Photocatalysed eosin Y mediated C(sp3)-H alkylation of amine substrates via direct HAT

Article abstract of DOI:10.1016/j.tetlet.2019.04.016

A visible light promoted, photoredox catalysed, green one-pot approach for the alkylation of amine substrates with sp² carbon has been developed. This eosin Y based organic transformations, can behave as an effective direct hydrogen-atom transfer catalyst for coupling reaction. The proposed strategy includes simple procedure which can make adduct product with sp² carbon. This eosin Y based photocatalytic hydrogen-atom transfer strategy may hold great potential for diverse functionalization of a wide range of native C[sbnd]H bonds in an economical and sustainable manner.

Full text of DOI:10.1016/j.tetlet.2019.04.016

Accepted Manuscript
Photocatalysed eosin Y mediated C(sp3)−H alkylation of amine substrates via
direct HAT
Vishal Srivastava, Pravin K. Singh, Praveen P. Singh
PII:
S0040-4039(19)30339-9
https://doi.org/10.1016/j.tetlet.2019.04.016
TETL 50731
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
22 February 2019
1 April 2019
6 April 2019
Please cite this article as: Srivastava, V., Singh, P.K., Singh, P.P., Photocatalysed eosin Y mediated C(sp3)−H
alkylation of amine substrates via direct HAT, Tetrahedron Letters (2019), doi: https://doi.org/10.1016/j.tetlet.
2019.04.016
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Graphical Abstract
Photocatalysed eosin Y mediated C(sp3)−H
alkylation of amine substrates via direct
HAT
Leave this area blank for abstract info.
Vishal Srivastavaa Pravin K. Singha and Praveen P. Singh*b
Br
Br
HO
Br
O
O
Br
COOH
NH2
R3
NH2
Eosin Y (2 mol%)
R1
R3
+
R2
R1
H
R2
MeCN, rt, 8-12 h
18 W blue LEDs
14 examples
upto 97% yield
• Metal free.
• Visible light region.
• No coupling reagent.
• Moisture tolerance.
• Highly selective.
• Mild reaction condition.

1
Tetrahedron Letters
Photocatalysed eosin Y mediated C(sp3)−H alkylation of amine substrates via direct
HAT
Vishal Srivastavaa , Pravin K. Singha and Praveen P. Singhb, 
aDepartment of Chemistry, CMP Degree College, University of Allahabad, Prayagraj 211002, India
bDepartment of Chemistry, United College of Engineering & Research, Naini, Prayagraj 211010, India
ARTICLE INFO
ABSTRACT
Article history:
Received
A visible light promoted, photoredox catalysed, green one-pot approach for the alkylation of
amine substrates with sp2 carbon has been developed. This eosin
based organic
Y
Received in revised form
Accepted
Available online
transformations, can behave as an effective direct hydrogen-atom transfer catalyst for coupling
reaction. The proposed strategy includes simple procedure which can make adduct product with
sp2 carbon. This eosin Y based photocatalytic hydrogen-atom transfer strategy may hold great
potential for diverse functionalization of a wide range of native C-H bonds in an economical and
sustainable manner.
Keywords:
Visible light
Eosin Y
2009 Elsevier Ltd. All rights reserved.
Amine substrates
Styrene
Amines are important substituents in many biologically active
compounds. Amines acts like a key functional group in
agrochemicals [1] as well as materials. [2,3] Aliphatic amines are
ubiquitously present in pharmaceuticals with a wide range of
biological activities [4-8]. In recent years, a number of medicines
containing aliphatic amine moieties are among the top 100 best-
selling drugs. The persistent need from drug discovery
programmes for elaborate amine containing architectures has led
to pioneering developments in the C(sp3)–H functionalization of
amines [9,10]. Due to the extreme popularity and importance of
aliphatic amines, development of efficient and straightforward
methods for the synthesis and derivatization of these compounds
is of great research interest in organic chemistry and medicinal
sciences [11,12]. Tertiary amine moiety has been extensively
found in many popular prodrugs [13], fluorescence anti-collapse
drilling fluid [14,15] etc. Tertiary amine drug, promethazine
hydrochloride [16] used as an antiemetic, antihistamine, allergies,
sedative and nauseas. Amine moiety is also found in popular
prodrugs like Rolitertracycline. [17] New researches [18,19] are
also in progress on amine prodrug due to their specific physical
and chemical properties.
catalysts to initiate single electron transfer (SET) processes
[27,28]. Visible light photoredox catalysis has recently received
much attention in organic synthesis owing to ready availability,
sustainability, non-toxicity and ease of handling [29-32]
Recently, a superior alternative to transition metal photoredox
catalysts, especially metal-free organic dyes such as eosin Y,
fluorescein, rose bengal, nile red, perylene and rhodamine B have
been used as economically and ecologically superior surrogates
for Ru(II) and Ir(II) complexes in visible-light promoted organic
transformations involving SET [35-37]. These organic dyes have
great potential for applications in visible-light-mediated organic
synthesis [38-41] which fulfils the basic principle of green
chemistry.
Previous work: J. Am. Chem. Soc. 2018, 140, 6818−6822.
Present work:
Br
Br
HO
Br
O
O
A potential of developing new synthetic methodologies using
visible light has recently received much attention from a number
of research groups [20-23]. This is because solar energy (visible
light) is clean, easy to handle and an unlimited energy source
having great prospects for the development of sustainable and
eco-friendly protocols for organic synthesis [24]. Some
pioneering researchers have dedicated to converting solar energy
into chemical energy for chemical transformations [25,26] which
Br
COOH
NH2
R2
R3
NH2
Eosin Y (2 mol%)
R1
R3
+
R1
H
R2
MeCN, rt, 8-12 h
18 W blue LEDs
Scheme 1. Eosin Y mediated C(sp3)−H alkylation of amine
includes a promising strategy for the application of photoredox
substrates via direct hydrogen atom transfer (HAT)
———
 Corresponding author. e-mail: ppsingh23@gmail.com (P.P. Singh).

