Visible-light-induced direct α-C(sp3)-H thiocyanation of tertiary amines

Article abstract of DOI:10.1016/j.tetlet.2015.10.048

Visible-light-induced, eosin Y catalyzed aerobic oxidative α-C(sp³)-H thiocyanation of tertiary amines is reported. The reaction proceeds through visible-light-induced in situ generation of the iminium ion followed by attack of ^-SCN nucleophile. This is the first example of visible-light-initiated formation of C(sp³)-S bond employing organo-photoredox catalysis. Mild reaction conditions and use of air and visible light as the greenest and sustainable reagents at room temperature are the salient features of the protocol.

Full text of DOI:10.1016/j.tetlet.2015.10.048

Tetrahedron Letters 56 (2015) 6696–6699
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Visible-light-induced direct
amines
a
-C(sp3)–H thiocyanation of tertiary
⇑
Arvind K. Yadav, Lal Dhar S. Yadav
Green Synthesis Lab, Department of Chemistry, University of Allahabad, Allahabad 211002, India
a r t i c l e i n f o
a b s t r a c t
Visible-light-induced, eosin Y catalyzed aerobic oxidative a
-C(sp3)–H thiocyanation of tertiary amines is
Article history:
Received 13 September 2015
Revised 11 October 2015
Accepted 14 October 2015
Available online 22 October 2015
reported. The reaction proceeds through visible-light-induced in situ generation of the iminium ion
followed by attack of ꢀSCN nucleophile. This is the first example of visible-light-initiated formation of
C(sp3)–S bond employing organo-photoredox catalysis. Mild reaction conditions and use of air and visible
light as the greenest and sustainable reagents at room temperature are the salient features of the
protocol.
Keywords:
Aerobic
Ó 2015 Elsevier Ltd. All rights reserved.
Iminium ion
Photoredox catalysis
Tertiary amines
Thiocyanation
Visible light
Chemical community desires
a
sustainable, environment
The in situ formation of iminium ion has attracted considerable
attention of synthetic organic chemists for the
-C(sp3)–H func-
friendly, and highly efficient protocol with selectivity. Thus, the
continued efforts for the development of more effective synthetic
protocols that fulfill these criteria are of global relevance. In this
regard, photoredox catalysis has recently offered a great opportu-
nity by utilizing unending resources like visible light and air in
organic synthesis.1 Certain electron rich substrates are capable of
engaging in single electron transfer (SET) for photoredox catalysis
processes to generate radicals, radical ions, or ions as intermedi-
ates to bring about the desired transformations.2
The success of this strategy started with the pioneering work of
MacMillan,3a Yoon,3b,c and Stephenson et al.3d involving the use of
photocatalysts such as Ru(bpy)3Cl2 (bpy = 2,20-bipyridine) and Ir
(dtbbpy)3Cl2 (dtbbpy = 4,40-di-tert butyl-2,20-bipyridine), which
absorb light in the visible region. Photocatalysts possess one
a
tionalization of tertiary amines.2 This is a tool that allows easy con-
struction of C–C and C–X bonds (X = N, P, O) adjacent to tertiary
amines through: (i) in situ formation of iminium ion transient
and (ii) attack of C, N, P, or O centered nucleophile (Scheme 1a).1
The photoredox catalysis is of great interest because it allows uti-
lization of visible light and atmospheric oxygen as the greenest and
readily available reagents in organic syntheses. Moreover, an alter-
native to the photochemistry of Ru(II) and Ir(II), eosin Y (EY)4, a
long known dye has recently been widely applied as an organo-
photoredox catalyst for the construction of C–C and C–X bonds
particularly in the field of pharmaceuticals, where traces of metals
are undesirable. Recently, our group has also applied eosin Y as an
organo-photoredox catalyst to bring about various synthetically
useful transformations.5
common characteristic, that is,
a facile intersystem crossing
(ISC) that allows the conversion of the initially formed
singlet photoexcited state to the relatively long-lived triplet
photoexcited state, which undergoes single-electron transfer
with organic molecules such as amines. Tertiary amines act as
sacrificial electron donors to reductively quench the photoexcited
state while they are oxidized to amine radical cations, which are
easily converted to its iminium ion.
