New catalytic effect of thiourea on the oxidative cyanation of N-aryltetrahydroisoquinolines

Article abstract of DOI:10.1016/j.tetlet.2018.12.050

Thiourea itself has been introduced as a mild and efficient organocatalyst for the oxidative α -cyanation of N-aryltetrahydroisoquinolines (THIQs) with trimethylsilyl cyanide (TMSCN), giving the corresponding products in good to excellent yields. Experime

Full text of DOI:10.1016/j.tetlet.2018.12.050

Accepted Manuscript
New catalytic effect of thiourea on the oxidative cyanation of N-aryltetrahy-
droisoquinolines
Bakhtar Ullah, Yuli Zhou, Jingwen Chen, Zongbi Bao, Yiwen Yang, Qiwei
Yang, Qilong Ren, Zhiguo Zhang
PII:
S0040-4039(18)31501-6
https://doi.org/10.1016/j.tetlet.2018.12.050
TETL 50513
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
24 September 2018
17 December 2018
21 December 2018
Please cite this article as: Ullah, B., Zhou, Y., Chen, J., Bao, Z., Yang, Y., Yang, Q., Ren, Q., Zhang, Z., New
catalytic effect of thiourea on the oxidative cyanation of N-aryltetrahydroisoquinolines, Tetrahedron Letters (2018),
doi: https://doi.org/10.1016/j.tetlet.2018.12.050
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1
Tetrahedron Letters
New catalytic effect of thiourea on the oxidative cyanation of N-
aryltetrahydroisoquinolines
Bakhtar Ullah, Yuli Zhou, Jingwen Chen, Zongbi Bao, Yiwen Yang, Qiwei Yang, Qilong Ren and
Zhiguo Zhang*
aKey Laboratory of Biomass Chemical Engineering of Ministry of Education, College of Chemical and Biological Engineering, Zhejiang University, Zheda
Road 38, Hangzhou 310027, China.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Thiourea itself has been introduced as a mild and efficient organocatalyst for the oxidative -
cyanation of N-aryltetrahydroisoquinolines (THIQs) with TMSCN, giving the corresponding
products in good to excellent yields. Experimental investigations demonstrated that thiourea
acts as a radical initiator by abstracting hydroxyl radical (∙OH) from tert-butyl hydroperoxide
(TBHP) directly instead of non-covalent H-bonding activation. The use of thiourea as a
radical initiator offers a new avenue for innovative chemical transformations in
organocatalyzed radical chemistry.
Available online
Keywords:
α-Aminonitriles
C−H activation
Cyanation
Organocatalysis
Thiourea
2009 Elsevier Ltd. All rights reserved.
Thiourea and its derivatives have been frequently employed
as organocatalysts for the acceleration of a wide range of
chemical transformations.1-7 The ready availability of
structure-diverse thiourea derivatives greatly facilitates their
development to be the main pillar of noncovalent
also been reported in chemical transformations.21,22 Inspired by
these works, we envisioned that thiourea might also be a
suitable catalyst for the oxidative cyanation of THIQs with a
nucleophilic cyanide. Herein, we present a novel catalytic
mode of thiourea as a radical initiator in the oxidative -
cyanation of THIQs using TBHP as a terminal oxidant
(Scheme 1c).
organocatalysts.1-3,8-10 A great deal of mechanistic
investigations has further intensified the notion that thioureas
activate electrophiles through hydrogen bonding (H-
bonding).11,12 Therefore, several strategies are often employed
to adjust the catalytic effect of thioureas, i.e. introduction of
electron-withdrawing groups to enhance H-bonding action,
incorporation of additional functionalities to generate
multifunctional H-bond donor catalysts, etc.1-3,13-17 In this
context, N,N’-bis[3,5-bis(trifluoromethyl)phenyl]thiourea,
introduced by Schreiner’s group (abbreviated here as T1),
represents a privileged organocatalyst and its applications
have been extended to a wide range of useful chemical
transformations.1-3,18 T1 is reported to promote the oxidation
of sulfides by TBHP through double hydrogen-bonding
interaction (Scheme 1a).12 We recently reported T1-catalyzed
cross-dehydrogenative coupling (CDC) of C(sp3)-H with
phosphites and nitroalkanes by using tert-butyl hydroperoxide
(TBHP) as a terminal oxidant (Scheme 1b).19,20 Experimental
investigation into the mechanism showed that the reaction
proceeds through the hydrogen bonding interaction of T1 with
TBHP and radical chain process.19,20 On the other hand,
thiourea itself or its derivatives work as radical initiators have

