
oxyl (TEMPO) as a radical scavenger. When 4 equiv of
TEMPO were used, the yield of α-boryl ester 3a was decreased
to 20%. When 6 equiv of TEMPO were used, 3a was not
We chose ethyl cinnamate 1a and 1,3-dimethylimidazoyl-2-
ylidine borane 212 as pilot reaction partners, and Table S1 (see
the Supporting Information (SI)) shows the results of an
assortment of preliminary reactions. In the first experiment,
irradiation of a room temperature acetonitrile solution of 1a, 2
(2 equiv), and the photocatalyst 3-DPAFIPN13 (10 mol %)
with a 30 W blue light-emitting diode (LED) for 12 h provided
α-boryl ester 3a in 56% isolated yield (entry 1). No product
was produced in the absence of the light or photocatalyst
(entries 2 and 3). Next, we reduced the amount of borane and
found that 1.1 equiv gave about the same yield as 2 equiv
(entries 4 and 5). Among the various photocatalysts tested (4-
DPAIPN, 4-CzIPN, 4-CzPN, 5-CzBN, eosin Y, and DCN,
entries 6−11), 4-DPAIPN gave the best yield (99% NMR,
82% isolated, entry 6).14 Decreasing the catalyst loading to 5
mol % resulted in a moderate decrease in yield (94% NMR,
79% isolated, entry 12), whereas increasing the amount of
catalyst gave about the same yield (entry 13). Finally,
decreasing the reaction time from 12 to 8 h did not change
the yield, while a further decrease to 5 h gave a moderate
reduction (compare entries 6, 14, and 15).
Based on these results, we selected the conditions of entry
14 (10% mol 4-DPAIPN, 8 h, rt) as standard for the ensuing
study of scope.
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Scheme 3. Scope of Photocatalytic Radical Borylation of β-Aryl-α,β-unsaturated Esters, Lactones, Amides, Nitriles, and
a b
,
Ketones
a
b
Standard conditions: alkene 1 (0.2 mmol), 2 (0.22 mmol), 4-DPAIPN (10 mol %), MeCN (2 mL), rt, 30 W blue LEDs, 8 h. The yield was
c
d
e
determined by 11B-NMR, and isolated yield is given in parentheses. 16 h. 24 h. 72 h.
formed. In both experiments adduct 15 was detected by
HRMS. These results suggest that an NHC-boryl radical
pathway is involved but that the reaction is not a radical chain
(only small amounts of TEMPO are needed to inhibit chains).
Deuteration experiments were performed to learn the source
of the new hydrogen atom, the three possibilities being the
solvent, the NHC-borane, or water from undried solvent.
There was no deuterium in product 3a when the reaction was
performed in CD3CN, so the solvent is not the source of the
hydrogen atom. When 2 was replaced with 2-d3, 25%
deuterium incorporation was found at the benzylic position
of the product 3a-d2/3a-d3. When the reaction was performed
with unlabeled 2 and 15 equiv of D2O, the product 3a/3a-d1
contained a single deuterium (95%) at the benzylic position.
These results show that the source of the hydrogen atom on
carbon is a proton, which can come from either residual water
or the NHC-borane (Scheme 5b).
radical cation 16 produces the NHC-boryl radical. In this way,
a hydrogen atom from the NHC-borane is incorporated into
the proton pool with residual water.
Next, the oxidatively generated the NHC-boryl radical
undergoes addition to the electron-deficient alkenes. For the β-
aryl substituted alkene, the NHC-boryl radical undergoes α-
addition, giving radical intermediate 17. For the β-alkyl
substituted alkene, addition occurs at the β-carbon to generate
radical intermediate 18. Both intermediates 17 and 18 are then
quickly reduced by PC−• to the corresponding anions 19 and
20 with the concurrent regeneration of the photocatalyst PC,
thus completing the photocatalytic cycle.16 Protonation of
these anions provides the hydroboration products.
