Solvent-promoted highly selective dehydrogenation of tetrahydroisoquinolines without catalyst and hydrogen acceptor

Article abstract of DOI:10.1016/j.tetlet.2016.01.008

An unusual solvent DMF-promoted dehydrogenation of 1-substituted 1,2,3,4-tetrahydroisoquinolines to synthesize cyclic imines is described. This environmentally friendly reaction features no requirement of any metal catalysts, oxidants, or hydrogen acceptors. A wide range of structurally varied 3,4-dihydroisoquinolines can be obtained with good yields and excellent chemoselectivities.

Full text of DOI:10.1016/j.tetlet.2016.01.008

Tetrahedron Letters 57 (2016) 747–749
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Solvent-promoted highly selective dehydrogenation of
tetrahydroisoquinolines without catalyst and hydrogen acceptor
⇑
⇑
Guang-Shou Feng, Yue Ji, Hui-Fang Liu, Lei Shi , Yong-Gui Zhou
State Key Laboratory of Catalysis, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 457 Zhongshan Road, Dalian 116023, China
a r t i c l e i n f o
a b s t r a c t
Article history:
An unusual solvent DMF-promoted dehydrogenation of 1-substituted 1,2,3,4-tetrahydroisoquinolines to
synthesize cyclic imines is described. This environmentally friendly reaction features no requirement of
any metal catalysts, oxidants, or hydrogen acceptors. A wide range of structurally varied 3,4-dihydroiso-
quinolines can be obtained with good yields and excellent chemoselectivities.
Ó 2016 Published by Elsevier Ltd.
Received 14 November 2015
Revised 29 December 2015
Accepted 5 January 2016
Available online 6 January 2016
Keywords:
Tetrahydroisoquinoline
Partial dehydrogenation
Imine
Transition-metal catalyzed dehydrogenation of organic com-
pounds is one of the powerful, atom-economic and environmen-
tally benign synthetic methodologies to introduce unsaturated
double bonds, such as C@C, C@N and C@O, because this process
avoids the utility of stoichiometric amounts of oxidants which will
also produce the undesired waste. Dehydrogenation of N-heterocy-
cles is a fundamental and important process in organic synthesis.
The corresponding dehydroaromatization products are prevalent
in pharmaceuticals, agrochemicals, and functional organic materi-
als.1 Dehydrogenative transformation is considered to be a thermo-
dynamically uphill process,2 therefore, the harsh reflux condition
or sacrificial hydrogen acceptor may sometimes be needed. So
far, catalytic dehydrogenation reactions of N-heterocycles usually
employed conventional heterogeneous metal catalysts, which usu-
ally show poor functionality tolerance and require harsh reaction
conditions.3 Recently, homogenous iridium,4 ruthenium,5 palla-
dium,6 iron,7 zinc,8, nickel,9 and platinum,10 complexes have been
found to be competent for the catalytic dehydrogenation of
tetrahydroquinolines, tetrahydroisoquinolines, indolines, tetra-
hydroquinoxalines, Hantzsch esters and saturated bicyclic ondec-
ahydro-1,5-naphthyridine with good to excellent results.
for the direct transformation of amines.11 Although many trials
have been devoted to dehydrogenation of N-heterocyclic com-
pounds, the partial dehydrogenative processes to obtain cyclic imi-
nes are still rare.12 It is easy to understand that hydroaromatic
compounds containing nitrogen atoms are prone to form the final
dehydroaromatization products for the aromatic stability and the
intermediates are normally short-living species during dehydro-
genating process. How to realize the high selectivity of partial dehy-
drogenation of N-heterocyclics is a challenging subject in this
research field. A critical issue to resolve is the suppression of
aromatization which in turn improves the chemoselectivity of
dehydrogenation. Given that the different dehydrogenation prod-
ucts of N-heterocyclics, including aromatic compounds and imines,
both are valuable organic building blocks, developing an efficient
and well controllable dehydrogenation process of N-heterocyclic
compounds is of great significance. Herein, we report an unusual
solvent-promoted partial dehydrogenation of tetrahydroisoquino-
lines to exclusively generate 3,4-dihydroisoquinolines as products
with high chemoselectivity, providing greener and more practical
approach for the preparation of useful cyclic imines (Fig. 1).
In the beginning of our research, we performed the dehydro-
genative oxidation reaction of 1-phenyl-1,2,3,4-tetrahydroiso-
quinoline (1a). Firstly, a survey of solvents was conducted to
examine the reaction. No product was obtained in most solvents
(Table 1, entries 1–3). To our surprise, when the DMF or DMSO
was used as the solvent, the imine product 2a was obtained with
excellent conversion and perfect chemoselectivity (Table 1, entries
4 and 5). Further investigation of temperature revealed that the
reaction temperature is a very important effect factor and 100 °C
is the best choice for a satisfied conversion and chemoselectivity
From the point of view of synthetic chemistry, imine bears the
reactive C@N bond and is capable of undergoing various types of
transformations, including cyclization reactions and the reactions
with nucleophiles. Generation of imine in situ by dehydrogenating
amine has been regarded as a new and substrate-activating strategy
⇑
Corresponding authors. Tel./fax: +86 411 84379220.
E-mail addresses: shileichem@dicp.ac.cn (L. Shi), ygzhou@dicp.ac.cn
(Y.-G. Zhou).
http://dx.doi.org/10.1016/j.tetlet.2016.01.008
0040-4039/Ó 2016 Published by Elsevier Ltd.

