The coupling of alkylboronic acids and esters with Baylis–Hillman derivatives by Lewis base/photoredox dual catalysis

Article abstract of DOI:10.1016/j.tetlet.2019.04.015

Utilizing Lewis base/photoredox dual catalysis, carbon radicals generated from either alkylboronic acids or esters were coupled with Baylis–Hillman derivatives under visible light irradiation. This protocol provides a mild and operationally simple method

Full text of DOI:10.1016/j.tetlet.2019.04.015

Accepted Manuscript
The Coupling of Alkylboronic Acids and Esters with Baylis−Hillman Deriva-
tives by Lewis Base/Photoredox Dual Catalysis
Hongqiang Ye, He Zhao, Shujian Ren, Hongfeng Ye, Dongping Cheng,
Xiaonian Li, Xiaoliang Xu
PII:
S0040-4039(19)30338-7
https://doi.org/10.1016/j.tetlet.2019.04.015
TETL 50730
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
9 January 2019
3 April 2019
4 April 2019
Please cite this article as: Ye, H., Zhao, H., Ren, S., Ye, H., Cheng, D., Li, X., Xu, X., The Coupling of Alkylboronic
Acids and Esters with Baylis−Hillman Derivatives by Lewis Base/Photoredox Dual Catalysis, Tetrahedron
Letters (2019), doi: https://doi.org/10.1016/j.tetlet.2019.04.015
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The Coupling of Alkylboronic Acids and Esters with Baylis−Hillman Derivatives by
Lewis Base/Photoredox Dual Catalysis
Hongqiang Ye,a He Zhao,a Shujian Ren,a Hongfeng Ye,a Dongping Cheng,*b Xiaonian Li,*a and Xiaoliang
Xua
aCollege of Chemical Engineering, Zhejiang University of Technology, Hangzhou 310014, P. R. China
bCollege of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou 310014, P. R. China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Utilizing Lewis base/photoredox dual catalysis, carbon radicals generated from either
alkylboronic acids or esters were coupled with Baylis−Hillman derivatives under visible light
irradiation. This protocol provides a mild and operationally simple method for the synthesis of a
variety of α,β-unsaturated carbonyl compounds in a broad scope of the substrates. The
mechanism of Lewis base activation and reductive quenching cycle was probably involved.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
Visible light photocatalysis
Lewis base activation
alkylboronic acids and esters
Baylis−Hillman derivatives
———
 Corresponding author. Tel.: +86-571-88320920; e-mail: chengdp@zjut.edu.cn; xnli@zjut.edu.cn; xuxiaoliang@zjut.edu.cn