Scheme 1. Thiourea and its derivatives catalyzed oxidative
reactions with TBHP.
This observation was further highlighted when an 84% yield
was obtained using tetramethylthiourea as the catalyst (Table
2, entry 2), suggesting that an alternative reaction pathway
may be involved instead of H-bonding activation. The
essential effect of thiourea functionality was demonstrated by
the significantly lower yield obtained when the reaction was
performed in the presence of urea as the catalyst (Table 2,
entry 4). The use of methanol as the solvent was also found to
be crucial for this oxidative cyanation of THIQ. No
We commenced our investigation with the oxidative -
cyanation of N-phenyltetrahydroisoquinoline 1a with TMSCN
as a model reaction in the presence of 20 mol% of T1 and 2.0
equiv. of THBP (Table 1). We were pleased to find that the
reaction gave the desired product 2a in 47% yield at room
temperature (rt) in 5 hours using CH3CN as the solvent (Table
1, entry 2). The reaction performed in toluene, CHCl3 or under
solvent-free conditions afforded similar amount of -
cyanation product (Table 1, entries 3–5). Notably, the yield
was dramatically
acceleration effect was observed with dimethyl sulfide and
triethylamine as catalysts (Table 2, entries 5 and 6).
With the optimum conditions in hand, the scope of the
oxidative -cyanation reaction was explored. A number of N-
Table 1. Optimization of reaction conditions for the oxidative
-cyanation of N-phenyltetrahydroisoquinoline with
TMSCN.a
Table 2. Catalysts screening for the oxidative -cyanation of
N-phenyltetrahydroisoquinoline with TMSCN.a
Entry Catalyst
1
Yield (%)b
90
Entry
T1 (mol %)
Solvent
Yield (%)b
1
2
3
4
5
6
7
8
9
20
20
20
20
20
15
20
−
MeOH
CH3CN
Toluene
CHCl3
Neat
81
47
40
2
3
84
81
35
45
MeOH
MeOH
MeOH
MeOH
70
60c
14d
21e
20
aReaction conditions: 1a (0.2 mmol), TMSCN (2.0 equiv.),
TBHP (2.0 equiv., 5.5 M in decane), 15–20 mol % of T1,
solvent (0.6 mL), rt, 5 h. bIsolated yield. cMalononitrile as a
cyanide source. dWithout a catalyst. eAdding 2.0 equiv. of a
radical inhibitor (BHT).
4
5
15
17
improved to 81% when the solvent was switched to methanol,
probably due to the formation of HCN, which works as
cyanide source instead of TMSCN (Table 1, entry 1).23-25 The
control experiment showed that only 14% yield of product can
be obtained in the absence of T1. Interestingly, malononitrile
can also be employed as a cyanide source, giving the product
in 60% yield (Table 1, entry 7). Only 21% yield of the
corresponding -aminonitriles was obtained in the presence of
a radical inhibitor 2,6-di-tert-butyl-4-methylphenol (BHT),
suggesting that a radical pathway was likely involved in this
reaction (Table 1, entry 9).
6
8
aReaction conditions: 1a (0.2 mmol), TMSCN (2.0 equiv.),
TBHP (2.0 equiv., 5.5 M in decane), 20 mol % of catalyst,
MeOH (0.6 mL), rt, 5 h. bDetermined by 1H NMR using
mesitylene as an internal standard.
To determine the catalytic role of T1 in the oxidative
cyanation of THIQ, we screened a series of thiourea
derivatives (Table 2). Much to our surprise, thiourea itself
demonstrated superior catalytic efficiency to T1 (Table 2,
entry 1), which are contradictory to common sense that the
ability of H-bond donor is decisive for reaction acceleration.
aryltetrahydroisoquinolines were tested for this protocol
(Table 3). All the substrates containing electron-withdrawing
groups (EWGs) and electron-donating groups (EDGs) on N-
aryl ring tolerated well with this catalytic protocol. THIQs
substituted with halogens (Br, Cl, and F) at the para-position