748
G.-S. Feng et al. / Tetrahedron Letters 57 (2016) 747–749
Table 2
Transition-metal catalyzed dehydroaromatization of amine
Scope for the 1-substituted tetrahydroisoquinolinea
Ir, Ru, Pd, Fe, Zn, Pt ect
R2
R2
R1
NH
N
-2 H2
DMF
100 oC, 24 h
R
R
H2
+
NH
N
Isoquinolines
R1
R3
R3
1
2
Stoichiometric and catalytic oxidation of amine to imine
S, I2, TCCA or tBuOCl
Oxidase, ZnI2/Quinone
Entry
R1/R2
R3
Yieldb 2 (%)
NH
N
N
1
H/H
H/H
H/H
H/H
H/H
H/H
H/H
H/H
Me/H
Cl/H
MeO/H
MeO/MeO
MeO/MeO
H/H
H/H
H/H
MeO/MeO
H/H
Ph
Ph
83 (2a)
87 (2a)
88 (2b)
82 (2c)
85 (2d)
90 (2e)
77 (2f)
76 (2f)
75 (2g)
75 (2h)
75 (2i)
72 (2j)
85 (2k)
79 (2l)
82 (2m)
87 (2n)
91 (2o)
64 (2p)
2c
3
R
R
4-ClC6H4
4-MeOC6H4
3-MeC6H4
4-MeC6H4
4-CF3C6H4
4-CF3C6H4
Ph
Ph
Ph
Ph
3,4-(MeO)2C6H3
2-ClC6H4
4-FC6H4
4-BrC6H4
4-ClC6H4
Cy
Imines
4
5
6
This work
Solvent-promoted dehydrogenation of amine to imine
DMF
7
H2
+
NH
8c
9
♦ No Catalyst
♦ No Hydr ogen Acceptor
♦ No Oxidant
R
R
10
11
12
13
14
15
16
17
18d
Imines
Figure 1. Selective dehydrogenation of amines.
Table 1
Examination of reaction parametersa
a
b
c
Reaction conditions: 1 (0.3 mmol), DMF (2.0 mL), 100 °C.
Solvent
NH
Isolated yields.
In DMSO.
80 °C.
N
N
+
T, 24 h
d
1a
Ph
2a Ph
3a
Ph
-H2
Entry
Solvent
T (°C)
Conv.b (%)
2a:3ab
products with good yields (Table 2, entries 1, 12, 13 and 17). In
addition, the bromo or chloro groups on the aromatic ring of sub-
strates could survive well through this process, thus provided a
handle for further potential functionalization (Table 2, entries 3,
14 and 16). The substrate scope exploration may offer the potential
application for some chiral pharmaceutical synthesis and resolu-
tion in the industry. On the other hand, we also investigated the
1-alkyl substituted tetrahydroisoquinoline on the reactivity and
chemoselectivity (Table 2, entry 18). The desired imine product
was also obtained with 64% yield when the reaction was carried
out at 80 °C for 24 h, which maintained an excellent chemoselec-
tivity. Extension of this reaction to other amines such as 2-
methyl-1,2,3,4-tetrahydroquinoline and 4-methoxy-N-(1-phenyl-
ethyl)aniline, however, met with failure and no desired products
were obtained.
To further highlight the practical utility of the current method,
the selective partial dehydrogenation of 1-phenyl-1,2,3,4-tetrahy-
droisoquinoline 1a was performed under the optimal condition
on a gram scale. As illustrated in Scheme 1, the desired product
cyclic imine 2a was obtained in gram scale with 84% isolated yield.
Prolongation of reaction time ensured that a complete conversion
and good chemoselectivity was maintained. Furthermore, the ( )-
FR115427 was rapidly synthesized from the resulting cyclic imine
2a in four steps (Scheme 1, for the detailed procedure, see SI).14
Racemization of enantiomerically enriched compound is very
useful in industry because it can recycle the undesired isomer in
resolution operation of a racemate, thus increasing the overall
yield.15 One-pot racemization of enantiomerically pure amine 1a
1
2
3
4
5
6
7
8c
Toluene
CH3CN
Cyclohexane
DMF
DMSO
DMF
DMF
111
82
81
100
100
80
<5
<5
<5
>95
>95
90
33
92
ND
ND
ND
>20:1
>20:1
>20:1
>20:1
>20:1
60
100
DMF
a
b
c
Reaction conditions: 1a (0.2 mmol), solvent (1.0 mL).
Determined by 1H NMR.
Degassed DMF and N2 atmosphere were used.
(Table 1, entries 5–7). Even if air was carefully excluded from reac-
tion system, the imine 2a was still obtained in excellent yield
(Table 1, entry 8). Moreover, the gas composition of the reaction
system was examined by TPD-MS (Temperature Programmed
Desorption-Mass Spectrometer), and the signal of hydrogen (m/
z = 2) released from substrates was detected (see the SI for details).
On the basis of the above two facts, we considered that this reac-
tion might be a solvent-promoted thermal-dehydrogenation pro-
cess. But it is still unclear how DMF promotes this process. We
assume that the NAH and C1AH bond are both weakened via the
hydrogen-bond interactions between DMF/DMSO and substrates,
which may result in a low dehydrogenation energy barrier.
With the optimal reaction condition in hand, we explored the
scope of the solvent-promoted partial dehydrogenation of tetrahy-
droisoquinoline. As shown in Table 2, to our delight, almost all the
aryl substituted substrates performed dehydrogenation very well
under the standard conditions. The reaction was found not signif-
icantly affected by the substituents on the aromatic ring of either
the tetrahydroisoquinoline structure or the 1-aryl group, providing
the desired products with good to excellent yields (Table 2, entries
1, 3–7, 9–17). It was noteworthy that some key synthetic interme-
diates for manufacturing some drug molecules or nature products
containing tetrahydroisoquinoline skeleton13 were also suitable
candidates for this reaction, and they underwent the partial dehy-
drogenation reaction smoothly to afford the corresponding imine
1. BnBr, CH3CN
2. MeMgBr, THF
DMF
oC
NH
Ph
1.000 g
N
NH•HCl
Ph Me
( )-FR115427
100
3. Pd/C, AcOH, H2
Ph 4. HCl, EtOH
6a
1a
2a
> 95% conv.
84% yield
Scheme 1. Gram scale experiment and synthesis of ( )-FR115427.