2
Tetrahedron Letters
Recent developments in photocatalysis over the past decade
Y (2 mol%) results increase in yield of desired product (Table 1,
entries 6 and 7). Using MeCN as a solvent with eosin Y (1
mol%) results decrease in yield of desired product (Table 1, entry
8). Using MeCN as a solvent with eosin Y (2 mol%) in presence
of 18W CFL results decrease yield of desired product in
comparison to blue LED (Table 1, entry 12 vs entry 1). The
scope of the present protocol across a range of amine and styrene
incorporating various substituents were studied. It was found that
substituted styrene with an electron-donating group on the
aromatic ring appear to react faster and afford marginally higher
yields in comparison to those bearing an electron-withdrawing
group (Table 2). It was found that the yield of product decreases
due to the ortho substituent as well as it increases at meta and
para position respectively.
have enabled previously inaccessible transformations [42-45]. In
addition to SET and energy transfer, HAT has been frequently
involved in photocatalysis, which can activate substrates without
the limitation of redox potentials, offering enormous
opportunities for C-H activations [46,47]. Upon light absorption,
HAT catalysis is normally achieved in three different ways:
direct HAT process, indirect HAT process [48,49] and proton-
coupled electron transfer (PCET) process [50,51]. Among these
three pathways, direct HAT catalysis represents the most reagent
and redox economical method, in which the activated
photocatalyst behaves as a HAT catalyst to abstract a H atom
from a substrate. The catalytic cycle is subsequently turned over
through a reverse hydrogen atom transfer (RHAT) to one of the
generated intermediates [52-56]. Thus, photoredox catalysis in
conjugation with HAT is an attractive approach to activating
organic molecules. Although, transition metal catalysed arylation
of amine substrate has been reported so far, [57], to the best of
our knowledge, this study represents the first example of
photocatalysed coupling of amine substrate with substituted
styrene via direct HAT. In continuation of our work on
development of environmentally benign synthesis [58-67] herein
we report a simple, visible light irradiated, efficient green
protocol for the eosin Y mediated C(sp3)−H alkylation of amine
substrates via direct HAT.
Table 2. Scope of the reaction.
Entry
Product
Yield
1
93
3a
Table 1. Optimization of reaction conditions.a
2
75
3b
3
4
5
6
85
88
78
65
3c
Entry
Catalyst
Catalyst
loading
(mol%)
Solvent
Time
(h)
Yieldb
(%)
3d
1
2
3
4
5
6
7
8
9
Eosin Y
Quinones
Benzophenones
Fluorescein
Rhodamine B
Eosin Y
2
2
2
2
2
2
2
1
3
2
-
MeCN
MeCN
MeCN
MeCN
MeCN
DCM
8
8
8
8
8
8
8
8
8
97
35
5
12
10
75
68
65
92
3e
3f
Eosin Y
Eosin Y
Eosin Y
Eosin Y
THF
MeCN
MeCN
MeCN
MeCN
MeCN
10
11
12
12
12
12
Tracec
Ndd
78e
7
-
72
90
83
Eosin Y
2
3g
aReaction conditions: 1 (1.0 mmol), 2 (1.0 mmol), catalyst (mol%), in 3
mL solvent irradiated using high power blue LEDs [18 W] at rt for 8–12 h.
8
9
bIsolated yield of the pure product 3. Reaction was performed in the dark.
c
dReaction was carried out without the catalyst. e18 W CFL (compact
fluorescent lamp, Philips) was used.
3h
3i
In order to realise our idea and optimise the reaction
conditions, the key reaction of substituted amine 1 and
substituted styrene 2 with a catalytic amount of eosin Y in a
solvent under irradiation with blue LEDs [18 W, λ = 469 nm]
was carried out (Table 1).
10
97
3j
We were delighted to obtain the desired substituted product 3,
in 97% yield (Table 1, entry 1). Then, the control experiments
were carried out, which show that eosin Y and visible light are
essential for the reaction, because in the absence of any of the
reagents/reaction parameters either the product was not detected
or was formed in traces (Table 1, entries 1 versus 11 and 10). By
application of quinones, benzophenones, fluorescein and
rhodamine B the yield of product become very less (Table 1,
entries 2, 3, 4 and 5). By using solvent DCM and THF with eosin
11
12
95
80
3k
3l

