The coupling reaction of α-silylamines with Baylis-Hillman adducts by visible light photoredox catalysis

Article abstract of DOI:10.1016/j.tetlet.2020.152746

The preparation of N-containing α,β-unsaturated carboxylate derivatives from α-silylamine and Baylis-Hillman adducts under visible light irradiation was reported. The formation of α-aminoalkyl radical is regioselective compared with the previous reports.

Full text of DOI:10.1016/j.tetlet.2020.152746

Tetrahedron Letters 65 (2021) 152746
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
The coupling reaction of
a-silylamines with Baylis-Hillman adducts by
visible light photoredox catalysis
b,
a,
He Zhao a, Niannian Ni a, Xiaonian Li a, , Dongping Cheng , Xiaoliang Xu
⇑
⇑
⇑
a College of Chemical Engineering, Zhejiang University of Technology, Hangzhou 310014, PR China
b College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou 310014, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
The preparation of N-containing
Hillman adducts under visible light irradiation was reported. The formation of
regioselective compared with the previous reports. The reaction was successfully performed without
additional additives under mild conditions.
a
,b-unsaturated carboxylate derivatives from
a
-silylamine and Baylis-
Received 8 October 2020
Revised 3 December 2020
Accepted 7 December 2020
Available online 30 December 2020
a-aminoalkyl radical is
Ó 2020 Elsevier Ltd. All rights reserved.
Keywords:
Visible light photocatalysis
a-Silylamine
a-Aminoalkyl radical
Baylis-Hillman adducts
Introduction
silylamine to give a,b-unsaturated carboxylate derivatives was
reported. Compared with our previous works [14], the use of base
or other additives in this reaction is avoided. In addition, by intro-
ducing TMS as a leaving group, the SET process should begin at the
Visible light catalysis has the characteristics of mild conditions,
high selectivity of products and avoiding the use of some additives
[1]. Thus it provides a new way to construct CAC and CAX bonds in
organic synthesis and has been widely used in oxidative decar-
boxylation [2], oxidative deboronation [3], alkylation [4], cycliza-
tion [5], dehalogenation [6] and polymerization [7].
nitrogen atom and then fragmentation occurred to afford the
a-
amino radicals at the silicon side. Thus the formation of
noalkyl radical has a specific regioselectivity.
a-ami-
a
-Aminoalkyl radical is an important intermediate for the CAH
Result and discussion
functionalization of amines and has been widely used in the syn-
thesis of amine derivatives [8], which is mainly formed by oxida-
tive deprotonation of tertiary amines under visible light
irradiation [9]. However, the redox potential of traditional tertiary
amines limits their application under some circumstances in
organic synthesis. There are few reports on the regioselective for-
mation of a-aminoalkyl radical under visible light conditions. For-
tunately, these situations could be largely improved by introducing
a leaving group such as TMS (trimethylsilyl). Recently Nishibayashi
[10], Yoon [11], and Rueping [12] have shown that
Initial studies were conducted on the starting materials
between methyl-(acetoxy(phenyl)methyl)acrylate 1a and N-
methyl-N-((trimethylsilyl)methyl)aniline 2a (Scheme 1). Firstly,
catalyzed by Ru(bpy)3(BF4)2, white 45 W CFL aZs visible light
source, DMSO as solvent, the reaction was performed under the
protection of nitrogen at room temperature. The product was iso-
lated in 26% yield by silica gel column chromatography and con-
firmed as target product 3a by 1H NMR and 13C NMR.
Subsequently, substrate 4a protected by Boc (tert butoxycarbonyl)
and unprotected Baylis-Hillman adduct 5a were tried under the
above conditions. When 4a was used as the substrate, no target
product was obtained. However, the reaction system was very
complicated while 5a was used. These results showed that only
1a had appropriate activity and selectivity.
a-silylamine
can be used to produce -aminoalkyl radicals in homogeneous,
a
heterogeneous and asymmetric visible light catalytic reactions.
Baylis-Hillman adducts are important intermediates and widely
used as electrophilic partners in organic synthesis [13]. Herein, a
photoredox catalysis reaction of Baylis-Hillman adduct with
a-
In order to find optimal conditions, the reaction of 2-(acetoxy
(phenyl)methyl)acrylate 1a and N-methyl-N-((trimethylsilyl)
methyl)aniline 2a was performed in the presence of 1 mol% photo-
catalyst under 45 W CFL irradiation at ambient temperature
⇑
Corresponding authors.