2
Introduction
Recently the visible light photoredox catalysis has seeded several types of novel chemical transformations.1 Visible light
photoredox catalysis has exhibited tremendous prospects and wide applications in organic synthesis owing to the rich and renewable
resource of visible light, high reaction efficiency, and mild conditions. Moreover, it showed obvious advantages over traditional
methods in sustainability for using visible light.
The trisubstituted alkene moieties have been found in a variety of bioactive molecules.2 Especially, they are also key
intermediates in organic synthesis. As a result, it’s very important to develop the methods for the preparation of trisubstituted
alkenes.3 The Baylis-Hillman adducts4 such as 3-hydroxy-2-methylene-alkanoates (derived from acrylate esters) have become one
of the important and attractive intermediates for stereoselective synthesis of different multifunctional trisubstituted alkene
molecules. Several traditional methods5 such as nucleophilic addition of Grignard reagent, Friedel-Crafts reaction and Pd-catalyzed
cross-coupling reaction have been developed for the synthesis of similar trisubstituted acrylate derivatives from Baylis-Hillman
adducts. While these methods have emerged as reliable tools in generating diverse trisubstituted alkenes, they have several
drawbacks such as harsh reaction condition and poor tolerance of functional groups. Carbon-centered radicals6 are currently
available to generate in the context of a photocatalytic cycle1 and some of them could be coupled with Baylis-Hillman adducts.
Recently we7 reported the coupling of potassium organotrifluoroborates with Baylis-Hillman derivatives via visible-light
photoredox catalysis.8 However, due to the unfavorable redox potential, primary alkyltrifluoroborates and phenyltrifluoroborate are
not suitable substrates.9 Recently, it was demonstrated that Lewis base catalysis could be introduced to enhance the reactivity of
electrophilic p orbitals.10 Based on this concept, we investigated the combination of Lewis base and photoredox catalysis could
promote the alkylboronic acid derivatives11 to generate carbon radicals. Herein, we report the synthesis of α,β-unsaturated carbonyl
compounds through a dual catalysis approach from a broad scope of alkylboronic acids and esters under mild conditions.
Result and discussion
In order to achieve the optimal conditions for the above transformation, a series of experiments were carried out (Table 1). The
initial reaction of methyl 3-phenyl-2-methylene-3-(tert-butoxycarbonyl)oxypropanoate 1a and cyclohexylboronic acid 2a was
performed in the presence of 0.2 equiv of 4-dimethylaminopyridine (DMAP) and 1 mol% photocatalyst PC(1) in N-methyl
pyrrolidone (NMP). Irradiation of the mixture with 45W CFL at ambient temperature for 20 h led to the coupling product 4a in 71%
yield (entry 1). Among other photocatalysts tested, none of them gave better yields (entries 2-4). A range of solvents such as
DMSO, DMF, acetone, MeCN, Et2O, EtOAc, DCE and DCM was tried but gave disappointing results (entries 5-12). Then we
decided to investigate the catalytic activity of other Lewis bases (entries 13-16). DABCO (triethylenediamine) was identified as an
excellent base, leading to the yield of 4a up to 82%. Based on above conditions, neither extending the reaction time nor switching to
blue LEDs could improve product yield (entries 17-18). However, increasing the amount of DABCO to 50 mol% provided 4a in a
lower yield (entry 19). It was finally revealed that the combination of Ir[dF(CF3)ppy]2(dtbbpy)PF6 as a photocatalyst, DABCO as a
Lewis base, NMP as a solvent and 20hrs was most effective and the desired product was obtained in 82% yield (entry 13). Notably,
the control experiments showed that there was no desired coupling product observed in the absence of photocatalyst, base or light
(entries 20-22).
Table 1: Optimization of the reaction conditionsa
Entry
Photocatalyst
PC(1)
Solvent
NMP
Base
yield(%) b
1
DMAP
DMAP
DMAP
DMAP
DMAP
DMAP
DMAP
DMAP
DMAP
DMAP
71
13
0
2
PC(2)
NMP
3
PC(3)
NMP
4
PC(4)
NMP
51
31
28
17
36
33
50
5
PC(1)
DMSO
DMF
6
PC(1)
7
PC(1)
Acetone
MeCN
Et2O
8
PC(1)
9
PC(1)
10
PC(1)
EtOAc

3
11
12
13
14
15
16
17c
18d
19e
20f
21
22
PC(1)
PC(1)
PC(1)
PC(1)
PC(1)
PC(1)
PC(1)
PC(1)
PC(1)
PC(1)
-
DCE
DCM
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
DMAP
DMAP
DABCO
DBU
65
46
82
66
22
67
82
81
69
0
DBN
PPh3
DABCO
DABCO
DABCO
DABCO
DABCO
-
0
PC(1)
0
aReaction conditions：1a (0.5 mmol), 2a (0.75 mmol), photocatalyst (0.005 mmol, 1 mol%), Lewis base (0.1 mmol), solvent (3 mL), 45 W CFL (compact
fluorescent lamp) irradiation under N2 atmosphere at ambient temperature for 20 h, unless otherwise noted. PC(1) Ir[dF(CF3)ppy]2(dtbbpy)PF6: 4,4'-di- tert-
butyl-2,2'-bipyridine)bis[3,5-difluoro-2-(5-trifluoromethyl-2-pyridinyl-kN)phenyl-kC]iridium(III) hexafluorophosphate. PC(2) Ir(ppy)2(dtbbpy)PF6: (4,4'-di-
tert-butyl-2,2'-bipyridine)bis(2-phenylpyridine)iridium(III) hexafluorophosphate. PC(3) Ir(ppy)3: tris(2-phenylpyridine)iridium(III). PC(4) Ru(bpz)3(PF6)2:
tris(2,2'-bipyrazine)ruthenium(II) hexafluorophosphate. bIsolated yield after silica gel flash column chromatography. cExtending the reaction time to 25 h.
dIrradiation with blue LEDs. e0.25 mmol of DABCO. fNo light.
With the optimal reaction conditions in hand, several structurally diverse organoboronic acids were examined. As
demonstrated in Table 2, the secondary alkylboronic acids possessing four-, five- and six-membered ring were coupled in good
yields (4a-4d) and the aliphatic, heterocyclic boronic acid containing protected nitrogen atom afforded product in 70% isolated
yield (4c). Specifically, Z/E isomers of 4c could be isolated by silica gel flash column chromatography. Moreover, isopropylboronic
acid was efficiently applied in this transformation (4e). Finally, primary alkylboronic acid could also be used under this protocol
and the coupling product was obtained, albeit in a slightly lower yield (4f). To our disappointment, arylboronic acids were not
suitable for the reaction but afforded different products (4g-4n). On the observed results and literatures, the reason may be that the
arylboronic acids could be oxidized to give substituted phenols easily under this condition.12 Subsequently, a catalytic successive
SN2’–SN2’ reaction happened due to the very suitable nucleophilicity of DABCO and phenol13.
Table 2: Scope of organoboronic acids