G.-S. Feng et al. / Tetrahedron Letters 57 (2016) 747–749
749
References and notes
DMF
NaBH4, MeOH
rt
NH
NH
N
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Ph
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(R)-1a
Ph
(rac)-1a
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85% yield
Scheme 2. Racemization of (R)-1-phenyl-1,2,3,4-tetrahydroisoquinoline 1a.
could be easily realized via a dehydrogenation/reduction one-pot
process by using this catalyst-free dehydrogention methodology.
(R)-1-Phenyl-1,2,3,4-tetrahydro-isoquinoline 1a with 97% ee was
subjected to the optimized reaction conditions to access the cyclic
imine after removing DMF under vacuum, and then reduction with
sodium borohydride in methanol afforded the racemic product
with 85% isolated yield (Scheme 2). Clean condition, brief opera-
tion and easy scalability of this racemization process may lead to
a further industrial application in the near future.
In summary, we have successfully developed a green protocol
for accessing cyclic imine in good yields with excellent chemose-
lectivities by an solvent-promoted highly selective dehydrogena-
tion of tetrahydroisoquinolines without catalyst and dehydrogen
acceptor. Moreover, efficient and practical racemization of enan-
tiomerically pure 1-substituted tetrahydroisoquinoline can be
realized via one-pot dehydrogenation/reduction treatment. This
metal-free and oxidant-free dehydrogenation process may apply
in industrial syntheses owing to some advantages such as simplic-
ity, easy operation, free of expensive mutagenic reagents, no harsh
reaction conditions, and so on. Our ongoing experiments are
focused on this solvent-promoted dehydrogenation reaction of
other substrates and further application in cascade process.
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Acknowledgments
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This work was financially supported by National Natural
Science Foundation of China (21202162, 21472188), and Youth
Innovation Promotion Association, Chinese Academy of Sciences
(2014167).
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Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2016.01.
008.