E-mail addresses: xnli@zjut.edu.cn (X. Li), chengdp@zjut.edu.cn (D. Cheng),
xuxiaoliang@zjut.edu.cn (X. Xu).
https://doi.org/10.1016/j.tetlet.2020.152746
0040-4039/Ó 2020 Elsevier Ltd. All rights reserved.

H. Zhao, N. Ni, X. Li et al.
Tetrahedron Letters 65 (2021) 152746
Table 2
Scope of Baylis-Hillman carbonates in coupling with 2a.a,b
Scheme 1. Reactions of 1a and 2a under visible light irradiation.
(Table 1). Firstly, several common visible light photocatalysts were
screened (entries 1–6). When Ru(phen)3(BF4)2 was used as visible
light catalyst, the isolated yield can be up to 68%. Besides DMSO,
other solvents such as MeCN, NMP, DCM, DCE, THF, DMF, toluene
were tried. The yield of target product was very low in most sol-
vents (entries 7–12). Use of DMF as a solvent, product could be
obtained in 42% yield. In addition, the yield reached 65% within
6 h and did not increase significantly when the reaction time
was extended to 48 h (entries 14–17). At the same time, the control
experiment (entries 18–19) showed that light and catalyst are
necessary.
With the optimal reaction conditions in hand, the scope of Bay-
lis-Hillman derivatives was examined (Table 2). The substrates
containing substituents such as methyl, methoxyl and isopropyl
on the aryl ring were used readily (3a-3c). It was found that the
yields decreased significantly when the methoxyl was in ortho
and meta positions (3d-3f). For substrates with halogenated aryl
ring, the desired products were isolated in moderate yields (3g-
3i). These results indicate that electron donating group or electron
withdrawing group in the aryl ring have no obvious effect on the
reaction. In addition, some strong electron. withdrawing groups
such as –CF3, –CN have no obvious effect on yield (3j-3k). Hetero-
Table 1
Optimization of the reaction conditions.a,b
Entry
Solvent
Photocatalyst
Time/h
Yield (%)b
1
2
3
4
5
6
7
8
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
MeCN
NMP
DCM
DCE
THF
Toluene
DMF
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
Ru(bpy)3(BF4)2
Ru(bpz)3(BF4)2
Ir(ppy)3
Ir(ppy)2(dtbbpy)PF6
Eosin Y
24
24
24
24
24
24
24
24
24
24
24
24
24
6
26
0
0
0
12
68
0
0
0
0
0
0
42
65
65
69
70
0
a
Ru(phen)3(BF4)2
Ru(phen)3(BF4)2
Ru(phen)3(BF4)2
Ru(phen)3(BF4)2
Ru(phen)3(BF4)2
Ru(phen)3(BF4)2
Ru(phen)3(BF4)2
Ru(phen)3(BF4)2
Ru(phen)3(BF4)2
Ru(phen)3(BF4)2
Ru(phen)3(BF4)2
Ru(phen)3(BF4)2
Ru(phen)3(BF4)2
–
Reaction conditions: 1a~1t (0.5 mmol), 2a (0.6 mmol, 1.2 equiv.), Ru(phen)3(-
BF4)2 (0.005 mmol, 1 mol%), DMSO (2.0 mL), 45 W CFL (compact fluorescent lamp)
irradiation under N2 atmosphere at ambient temperature. Time: 6h.
b
9
Isolated yields.
10
11
12
13
14
15
16
17
18c
19d
cyclic substituted Baylis-Hillman carbonates were also suitable for
the reaction except pyridine heterocycle (3l-3n). When the phe-
noxy group (3o) is attached to the aryl ring, and the target product
can also be obtained in 38% yield. While Baylis-Hillman derivatives
are replaced by other electron withdrawing groups such as ethyl
ester, tert-butyl ester and cyano, the reactions were also success-
fully performed (3p-3r). And Z/E isomers of 2-benzylidene-4-
(methyl(phenyl)amino)butanenitrile is 1:2 (3r). Then naphthyl
substituted starting material was examined and the corresponding
product 3swas obtained in moderate yield. While aliphatic substi-
tuted Baylis-Hillman carbonates were introduced (3t-3u), the
yields were slightly lower than aromatic substituted substrates.