3
and styrene in the repertoire of chemistry and biology might be
paved with the implementation of our developed strategy.
13
14
68
72
3m
Acknowledgments
We sincerely thank Emerging Science Society (ESS01/2018)
for financial support as well as SAIF, CDRI, Lucknow and IISc
Bangalore for providing microanalyses and spectra.
3n
References
On the basis of our observations and the literature reports,
[57] a plausible mechanistic pathway is depicted in Scheme 2. It
has been illustrated that the anionic forms of eosin Y were the
active catalysts that promote SET-based redox catalytic cycles in
majority of previous studies, where neutral eosin Y was
considered inactive [68,69]. In order to elucidate the actual
species of eosin Y in the HAT-based catalytic cycle, various
control experiments were performed in presence of blue LED
with excellent yield [70]. The formation of a carbon-centered
radical was promoted by visible-light activated *eosin Y through
a HAT process. The derived carbon radical was subsequently
trapped by an electron deficient styrene to selectively form
radical adduct B. The RHAT process between eosin Y-H II and
radical B exhibited a high free energy barrier (path a). Instead,
another amine molecule and radical B might undergo a reversible
HAT process to deliver the desired product, followed by RHAT
between amine radical A and eosin Y-H II to regenerate ground
state eosin Y catalyst (path b).
1. J. W. Beatty, C. R. J. Stephenson, Acc. Chem. Res. 48 (2015)
1474.
2. V. Froidevaux, C. Negrell, S. Caillol, J. P. Pascault, B. Boutevin,
Chem. Rev. 116 (2016) 14181.
3. B. Dutcher, M. Fan, A. G. Russell, ACS Appl. Mater. Interfaces, 7
(2015) 2137.
4. P. Kittakoop, C. Mahidol, and S. Ruchirawat, Curr. Top. Med.
Chem. 14 (2014) 239.
5. T. P. Cushnie, B. Cushnie, A. J. Lamb, Int. J. Antimicrobial.
Agents 44 (2014) 377.
6. S. Funayama, G. A. Cordell, Eds.; Academic Press: Waltham,
MA, 2014.
7. S. A. Lawrence, Amines:ꢀSynthesis, Properties and Applications
Cambridge University Press, 2004.
8. K. S. Hayes, Applied Catalysis A: General, 2001, 221, 187.
9. C. Le, Y. Liang, R. W. Evans, X.Li, D. W. C. MacMillan, Nature
547 (2017) 79.
10. D. Vasu, A. L. F. de Arriba, J. A. Leitch, A. de Gombert, D. J.
Dixon, Chem. Sci. 10 (2019) 3401.
11. R. N. Salvatore,C. H. Yoon, K. W. Jung, Tetrahedron 57 (2004)
7785.
12. A. Hager, N. Vrielink, D. Hager, J. Lefranc, D. Trauner, Nat.
Prod. Rep. 33 (2016) 491.
13. A. Chandy, A. S. Thakur, R. Panik P Tiwari, Medicinal Chemistry
& Drug Discovery 4(2) (2013) 108.