In summary, we have developed a photoredox radical
hydroboration of electron-deficient alkenes with NHC-boranes
that uses only an organocatalyst. The substrate scope is broad,
and a wide variety of stable α- or β-boryl esters, amides,
ketones, and nitriles are formed in good yields. The α/β
regioselectivity is high and is dictated by the substituents of the
alkene component. Neither reaction component is used in
excess, the conditions are mild, and both the reaction and
purification protocols are convenient.
Taken together, results support a photoredox catalysis
mechanism as outlined in Scheme 6. The organic photocatalyst
PC absorbs a photon to give an excited state PC*,15 which is
quenched by NHC-BH3 to generate the photocatalyst radical
PC−• and radical cation 16. Subsequent deprotonation of the
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Scheme 4. Scope of Photocatalytic Radical β-Borylation
with β-Alkyl-α,β-unsaturated Esters, Lactones, Amides, and
Nitriles
Scheme 6. Proposed Mechanistic for Radical Borylation of
Alkenes with NHC-Boranes
a b
,
NHC-boryl radicals from NHC-boranes. This opens the way
for further development of visible-light-driven radical bor-
ylation reactions, thereby enabling the unique features of
NHC-boranes to be used in new transformations.
a
Standard conditions: alkene 1 (0.2 mmol), 2a (0.22 mmol), 4-
b
DPAIPN (10 mol %), MeCN (2 mL), rt, 30 W blue LEDs, 8 h. The
yield was determined by 11B-NMR, and isolated yield is given in
c
d
e
f
g
parentheses. 24 h. 16 h. 2a (0.30 mmol), 16 h. 72 h. 48 h.
ASSOCIATED CONTENT
* Supporting Information
■
sı
Scheme 5. Mechanistic Experiments
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c01270.
Experimental, compound characterization, and copies of
spectra (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
Dennis P. Curran − Department of Chemistry, University of
Pittsburgh, Pittsburgh, Pennsylvania 15208, United States;
orcid.org/0000-0001-9644-7728; Email: curran@
pitt.edu
Wen Dai − Dalian Institute of Chemical Physics, Chinese
Academy of Sciences, Dalian 116023, China; orcid.org/
0000-0002-9098-5215; Email: daiwen@dicp.ac.cn
Authors
Guosong Li − Dalian Institute of Chemical Physics, Chinese
Academy of Sciences, Dalian 116023, China
Guanwang Huang − Dalian Institute of Chemical Physics,
Chinese Academy of Sciences, Dalian 116023, China
Ruixia Sun − Dalian Institute of Chemical Physics, Chinese
Academy of Sciences, Dalian 116023, China
Compared to other recent hydroboration reactions with
NHC-boranes, this method has a broader scope.5,6 In addition,
it does not require a metal catalyst and has no other additives
besides the organocatalyst itself. The method directly delivers
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c01270
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(10) Zhou, N.; Yuan, X. A.; Zhao, Y.; Xie, J.; Zhu, C. Synergistic
photoredox catalysis and organocatalysis for inverse hydroboration of
imines. Angew. Chem., Int. Ed. 2018, 57, 3990.
Author Contributions
§G.L. and G.H. contributed equally.
(11) Telitel, S.; Schweizer, S.; Morlet-Savary, F.; Graff, B.;
Notes
̂
Tschamber, T.; Blanchard, N.; Fouassier, J. P.; Lelli, M.; Lacote, E.;
The authors declare no competing financial interest.
Lalevée, J. Soft photopolymerizations initiated by dye-sensitized
formation of NHC-boryl radicals under visible light. Macromolecules
2013, 46, 43.
ACKNOWLEDGMENTS
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(12) Gardner, S.; Kawamoto, T.; Curran, D. P. 1,3-dimethylimida-
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Chem. Soc. 2020, 142, 9163.
Financial support from Dalian Institute of Chemical Physics
and the National Natural Science Foundation of China
(21773232) is acknowledged.
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