Several communications have appeared on utilization of these
photocatalysts (Ru(II), Ir(II), and eosin Y etc.) during the last five
years for the
We have already extended the scope of this methodology by apply-
a
-functionalization of C(sp3)–H of tertiary amines.2
ing it to aza-Baylis–Hillman adducts to access c-functionalized ter-
tiary amines.2d To the best of our knowledge, there is no report on
the C–S bond construction on C(sp3)–H carbon adjacent to tertiary
amines using visible light photoredox catalysis.
Incorporation of thiocyanate function in organic molecules
enhances their scope of biological and chemical applications,6
⇑
Corresponding author. Tel.: +91 532 2500652; fax: +91 532 2460533.
E-mail address: ldsyadav@hotmail.com (L.D.S. Yadav).
because it allows the functional group manipulation in
a
http://dx.doi.org/10.1016/j.tetlet.2015.10.048
0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.

A. K. Yadav, L. D. S. Yadav / Tetrahedron Letters 56 (2015) 6696–6699
6697
Table 1
(a) Reported work
Optimization of reaction conditionsa
Br
Br
Ar
Ar
N
N
Ref. 1
HO
Br
O
O
Ar
Ar
C, N, P, O
catalyst
(mol%)
bond
air
(O2)
Br
photocatalyst
visible light
COOH
(eosin Y)
(b) Present work
N
N
Ar
SCN, solvent, rt, 6-12 h
NH4
Ph
N
Ph
Ar
1a
SCN
2a
eosin Y
SCN
(C-S bond)
Entry
Catalyst (mol %)
Solvent
Time (h)
Yieldb (%)
1
2
3
4
5
6
7
8
Eosin Y (1)
Rose bengal (1)
Eosin Y (1)
Eosin Y (1)
Eosin Y (1)
Eosin Y (0.5)
Eosin Y (2)
Eosin Y (1)
Eosin Y (1)
—
CH3CN
CH3CN
THF
6
6
6
6
6
90
68
73
86
81
64
90
Scheme 1. Visible-light-induced
quinolines (THIQs).
a
-C(sp3)–H functionalization of tetrahydroiso-
DMF
DMSO
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
straightforward and atom economical fashion.7 Organic thio-
cyanates usually serve as synthetic precursors that can be conve-
niently converted into various sulfur-containing derivatives,
including thiophenols,7a thioethers,7b and disulfides by using
SmI2,7c and thiocarbamates on acid hydrolysis.7d Moreover, the
SCN functionality undergoes intramolecular heterocyclization
to afford 1,3-oxathiolane, an important biologically and
pharmaceutically active five member heterocycle.8 Thus, a new
protocol that successfully installs the SCN group into C(sp3)–H of
organic molecules is of considerable interest.
Thiocyanates can be prepared via two classic routes, one is the
direct electrophilic thiocyanation of enolisable ketones in the pres-
ence of an oxidant7a and the other is the direct nucleophilic
substitution by ꢀSCN.7,9 However, the major drawback associated
with most of them is atom economy, use of oxidant, low regio-
and chemo-selectivity, as well as narrow substrate scope.7
Intrigued by the earlier reports on the application of eosin Y in
the visible light photoredox process for the iminium ion formation4
and of our work on the introduction of SCN functionality,9 we
report herein a pot efficient, eco-friendly, and novel method for
6
6
12
12
12
12
12
12
6
Tracesc
Tracesd
0e
9
10
11
12
13
14
Eosin Y (1)
Eosin Y (1)
Eosin Y (1)
Eosin Y (1)
Tracesf
63g
58h
91i
a
Reaction conditions: 1a (1.0 mmol), NH4SCN (1.0 mmol), catalyst (mol %), in
3 mL solvent irradiated using Luxeon Rebel high power green LEDs [2.50 W,
k = 535 nm] under an air atmosphere at rt for 6–12 h.
b
Isolated yield of the pure product 2a.
Reaction was performed under nitrogen.