12
24
48
6
6
0
a
Reaction conditions:1a (0.5 mmol), 2a (0.6 mmol, 1.2equiv.), photocatalyst
(0.005 mmol, 1 mol%), solvent (2.0 mL), 45 W CFL (compact fluorescent lamp)
irradiation under N2 atmosphere at ambient temperature.
b
Isolated yield after silica gel flash column chromatography.
No light.
No photocatalyst.
c
d
2

H. Zhao, N. Ni, X. Li et al.
Tetrahedron Letters 65 (2021) 152746
In order to further explore the generality of this method to
other a-silylamines, several structurally diverse a-silylamine were
examined. As demonstrated in Table 3, the effect of electron with-
drawing and electron donating groups on the yield is not obvious
(3aa~3ad), However the position of substituent in aryl ring is an
important influencing factor (3aa~3ab). In addition, N-phenyl-N-
((trimethylsilyl)methyl)aniline proceeded smoothly to give pro-
duct (3ae). It is worth mentioned that N-ethyl-N-((trimethylsilyl)
methyl)aniline is also a good substrate in this reaction (3af). This
result indicates that the introduction of -TMS as a leaving group
Scheme 3. Amplification experiment.
makes the formation of
selectivity.
a-aminoalkyl radical has specific location
In addition to
a-silylamine, b-silylamine was also tried
(Scheme 2). The desiliconization coupling products could not be
obtained under the optimal conditions. However, when NaOAc
was added into the reaction system, the product 3ag was formed
in 62% yield.
Considering the importance of
a,b-unsaturated carboxylate
derivatives in organic synthesis, the amplification experiment
was carried out (Scheme 3). 1a and 2a were expanded by 20 times
at the same time under the optimal conditions. The product 3a was
obtained in 57% isolated yield.
Table 3
Scope of a
-silylamine.a,b,c
Scheme 4. A plausible reaction mechanism.
To explore the mechanism, radical scavenger TEMPO (2,2,6,6-
tetramethylpiperidine oxide) was added. The product 3a was
obtained in only 5% yield after 12 h. On the basis of experimental
results and literatures [10–12], a plausible reaction mechanism is
proposed in Scheme 4. Firstly, the ground state of Ru3+ is excited
to provide Ru*3+ under the irradiation of visible light, which is then
reduced by a a-aminoalkyl rad-
-silylamine A to produce Ru2+ and
ical C. Intermediate C can react with Baylis-Hillman carbonate B to
produce the alkyl radical D. The key intermediate alkyl anion E was
generated from the reduction of D by the photocatalyst Ru2+, which
itself was oxidized to the initial photocatalyst Ru2+. Subsequently,
elimination of AOAc from the alkyl anion E formed the product.
Conclusions
In summary, we have developed the coupling reaction of
lamines with Baylis-Hillman derivatives by visible light photore-
dox catalysis. The -silylamine can serve as a useful synthon in
this CAC bond-forming reaction containing nitrogen. The advan-
tages of this reaction are mild conditions and regional selectivity.
a-sily-
a
a
Reaction conditions: 1a (0.5 mmol), 2a~2f (0.6 mmol, 1.2equiv.), Ru(phen)3
(BF4)2 (0.005 mmol, 1 mol%), DMSO (2.0 mL), 45 W CFL (compact fluorescent lamp)
irradiation under N2 atmosphere at ambient temperature. Time: 12 h.
b
Isolated yields.
Photocatalyst: Ru(bpy)3(BF4)2 (1 mol%).
c
Declaration of Competing Interest
The authors declare that they have no known competing finan-
cial interests or personal relationships that could have appeared
to influence the work reported in this paper.
Acknowledgments
The authors are grateful to Natural Science Foundation of Zhe-
jiang Province (No. LY18B020018) and National Natural Science
Foundation of China (No. 21602197).
Scheme 2. Experiment of b-silylamine.
3

H. Zhao, N. Ni, X. Li et al.
Tetrahedron Letters 65 (2021) 152746
12387;
Appendix A. Supplementary data
(d) P. Zhang, T. Xiao, S. Xiong, X. Dong, L. Zhou, Org. Lett. 16 (2014) 3264.