4
aReaction conditions：1 (0.5 mmol), 2 (0.75 mmol), Ir[dF(CF3)ppy]2(dtbbpy)PF6 (0.005 mmol), DABCO (0.1 mmol), NMP (3 mL), 20 h, 45W compact
fluorescent lamp irradiation under N2 atmosphere at rt. bIsolated yield based on 4a-4n.
In order to further explore the generality of this method, we assessed the scope of Baylis−Hillman tert-butyl carbonates and
boronic pinacol esters (Table 3). The Baylis−Hillman tert-butyl carbonates containing substituents such as methyl, isopropyl and
methoxyl on the aryl rings underwent the reaction smoothly (5b-5d). For substrates with halogenated aryl ring, the desired products
were also isolated in good yields (5e-5g). However, the fluoro substituted reactant gave the corresponding product in slightly lower
yield (5e). There was no obvious steric effect (5g-5i). Pleasingly, the strong electron withdrawing group trifluoromethyl had no
influence on the reaction and 5j was provided in good yield. Heterocyclic substituted Baylis–Hillman tert-butyl carbonates were
also suitable for the reaction (5k-5l). While aliphatic substituted Baylis–Hillman tert-butyl carbonates were introduced, the
reactions were successfully performed and E-isomers of desired products were not detected (5m-5n). Then, naphthyl substituted
starting material was examined and the corresponding product 5o was obtained in moderate yield. The reaction of ethyl 3-phenyl-2-
methylene-3-(tert-butoxycarbonyl)oxypropanoate and t-butyl 3-phenyl-2-methylene-3-(tert-butoxycarbonyl)oxypropanoate with
benzyl boronic ester 3a proceeded smoothly to give 5p and 5q in 65% and 63% yields, respectively. The coupling reaction of
isopropyl boronic ester 3b with 1a proceeded well. In contrast to primary and secondary alkylboronic ester, tertiary butyl boronic
ester 3c was not a suitable substrate. It is important to note that Z/E isomers of 5d could be isolated by silica gel flash column
chromatography and the Z/E isomers were confirmed by NOE spectra (See Supporting Information).
Table 3: Scope of Baylis–Hillman tert-butyl carbonates and boronic pinacol esters.

5
aReaction conditions：1a-1q (0.5 mmol), 3a-3c (0.75 mmol), Ir[dF(CF3)ppy]2(dtbbpy)PF6 (0.005 mmol), DABCO (0.1 mmol), NMP (3 mL), 20 h, 45W
compact fluorescent lamp irradiation under N2 atmosphere at rt. bIsolated yield based on 5a-5q, 4e. cZ/E isomers of 5d were confirmed by NOE spectra.
To explore the mechanism, radical scavenger TEMPO was added. The product 4a was obtained in only 5% yield after 30 h
with most of reactant 1a left. Moreover, a dynamic equilibrium between the boronic acid or boronic ester and the Lewis base
catalyst (LB) was confirmed by Steven V. Ley.11 On the basis of literatures14 and above experimental results, a plausible reaction
mechanism is proposed in Scheme 1. Firstly, boronic acid or boronic ester A can be activated by Lewis base to form intermediate B.
The ground state of Ir3+ is excited to provide Ir*3+ under the irradiation of visible light, which is reduced by intermediate B to
produce Ir2+. Simultaneously, B is oxidized to generate D and the alkyl radical C, which can react with Baylis-Hillman tert-butyl
carbonate E to produce radical F. The key intermediate alkyl anion G was generated from the reduction of F by the photocatalyst
Ir2+, which itself was oxidized to the initial photocatalyst Ir3+. Subsequently, the target product H was formed after the elimination
of CO2 and tBuO- from anion G. Finally, Lewis base is regenerated from D and tBuO-.
Scheme 1: A plausible reaction mechanism.