Reaction was carried out in the dark.
Reaction was carried out in the absence of catalyst.
c
d
e
f
Reaction was quenched with 2,2,6,6-tetramethylpiperidyl-1-oxyl (TEMPO
(1.0 mmol).
g
18 W CFL (compact fluorescent lamp, Philips) was used.
KSCN was used as instead of NH4SCN.
O2 balloon was used.
h
i
the incorporation of SCN into
(Scheme 1b).
a
-C(sp3)–H of tertiary amines
Br, and Cl in the aryl moiety, and THIQ substrates bearing an
N-alkyl or N-heteroaryl moiety (Table 2). The reaction worked well
in all the cases and afforded products 2 in good to excellent yields
(74–95%). However, THIQs 1 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, products 2b–2e and 2h–2j vs 2f, 2g,
2k, 2l). Tertiary amines other than THIQs were also well compati-
ble with the present protocol (Table 2, entries 2m, 2n, and 2o).
Intrigued by our previous work,2d we applied the present
protocol to the aza-Baylis–Hillman adduct 1r containing benzylic
amine in conjugation with the double bond. Under the photoreox
To realize our idea and optimize the reaction conditions, the key
reaction of THIQ (1a) with NH4SCN was carried out using a cat-
alytic amount of eosin Y in CH3CN under irradiation with green
LEDs [2.50 W, k = 535 nm]10 in open air (Table 1). We were
delighted to get the desired product 2a in 90% yield (Table 1, entry
1). Then, the control experiments were carried out, which show
that eosin Y, air (O2), and visible light are essential for the reaction,
because in the absence of any of the reagents/reaction parameters
the product was not detected/formed in traces (Table 1, entry 1 vs
8–10). The reaction was quenched with TEMPO (1 mol %), which
indicates that a radical intermediate may be involved in the reac-
tion (Table 1, entry 1 vs 11). The optimum amount of eosin Y
required for the reaction was 1 mol %. On decreasing the amount
of eosin Y from 1 mol % to 0.5 mol % the yield was considerably
reduced (Table 1, entry 6), whereas the yield was not enhanced
even on the use of 2 mol % of eosin Y (Table 1, entry 7). The use
of another photo-organocatalyst like rose bengal (1 mol %) was
not so effective as eosin Y (1 mol %) (Table 1, entry 1 vs 2). For
the photo-activation of eosin Y, green LEDs give a much better
result than the normal house hold light (Table 1, entry 12). When
O2 balloon was used instead of open air, there was no appreciable
enhancement in the yield (Table 1, entry 14).
catalysis, it generates
selectively affords the expected
4p-conjugated iminium ion, which
c-thiocyanated product 2r with
NH4SCN in 89% yield (Scheme 2).
On the basis of our observations and the literature reports,1–5
a
plausible mechanistic pathway is depicted in Scheme 3. Eosin Y
(EY) on absorption of light goes to its excited state (EY⁄). Single
electron transfer between 1 and EY⁄ affords A and EYÅꢀ 4
, The pho-
toredox cycle of eosin Y is completed by the aerobic oxidation of
EYÅꢀ by O2 to its ground state (EY). The in situ generated superox-
ide radical anion (O2ꢀÅ) abstracts a proton from
a-position of A to
form iminium ion B, which is further attacked by ꢀSCN nucleophile
to afford the final product 2. The formation of superoxide radical
anion (Oꢀ2 Å) during the reaction was confirmed by the detection
of the resulting H2O2 (HOꢀ2 + NH4+ ? H2O2 + NH3) using KI/starch
indicator.12
Next, the reaction was optimized for an effective solvent system
and source of SCN ion. It was found that CH3CN was the best
among the tested solvents THF, DMF, DMSO, and CH3CN, hence it
was used throughout the present study (Table 1, entry 1 vs 3–5).
As the SCN sources, NH4SCN was better than KSCN in terms of
the yield and reaction time (Table 1, entry 1 vs 13).