[6] (a) S. Priya, J.D. Weaver, J. Am. Chem. Soc. 140 (2018) 16020;
(b) J.D. Weaver, M.D. Rathnayake, Org. Lett. 21 (2019) 9681;
(c) A. Singh, A. Arora, J.D. Weaver, Org. Lett. 15 (2013) 5390;
(d) J.J. Devery III, J.D. Nguyen, C. Dai, C.R. Stephenson, ACS Catal. 6 (2016)
5962;
Supplementary data (copies of 1H NMR, 13C NMR spectra of all
products) to this article can be found online at https://doi.org/10.
1016/j.tetlet.2020.152746.
(e) T. Xiao, L. Li, L. Zhou, J. Am. Chem. Soc. 137 (2015) 1400.
[7] (a) L. He, C. Jia, Y. Zhang, J. He, Macromol. Rapid Commun. 41 (2020) 1900640;
(b) K.A. Ogawa, A.E. Goetz, A.J. Boydston, J. Am. Chem. Soc. 137 (2015) 1400.
[8] (a) K. Nakajima, S. Nojima, Y. Nishibayashi, Acc. Chem. Res. 49 (2016) 146;
(b) J. Chen, X. Hu, L.Q. Lu, W. Xiao, Acc. Chem. Res. 2016 (1911) 49;
(c) D.W. Cho, U.C. Yoon, P.S. Mariano, Acc. Chem. Res. 44 (2011) 204;
(d) T. Constantin, M. Zanini, A. Regni, N.S. Sheikh, F. Julia, D. Leonori, Science
367 (2020) 1021;
References
[1] (a) J. Twilton, P. Zhang, M.H. Shaw, R.W. Evans, D.W.C. MacMillan, Nat. Rev.
Chem. 1 (2017) 1;
(b) J. Xuan, X. He, W. Xiao, Chem. Soc. Rev. 49 (2020) 2546;
(c) X. Yu, J. Chen, W. Xiao, Chem. Rev. (2020), https://doi.org/10.1021/acs.
chemrev.0c00030;
(d) H. Yi, G. Zhang, H. Wang, Z. Huang, J. Wang, A.K. Singh, A. Lei, Chem. Rev.
117 (2017) 9016;
(e) J. Ji, Z. Zhu, L. Xiao, X. Zhu, Z. Le, Org. Chem. Front. 6 (2019) 3693;
(f) J. Li, M. Kong, B. Qiao, R. Lee, X. Zhao, Z. Jiang, Nat. Commun. 9 (2018) 2445;
(g) J.J. Murphy, D. Bastida, S. Paria, M. Fagnoni, P. Melchiorre, Nature 532
(2016) 218;
(h) Z. Xi, L. Yang, D. Wang, C.D. Pu, Y. Shen, C. Wu, X. Peng, J. Org. Chem. 83
(2018) 11886;
(e) C. Wang, P.H. Dixneuf, J. Soulé, Chem. Rev. 118 (2018) 7532;
(f) J.M. Narayanam, C.R. Stephenson, Chem. Soc. Rev. 40 (2011) 102.
[2] (a) Y. Zheng, X. Shao, V. Ramadoss, L. Tian, Y. Wang, Synthesis 52 (2020) 1357;
(b) Z. Zuo, D.W.C. MacMillan, J. Am. Chem. Soc. 136 (2014) 5257;
(c) J. Li, Z. Gu, X. Zhao, B. Qiao, Z. Jiang, Chem. Comm. 55 (2019) 12916;
(d) W. Tian, C. Hu, K. He, X. He, Y. Li, Org. Lett. 21 (2019) 6930;
(e) T.M. Faraggi, W. Li, D.W.C. MacMillan, Isr. J. Chem. 60 (2020) 410;
(f) S. Senaweera, K.C. Cartwright, J.A. Tunge, J. Org. Chem. 84 (2019) 12553;
(g) A. Noble, R.S. Mega, D. Pflasterer, E.L. Myers, V.K. Aggarwal, Angew. Chem.
Int. Ed. 57 (2018) 2155.
(h) A. McNally, C.K. Prier, D.W.C. MacMillan, Science 334 (2011) 1114;
(i) P. Kohls, D. Jadhav, G. Pandey, O. Reiser, Org. Lett. 14 (2012) 672.
[9] (a) U.C. Yoon, P.S. Mariano, Acc. Chem. Res. 25 (1992) 233;
(b) D.W. Cho, U.C. Yoon, P.S. Mariano, Acc. Chem. Res. 44 (2011) 204.