14. M. Sun, C. Y. Hong, C. Y. Pan, J. Am. Chem. Soc. 134 (51)
(2012) 20581.
15. M. Zhang, T. Li, D. Li, D. Yi, Journal of Chemical and
Pharmaceutical Research 6 (7) (2014) 2584.
16. Promethazine Hydrochloride Monograph for Professionals".
Drugs.com. American Society of Health-System Pharmacists.
Retrieved 24 October 2018.
17. G. Goissisa, M. H. de Sousa, Materials Research 12 (1) (2009) 69.
18. D. H. Jornada, G. F. S. Fernandes, D. E. Chiba, T. R. F. de Melo,
J. L. dos Santos, M. C. Chung, Molecules 21 (42) (2016)
doi:10.3390/molecules21010042.
19. G. W. Sluggett, T. Zelesky, E. M. Hetrick, Y. Babayan, S. W.
Baertschi, Journal of Pharmaceutical and Biomedical Analysis 149
(2018) 206.
20. J. W. Tucker, C. J. R. Stephenson, J. Org. Chem. 77 (4) (2012)
1617.
21. D. R. Heitz, K. Rizwan G. A. Molander, J. Org. Chem. 81(16)
(2016) 7308.
22. L. Capaldo, D. Ravelli, Eur. J. Org. Chem. (2017) 2056.
23. H. Chen, L. Guo, Shouyun Yu, Org. Lett. 20 (19) (2018), 6255.
24. X. Sala, I. Romero, M. Rodriguez, L. Escriche, A. Llobet, Angew.
Chem. Int. Ed. 48 (16) (2009) 2842.
25. D. Mandler, I. Willner, J. Am. Chem. Soc. 106 (18) (1984) 5352.
26. O. Ishitani, S. Yanagida, S. Takamuku C. Pac, J. Org. Chem. 52
(13) (1987) 2790.
27. A. Inagakia, M. Akita, Coord. Chem. Rev. 254 (2010) 1220.
28. C. K. Prier, D. A. Rankic, D. W. C. MacMillan, Chem. Rev. 113
(7) (2013) 5322.
Scheme 2. Plausible mechanistic pathway.
29. D. A. Nicewicz, T. M. Nguyen, ACS Catal. 4 (1) (2014) 355.
30. J. Xie, H. Jina, P. Xu, C. Zhu, Tetrahedron Lett. 55 (1) (2014), 36.
31. X. Lang, X. Chen, J. Zhao, Chem. Soc. Rev. 43 (1) (2014), 473.
32. J. Hu, J. Wang, T. H. Nguyen, N. Zheng, Beilstein J. Org. Chem.
9 (2013) 1977.
33. D. Rovelli, M. Fagnoni, A. Albini, Chem. Soc. Rev. 42 (1) (2013)
97.
34. T. P. Yoon, M. A. Ischay, J. J. Du, Nat. Chem. 2 (7) (2010) 527.
35. X. J. Yang, B. Chen, L. Q. Zheng, L. Z. Wu, C. H. Tung, Green
Chem. 16 (2014) 1082.
In conclusion, we have developed
a novel, one-pot
photocatalysed C(sp3)−H alkylation of amine substrates using
eosin Y as a catalyst via direct HAT. Thus, it is a superior
alternative to the existing method with respect to green and
sustainable chemistry (better atom and step-economy). Due to
metal-free, readily available, eco-sustainable, economical nature
and in addition to light absorption in the visible region makes
eosin Y an ideal direct HAT photocatalyst. Thus, it would
become a novel protocol for coupling between amine substrate
36. . idaly, C. Ceballos, A. al ui res, M. S. I. Veitia, A. Guy C.
Ferroud, Green Chem. 14 (2012) 1293.