In conclusion, we have disclosed an efficient protocol for the
a
-C(sp3)–H thiocyanation of tertiary amines at room temperature
using readily available and inexpensive NH4SCN as the source of
Under the established reaction conditions, we surveyed the
generality and scope of the present protocol across a range of THIQ
incorporating various substituents like Me, Et, MeO, COOEt, NO2,
ꢀSCN. It is also applicable to aza-Baylis–Hillman adduct to afford
the
c-thiocyanated product. The present protocol extends the

6698
A. K. Yadav, L. D. S. Yadav / Tetrahedron Letters 56 (2015) 6696–6699
Table 2
scope of nucleophiles applicable to iminium ion chemistry through
Scope of reactiona
photoredox catalysis using eosin Y. The reaction requires very
low loading (1 mol %) of eosin Y and utilizes atmospheric oxygen
and visible light as the greenest and sustainable reagents. The
present protocol affords a new route for the construction of C–S
bond.
eosin Y
air
(O2)
(1 mol%)
Ar
Ar
N
N
NH4SCN,CH3CN, rt, 6-10 h
Ar
Ar
2b SCN
1
Acknowledgment
N
N
N
We sincerely thank the SAIF, Punjab University, Chandigarh, for
providing spectra. One of us (A.K.Y.) is grateful to the CSIR, New
Delhi, for the award of a Senior Research Fellowship.
SCN
SCN
SCN
6 h, 90%c
2b, 6 h, 92%
2c, 6 h, 93%
2a,
Supplementary data
N
N
N
SCN
SCN
SCN
NO2
OMe
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2015.10.
048.
2e, 6 h, 92%
2d, 6 h, 95%
2f, 10 h, 74%
N
N
OMe
N
References and notes
SCN
SCN
SCN
Br
1. For selected reviews on visible-light-photoredox catalysis, see: (a) Xiea, J.; Jina,
H.; Xua, P.; Zhu, C. Tetrahedron Lett. 2014, 55, 36; (b) Nicewicz, D. A.; Nguen, T.
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43, 473; (d) Reckenthäler, M.; Griesbeck, A. G. Adv. Synth. Catal. 2013, 355,
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J.; Wang, J.; Nguyen, T. H.; Zheng Beilstein J. Org. Chem. 1977, 2013, 9; (g) Xi, Y.;
Yia, H.; Lei, A. Org. Biomol. Chem. 2013, 11, 2387; (h) Xuan, J.; Lu, L.-Q.; Chen, J.-
R.; Xiao, W.-J. Eur. J. Org. Chem. 2013, 6755; (i) Xuan, J.; Xiao, W.-J. Angew.
Chem., Int. Ed. 2012, 51, 6828; (j) Tucker, J. W.; Stephenson, C. R. J. J. Org. Chem.
2012, 77, 1617; (k) Shi, L.; Xia, W. Chem. Soc. Rev. 2012, 41, 7687; (l) Zou, Y.-Q.;
Chen, J.-R.; Liu, X.-P.; Lu, L.-Q.; Devis, R. L.; Jorgensen, K. A.; Xiao, W.-J. Angew.
Chem., Int. Ed. 2012, 51, 784; (m) Maity, S.; Zheng, N. Synlett 1851, 23; (n)
Narayanam, J. M. R.; Stephenson, C. R. J. Chem. Soc. Rev. 2011, 40, 102.
2. For recent developments on amines radical cation chemistry using visible-light
photoredox catalysis, see: (a) Wang, J.; Zheng, N. Angew. Chem. Int. Ed. 2015, 54,
11424; (b) Li, W.; Zhu, Y.; Duan, Y.; Zhang, M.; Zhu, C. Adv. Synth. Catal. 2015,
357, 1277; (c) Yadav, A. K.; Yadav, L. D. S. Tetrahedron Lett. 2015, 56, 686; (d)
Srivastava, V. P.; Yadav, A. K.; Yadav, L. D. S. Tetrahedron Lett. 2014, 55, 1788; (e)
Mathis, C. L.; Gist, B. M.; Frederickson, C. K.; Midkiff, K. M.; Marvin, C. C.