[10] (a) Y. Miyake, Y. Ashida, K. Nakajima, Y. Nishibayashi, Chem. Commun. 48
(2012) 6966;
(b) K. Nakajima, M. Kitagawa, Y. Ashida, Y. Miyake, Y. Nishibayashi, Chem.
Commun. 50 (2014) 8900;
(c) Y. Miyake, Y. Ashida, K. Nakajima, Y. Nishibayashi, Chem. Eur. J. 20 (2014)
6120;
(d) K. Nakajima, Y. Ashida, S. Nojima, Y. Nishibayashi, Chem. Lett. 44 (2015)
545.
[3] (a) Y. Iwata, Y. Tanaka, S. Kubosaki, T. Morita, Y. Yoshimi, Chem. Commun. 54
(2018) 1257;
(b) K. Duan, X. Yan, Y. Liu, Z. Li, Adv. Synth. Catal. 360 (2018) 2781;
(c) H. Huang, G. Zhang, L. Gong, S. Zhang, Y. Chen, J. Am. Chem. Soc. 136 (2014)
2280;
(d) G.X. Li, C.A. Morales-Rivera, Y. Wang, F. Gao, G. He, P. Liu, G. Chen, Chem.
Sci. 7 (2016) 6407;
[11] L. Ruiz Espelt, I.S. McPherson, E.M. Wiensch, T.P. Yoon, J. Am. Chem. Soc. 137
(2015) 2452.
[12] Y. Cai, R. Yu, L. Fan, H. Hou, Q. Lefebvre, M. Rueping, ACS Catalysis. 8 (2018)
9471.
[13] (a) A.K. Yadav, A.K. Sharma, K.N. Singh, Org. Chem. Front. 6 (2019) 989;
(b) T.Y. Liu, M. Xie, Y. Chen, Chem. Soc. Rev. 41 (2012) 4101;
(c) D. Basavaiah, B.S. Reddy, S.S. Badsara, Chem. Rev. 110 (2010) 5447;
(d) B.M. Trost, M.K. Brennan, Org. Lett. 9 (2007) 3961.
[14] (a) X. Dai, D. Cheng, B. Guan, W. Mao, X. Xu, X. Li, J. Org. Chem. 79 (2014)
7212;
(e) F. Lima, U.K. Sharma, L. Grunenberg, D. Saha, S. Johannsen, J. Sedelmeier, S.
V. Ley, Angew. Chem. Int. Ed. 20 (2017) 15136;
(f) J.K. Matsui, G.A. Molander, Org. Lett. 19 (2017) 950.
[4] (a) J. Liu, S. Wu, J. Yu, C. Lu, Z. Wu, X. Wu, C. Zhu, Angew. Chem. Int. Ed. 59
(2020) 8195;
(b) F. Rammal, D. Gao, S. Boujnah, A.C. Gaumont, A.A. Hussein, S. Lakhdar, Org.
Lett. 22 (2020) 767;
(c) C.S. Wang, P.H. Dixneuf, J.F. Soule, Chem. Rev. 118 (2018) 7532;
(d) D.A. Nicewicz, D.W.C. MacMillan, Science. 322 (2008) 77;
(e) A. Bahamonde, P. Melchiorre, J. Am. Chem. Soc. 138 (2016) 8019;
(f) E.R. Welin, A.A. Warkentin, J.C. Conrad, D.W.C. MacMillan, Angew. Chem.
Int. Ed. 54 (2015) 9668.
(b) Q. Ye, X. Xu, D. Cheng, B. Guan, H. Ye, X. Li, Arkivoc (2017) 314;
(c) X. Dai, R. Mao, B. Guan, X. Xu, X. Li, RSC Adv. 5 (2015) 55290;
(d) H. Ye, Q. Ye, X. Xu, X. Li, Tetrahedron Lett. 59 (2018) 2046;
(e) H. Ye, H. Zhao, S. Ren, H. Ye, D. Cheng, X. Li, X. Xu, Tetrahedron Lett. 60
(2019) 1302.
[5] (a) Y. Jiang, Z. Yu, Y. Zhang, B. Wang, Org. Lett. 20 (2018) 3728;
(b) T. Matsushima, S. Kobayashi, S. Watanabe, J. Org. Chem. 81 (2016) 7799;
(c) T. Kang, W. Zhang, T. Wang, Y. Liang, Z. Zhang, J. Org. Chem. 84 (2019)
4