6
Conclusions
In conclusion, we have developed a new coupling reaction of alkylboronic acids and esters with Baylis−Hillman adducts via
visible light photoredox catalysis. The alkylboronic acids and esters can serve as a useful synthon in the C-C bond-forming reaction
utilizing Lewis base/photoredox dual catalysis. The reaction can proceed with a broad scope of substrates under mild conditions.
Acknowledgments
The authors are grateful to Zhejiang Provincial Natural Science Foundation of China (No. LY18B020018) and National Science
Foundation of China (No. 21602197).
Supplementary Material
Supplementary data (copies of 1H NMR, 13C NMR spectra of all products) associated with this article can be found in the online
version at http://.
References and notes
1.
(a) Nicewicz, D. A.; MacMillan, D. W. C. Science 2008, 322, 77. (b) Yoon, T. P.; Ischay, M. A.; Du, J. Nat. Chem. 2010, 2, 527. (c) Narayanam, J. M.
R.; Stephenson, C. R. J. Chem. Soc. Rev. 2011. 40, 102. (d) Teply, F. Collect. Czech. Chem. Commun. 2011, 76, 859. (e) Xuan, J.; Xiao, W. J. Angew.
Chem. Int. Ed. 2012, 51, 6828. (f) Johnston, C. P.; Smith, R. T.; Allmendinger, S.; MacMillan, D. W. C. Nature 2016, 536, 322. (g) Chen, J.; Cen, J.;
Xu, X.; Li, X. Catal. Sci. Technol. 2016, 6, 349. (h) Goddard, J. P.; Ollivier, C.; Fensterbank, L. Acc. Chem. Res. 2016, 49, 1924. (i) Roslin, S.; Odell,
L. R. Eur. J. Org. Chem. 2017, 1993. (j) Chen, J.; Yan, D.; Wei, Q.; Xiao, W. ChemPhotoChem 2017, 1, 148. (k) Chen, Y.; Lu, L.; Yu, D.; Zhu, C.;
Xiao, W. Sci. China Chem. 2019, 62, 24.
2.
3.
4.
5.
(a) Bradshaw, J. W. S.; Baker, R.; Howse, P. E. Nature 1975, 258, 230. (b) Rossi, R.; Carpita, A.; Messari, T. Synth. Commun. 1992, 22, 603. (c)
Garson, M. J. Chem. Rev. 1993, 93, 1699.
(a) Masaki, Y.; Sakuma, K.; Kaji, K. J. Chem. Soc., Chem. Commun. 1980, 434. (b) Brown, H. C.; Basavaiah, D. J. Org. Chem. 1982, 47, 5407. (c)
Denmark, S. E.; Amburgey, J. J. Am. Chem. Soc. 1993, 115, 10386. (d) Amri, H.; Rambaud, M.; Villieras, J. Tetrahedron 1990, 46, 3535.
(a) Basavaiah, D.; Rao, A. J.; Satyanarayana, T. Chem. Rev. 2003, 103, 811. (b) Price, K. E.; Broadwater, S. J.; Walker, B. J.; McQuade, D. T. J. Org.
Chem. 2005, 70, 3980. (c) Singh, V.; Batra, S. Tetrahedron 2008, 64, 4511. (d) Basavaiah, D.; Reddy, B. S.; Badsara, S. S. Chem. Rev. 2010, 110, 5447.
(a) Basavaiah, D.; Sarma, P. K. S.; Bhavani, A. K. D. J. Chem. Soc., Chem. Commun. 1994, 1091. (b) Basavaiah, D.; Krishnamacharyulu, M.; Hyma,
R. S.; Pandiaraju, S. Tetrahedron Lett. 1997, 38, 2141. (c) Navarre, L.; Darses, S.; Genet, J. P. Chem. Commun. 2004, 1108. (d) Das, B.; Banerjee, J.;
Mahender, G.; Majhi, A. Org. Lett., 2004, 6, 19. (e) Kabalka, G. W.; Dong, G.; Venkataiah, B.; Chen, C. J. Org. Chem. 2005, 70, 9207. (f) Mandal, S.
K.; Paira, M.; Roy, S. C. J. Org. Chem. 2008, 73, 3823
6.
7.
(a) Ollivier, C.; Renaud, P. Angew. Chem. Int. Ed. 2000, 39, 925. (b) Schaffner, A. P.; Darmency, V.; Renaud, P. Angew. Chem. Int. Ed. 2006, 45, 5847.
(c) Duret, G.; Quinlan, R.; Bisseret, P.; Blanchard, N. Chem. Sci. 2015, 6, 5366. (d) Fyfe, J. W. B.; Watson, A. J. B. Chem 2017, 3, 31.
(a) Dai, X.; Cheng, D.; Guan, B.; Mao, W.; Xu, X.; Li, X. J. Org. Chem. 2014, 79, 7212. (b) Dai, X.; Mao, R.; Guan, B.; Xu, X.; Li, X. RSC Adv. 2015,
5, 55290. (c) Guan, B.; Xu, X.; Wang, H.; Li, X. Chin. J. Org. Chem. 2016, 36, 1564. (e) Ye, Q.; Xu, X.; Cheng, D.; Guan, B.; Ye, H.; Li, X. Arkivoc