were all efficiently transformed into corresponding products in
80-81% yield (2b-d).
bromo-4-pyridinyl group gave the corresponding product (2m)
in 59% yield. THIQ substrate substituted with an N-thiophen-
3-yl group produced the target compound (2n) in 56% yield.
The relatively inert heteroaromatic tertiary amine 1o was also
tolerated with this protocol, albeit only 20% yield of the
corresponding product was isolated.
THIQs with the para-substituted nitro group gave moderate
yield (52%) after 24 hours which may be due to the inhibitory
effect of nitro group in the formation of active iminium
intermediate. The p-methyl and p-methoxy substituted
substrates also provided excellent yields of 84% and 87%
respectively. The di-substituted substrate with methoxy groups
on the main skeleton of THIQ gave 58% yield of the product
2h after 24 hours. It is worthy of pointing out that inert N,N-
dimethylanilines were also viable substrates for this protocol,
giving 80% yield after 24 hours when the reaction temperature
increases from rt to
Presently the exact mechanism of thiourea itself catalyzed
oxidative cyanation of THIQs is not clear. Keeping in view
that tetramethylthiourea can also promote the
Table 3. The substrate scope of thiourea catalyzed oxidative
-cyanation of tertiary amines.a, b
Scheme 2. A plausible mechanism of thiourea itself catalyzed
oxidative cyanation of N-aryltetrahydroisoquinolines.
2b: 80%
rt, 5 h
2a: 86%
rt, 5 h
2c: 80%
rt, 5 h
oxidative cyanation of THIQs, a plausible mechanism is
proposed as illustrated in Scheme 2. In comparison to the
previous mechanistic proposal that thiourea derivatives
facilitate the formation of active iminium intermediate through
hydrogen-bonding interaction with TBHP.19,20 However, in
this case, thiourea itself presumably operates as a radical
initiator by accepting hydroxyl radical (∙OH) from TBHP to
generate a tert-butoxyl radical (t-BuO·).21,22,26-29 This tert-
butoxyl radical trigger a SET from 1 to form a radical ion pair
composed of an N-aryltetrahydroisoquinoline radical cation 4
and a tert-butoxyl anion. Subsequently, radical cation 4 goes
through hydrogen radical (·H) transfer to thiourea-hydroxyl
radical, giving iminium ion 5 as an intermediate, while
thiourea is regenerated with production of water (H2O). The
iminium ion 5 undergoes a nucleophilic attack of HCN to
form the desired product 2.
2e: 52%
rt, 24 h
2f: 84%
rt, 5 h
2d: 81%
rt, 5 h
2i: 80%
2h: 58%
rt, 24 h
2g: 87%
rt, 5 h
60 oC, 24 h
2k: 78%
2j: 76%
2l: 78%
Conclusions
60 oC, 24 h
60 oC, 24 h
60 oC, 24 h
In conclusion, we have developed the thiourea itself catalyzed
oxidative cyanation of N-aryltetrahydroisoquinolines. This
method provides mild, efficient, and environmentally friendly
access to C-C coupling product in good to excellent yields,
while avoiding the use of metal catalysts. Experimental
investigation reveals that the reaction proceeds via the
function of thiourea as a radical initiator instead of hydrogen
bonding activation. Given the widespread applications of
radical chemistry and the ready availability of thioureas, this
mode of action may serve as a stimulus for exploratory
research of thiourea derivatives in synthetic chemistry.
2o: 20%
2n: 56%
2m: 59%
60 oC, 24 h
60 oC, 5 h
60 oC, 24 h
aThe reaction was carried out with tertiary amines (0.2 mmol),
TMSCN (2.0 equiv.), TBHP (2.0 equiv., 5.5 M in decane) in
the presence of 20 mol % of thiourea for 5-24 h using MeOH
(0.6 mL) as a solvent system at room temperature (2a-h) and
at 60 oC (2i-l). bIsolated yield.
60 oC. Furthermore, substituted N,N-dimethylanilines
derivatives with a methyl group at o-, m-positions and bromo
at p-position were all tolerant with this protocol, affording the
corresponding products in yield of 76%, 78% and 78%
respectively (2j-l).
Author information
Corresponding Author
*E-mail: zhiguo.zhang@zju.edu.cn
Authors Contributions
We further extended substrates scope to THIQ substituted
with heteroaromatic groups. The THIQ substrate bearing N-2-

28. Bhaskara Reddy, M. V., Srinivasulu, D., Peddanna, K.,
Apparao, C. & Ramesh, P.; Synth Commun, 2015, 45, 2592-
2600.
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Hutchison, D. & Baum, H.; Biochem J, 1987, 243, 867-870.
The manuscript was written through the contributions of all
authors. All authors have given approval to the final version of
the manuscript.
Notes
The authors declare no competing financial interest.
Acknowledgments
We are grateful for financial support from the National Key
R&D Program of China (grant number 2016YFA0202900),
the National Natural Science Foundation of China (grant
numbers 21878266, 21722609), the Fundamental Research
Funds for the Central Universities (grant number
2018FZA4021).
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Graphical Abstract
New catalytic effect of thiourea on the oxidative
Leave this area blank for abstract info.
cyanation of N-aryltetrahydroisoquinolines
Bakhtar Ullah, Yuli Zhou, Jingwen Chen, Zongbi Bao, Yiwen Yang, Qiwei Yang, Qilong Ren and Zhiguo
Zhang*

4
Highlights
 Thiourea itself was used as an organocatalyst for C(sp3)−H bond activation.
 -Aminonitriles were obtained in good to excellent yields.
 Thiourea acts as a radical initiator instead of non-covalent H-bond donor.