Tetrahedron Lett. 2013, 54, 2101; (f) Zhu, S.; Rueping, M. Chem. Commun. 2012,
11960; (g) Freeman, D. B.; Furst, L.; Condie, A. G.; Stephenson, C. R. J. Org. Lett.
2012, 14, 94; (h) DiRocco, D. A.; Rovis, T. J. Am. Chem. Soc. 2012, 134, 8094; (i)
Zhao, G.; Yang, C.; Guo, L.; Sun, H.; Chen, C.; Xia, W. Chem. Commun. 2012,
2337; (j) Rueping, M.; Koenigs, R. M.; Poscharny, K.; Fabry, D. C.; Leonori, D.;
Vila, C. Chem.-Eur. J. 2012, 18, 5170; (k) Rueping, M.; Zhu, S.; Koenigs, R. M.
Chem. Commun. 2011, 8679; (l) Rueping, M.; Zhu, S.; Kόnigs, R. M. Chem.
Commun. 2011, 12709; (m) Xuan, J.; Cheng, Y.; An, J.; Lu, L.-Q.; Zhang, X.-X.;
Xiao, W.-J. Chem. Commun. 2011, 8337.
2h, 6 h, 92%
2i, 6 h, 91%
2g, 8 h, 84%
O2N
MeO
N
N
N
Cl
MeO
SCN
2k, 8 h, 87%
SCN
SCN
2j, 6 h, 95%
2l, 10 h, 76%
N
COOEt
SCN
N
SCN
SCN
N
SCN
N
N
2p, 10 h, 78%
2o, 8 h, 80%
N
SCN
2m, 8 h, 82%
2n, 6 h, 89%
2q, 10 h, 76%
a
Reaction conditions: 1 (1.0 mmol), NH4SCN (1.0 mmol), eosin Y (1 mol %) in
CH3CN (3 mL) irradiated using Luxeon Rebel high power green LEDs [2.50 W,
k = 535 nm]10 in open air at rt for 6–10 h.
b
For the general procedure, see: Ref. 11 or Supplementary data.
Isolated yield of the pure product 2.
c
3. (a) Nicewicz, D. A.; MacMillan, D. W. C. Science 2008, 322, 77; (b) Yoon, T. P.;
Ischay, M. A.; Du, J. N. Nat. Chem. 2010, 2, 527; (c) Ischay, M. A.; Anzovino, M. E.;
Du, J.; Yoon, T. P. J. Am. Chem. Soc. 2008, 130, 12886; (d) Condie, A. G.; González-
Gómez, J. C.; Stephenson, C. R. J. J. Am. Chem. Soc. 2010, 132, 1464.
air
eosin Y
(1 mol%)
N
N
(O2)
COOMe
COOMe
4. For photocatalytic applications of eosin Y, see: (a) Hari, D. P.; König, B. Chem.
Commun. 2014, 6688; (b) Zhang, J.; Wang, L.; Liu, Q.; Yang, Z.; Huang, Y. Chem.
Commun. 2013, 11662; (c) Majek, M.; von Wanglin, A. J. Chem. Commun. 2013,
5507; (d) Hari, D. P.; Schroll, P.; König, B. J. Am. Chem. Soc. 2012, 134, 2958; (e)
Hari, D. P.; Hering, T.; König, B. Org. Lett. 2012, 14, 5334; (f) 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; (g) Fidaly, K.; Ceballos, C.; Falguières, A.; Veitia, M. S.-I.; Guy,
A.; Ferroud, C. Green Chem. 2012, 14, 1293; (h) Neumann, M.; Füldner, S.; König,
B.; Zeitler, K. Angew. Chem., Int. Ed. 2011, 50, 951; (i) Hari, D. P.; König, B. Org.
Lett. 2011, 13, 3852.
NH4SCN ,CH3CN, rt, 6 h
SCN
yield: 89%
2r,
1r
Scheme 2.
c
-Thiocyanation of the aza-Baylis–Hillman adduct.