4
Tetrahedron Letters
37. D. T. Yang, Q. Y. Meng, J. J. Zhong, M. Xiang, Q. Liu, L. Z.
58. V. Srivastava, P. K. Singh, P. P. Singh, Chem. Heterocycl.
Compd. 50 (2014) 573.
Wu, Eur. J. Org. Chem. 33 (2013) 7528.
38. Y. Q. Zou, J. R. Chen, X. P. Liu, L. Q. Lu, R. L. Davis, K. A.
Jørgense, W. J. Xiao, Angew. Chem. Int. Ed. 51 (2012) 784.
39. D. P. Hari, . ni , Org. Lett. 13 (15) (2011) 3852.
40. M. Neumann, S. ldner, . ni , K. Zeitler, Angew. Chem. Int.
Ed. 50 (4) (2011) 951.
41. V. Rey, S. M. S. Catro, J. E. Arguello, A. B. Pe ory,
Tetrahedron Lett. 50 (33) (2009) 4720.
42. N. A. Romero, D. A. Nicewicz, Chem. Rev. 116 (2016) 10075.
43. D. Ravelli, S. Protti M. Fagnoni, Chem. Rev. 116 (2016) 9850.
44. C. K. Prier, D. A. Rankic, D. W. C. MacMillan, Chem. Rev. 113
(2013) 5322.
59. V. Srivastava, P. K. Singh, P. P. Singh, Croat. Chem. Acta, 87 (2)
(2014) 91.
60. V. Srivastava, P. K. Singh, P. P. Singh, Croat. Chem. Acta 88 (1)
(2015), 59.
61. V. Srivastava, P. K. Singh, P. P. Singh, Croat. Chem. Acta 88 (3)
(2015) 227.
62. V. Srivastava, P. K. Singh, P. P. Singh, Asian J. Chem. 8 (10)
(2016) 2159.
63. V. Srivastava, P. K. Singh, S. Sinha, P. P. Singh, Rev. Roum.
Chim. 61 (10) (2016) 755.
64. V. Srivastava, P. P. Singh, RSC Adv. 7 (2017) 31377.
65. V. Srivastava, P. K. Singh, S. Kanaujia, P. P. Singh, New J. Chem.
42 (2018) 688.
45. M. R. Narayanam, C. R. J. Stephenson, Chem. Soc. Rev. 40
(2011) 102.
46. L. Capaldo and D. Ravelli, Eur. J. Org. Chem. (2017) 2056.
47. D. Ravelli, D. Dondi, M. Fagnoni, A. Albini, Chem. Soc. Rev. 38
(2009) 1999.
48. M. H. Shaw, V. W. Shur- tleff, J. A. Terrett, J. D. Cuthbertson, D.
W. C. MacMillan, Science 352 (2016) 1304.
66. P. K. Singh, P. P. Singh, V. Srivastava, Croat. Chem. Acta, 2018,
91 (3) (2018), 383.
67. V. Srivastava, P. K. Singh, P. P. Singh, Tetrahedron Lett. 60
(2019) 40.
68. M. Majek, A. J. Wangelin, Acc. Chem. Res. 49 (2016) 2316.
69. M. Majek, F. Filace, A. J. Wangelin, Beilstein J. Org. Chem., 10
(2014) 981.
49. S. Mukherjee, B. Maji, A. Tlahuext Aca, F. Glorius, J. Am. Chem.
Soc. 138 (2016) 16200.
50. G. J. Choi, Q. Zhu, D. C. Miller, C. J. Gu, R. R. Knowles, Nature
539 (2016) 268.
51. J. C. K. Chu, T. Rovis, Nature 539 (2016) 272.
52. V. De Waele, O. Poizat, M. Fagnoni, A. Bagno, D. Ravelli, ACS
Catal. 6 (2016) 7174.
70. X. Z. Fan, J. W. Rong, H. L. Wu, Q. Zhou, H. P. Deng, J. D. Tan,
C. W. Xue, L. Z. Wu, H. R. Tao, J. Wu, Angew. Chem. Int. Ed. 57
(2018) 8514.
Supplementary Material
53. S. Kamijo, G. Takao, K. Kamijo, M. Hirota, K. Tao, T. Murafuji,
Angew. Chem. Int. Ed. 55 (2016) 9695.
Supplementary material that may be helpful in the review
process should be prepared and provided as a separate electronic
file. That file can then be transformed into PDF format and
submitted along with the manuscript and graphic files to the
appropriate editorial office.
54. J. Murphy, D. Bastida, S. Paria, M. Fagnoni, P. Melchiorre,
Nature 532 (2016) 218.
55. S. Kamijo, G. Takao, K. Kamijo, T. Tsuno, K. Ishiguro, T.
Murafuji, Org. Lett. 18 (2016) 4912.
56. N. Ishida, Y. Masuda, S. Uemoto, M. Murakami, Chem. Eur. J. 22
(2016) 6524.
57. M. Kapoor, D. Liu, M. C. Young, J. Am. Chem. Soc. 140 (2018)
6818.

5
Highlights

A mild and efficient one-pot visible light-
induced method


Metal-free organic dyes have been used
Functionalization of a wide range of native
C-H bonds in an economical and
sustainable manner