7
2017, v, 314. (f) Ye, Q.; Ye, H.; Cheng, D.; Li, X.; Xu, X. Tetrahedron Lett. 2018, 59, 2546.
Ye, H.; Ye, Q.; Cheng, D.; Li, X.; Xu, X. Tetrahedron Lett. 2018, 59, 2046.
Yasu, Y.; Koike, T.; Akita, M. Adv. Synth. Catal. 2012, 354, 3414.
8.
9.
10. Denmark, S. E.; Beutner, G. L. Angew. Chem. Int. Ed. 2008, 47, 1560.
11. Lima, F.; Kabeshov, M. A.; Tran, D. N.; Battilocchio, C.; Sedelmeier, J.; Sedelmeier, G.; Schenkel, B.; Ley, S. V. Angew. Chem. Int. Ed. 2016, 55,
14085.
12. (a) Zou, Y. Q.; Chen, J. R.; Liu, X. P.; Lu, L. Q.; Davis, R. L.; Jørgensen, K. A.; Xiao, W. J. Angew. Chem. Int. Ed. 2012, 51, 784. (b) Weng, W. Z.;
Liang, H.; Zhang, B. Org. Lett. 2018, 20, 4979.
13. (a) Basavaiah, D.; Kumaragurubaran, N.; Sharada, D. S.; Reddy, R. M. Tetrahedron 2001, 57, 8167. (b) Du, Y.; Han, X.; Lu, X. Tetrahedron Letters
2004, 45, 4967. (c) Xie, P.; Huang, Y. Org. Biomol. Chem. 2015, 13, 8578
14. Lima, F; Sharma, U. K.; Grunenberg, L.; Saha, D.; Johannsen, S.; Sedelmeier, J.; Van der Eycken, E. V.; Ley, S. V. Angew. Chem. Int. Ed. 2017, 56,
15136.

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The Coupling of Alkylboronic Acids and
Esters with Baylis−Hillman Derivatives by
Lewis Base/Photoredox Dual Catalysis
Leave this area blank for abstract info.
Hongqiang Ye,a He Zhao,a Shujian Ren,a Hongfeng Ye,a Dongping Cheng,*b Xiaonian Li,*a and Xiaoliang Xu*a

9
Highlights
The coupling of alkylboronic acids or esters with
B-H adducts via dual catalysis
New method for the synthesis of 2-alkyl substituted
acrylate derivatives
Broad scope of the substrates, moderate to excellent
yields, simple operations