5. (a) Keshari, T.; Yadav, V. K.; Srivastava, V. P.; Yadav, L. D. S. Green Chem. 2014,
16, 3986; (b) Yadav, A. K.; Yadav, L. D. S. Tetrahedron Lett. 2014, 55, 686; (c)
Srivastava, V. P.; Yadav, A. K.; Yadav, L. D. S. Synlett 2014, 625; (d) Yadav, A. K.;
Srivastava, V. P.; Yadav, L. D. S. RSC Adv. 2014, 4, 4181; (e) Srivastava, V. P.;
Yadav, L. D. S. Synlett 2013, 2758; (f) Srivastava, V. P.; Yadav, A. K.; Yadav, L. D.
S. Synlett 2013, 465; (g) Yadav, A. K.; Srivastava, V. P.; Yadav, L. D. S. New J.
Chem. 2013, 37, 4119.
Ar
Ar
N
N
Ar
Ar
Y*
E
Photocatalytic
1
EY
A
cycle of eosin
Y
O2
EY
O2
HO2
6. (a) Mitra, S.; Ghosh, M.; Mishra, S.; Hajra, A. J. Org. Chem. 2015, 80, 8275; (b)
Fan, W.; Yang, Q.; Xu, F.; Li, P. J. Org. Chem. 2014, 79, 10588.
(air)
7. (a) Grant, M. S.; Snyder, H. R. J. Am. Chem. Soc. 1960, 82, 2742; (b) Melzig, L.;
Stemper, J.; Knochel, P. Synthesis 2010, 2085; (c) Sengupta, D.; Basu, B.
Tetrahedron Lett. 2013, 54, 2277; (d) Wei, Z. L.; Kozikowski, A. P. J. Org. Chem.
2003, 68, 9116; (e) Reddy, S. B. V.; Madhu, S. S. R.; Madan, C. Tetrahedron Lett.
2011, 52, 1432.
NH4SCN
Ar
Ar
N
N
Ar
Ar
B
2
SCN
8. (a) Yadav, A. K.; Yadav, L. D. S. Green Chem. 2015, 17, 3505; (b) Bisogno, F. R.;
Cuetos, A.; Lavandera, I.; Gotor, V. Green Chem. 2009, 11, 452; (c) Lv, X.; Liu, Y.;
Qian, W.; Baoa, W. Adv. Synth. Catal. 2008, 350, 2507.
Scheme 3. Plausible mechanistic pathway for the
tertiary amines.
a
-C(sp3)–H thiocyanation of

A. K. Yadav, L. D. S. Yadav / Tetrahedron Letters 56 (2015) 6696–6699
6699
9. (a) Yadav, L. D. S.; Garima; Kapoor, R. Synth. Commun. 2011, 41, 100; (b) Yadav,
L. D. S.; Srivastava, V. P.; Patel, R. Tetrahedron Lett. 2008, 49, 3142.
the reaction (as monitored by TLC), water (5 mL) was added, and the mixture
was extracted with EtOAc (3 ꢁ 5 mL). The combined organic phase was dried
over MgSO4, filtered, and evaporated under reduced pressure. The resulting
product was purified by silica gel column chromatography using a gradient
mixture of hexane/ethyl acetate as eluent to afford an analytically pure sample
of 2. All the compounds were characterized by IR, NMR, and MS analysis. The
characterization data of compounds 2a–2r are given in Supplementary data.
12. Fekarurhobo, G. K.; Angaye, S. S.; Obomann, F. G. J. Emerg. Trends Engg. Appl. Sci.
(JETEAS) 2013, 4, 394.
10. Green LEDs (2. 5 W, 535 nm) Rebel LED, mounted on a 25 mm cool base was
purchased from commercial supplier Luxeon Star LEDs Quadica Developments
Inc. 47 6th Concession Rd. Brantford, Ontario N 32 5L7 Canada.
11. General procedure for the a
-C(sp3)–H thiocyanation of tertiary amines (Table 2): A
mixture of tertiary amine 1 (1.0 mmol), NH4SCN (1.0 mmol), and eosin Y
(1 mol %) in CH3CN (3 mL) was irradiated with green LEDs from bottom sides of
a flask open to air with stirring at rt for 6–10 h (Table 2). After completion of