DDQ-mediated Direct C(sp3)-H Cyanation of Benzyl Ethers and 1,3-Diarylpropenes under Solvent- and Metal-free Conditions

Article abstract of DOI:10.1002/adsc.201500096

A direct cyanation of benzyl ethers and 1,3-diarylpropenes with TMSCN was performed under solvent- and metal-free conditions. This oxidative cross dehydrative coupling (CDC) reaction was promoted by 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) and provided rapid access to a broad range of nitriles in good to excellent yields.

Full text of DOI:10.1002/adsc.201500096

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DOI: 10.1002/adsc.201500096
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DDQ-mediated Direct C(sp ) H Cyanation of Benzyl Ethers and
1,3-Diarylpropenes under Solvent- and Metal-free Conditions
Shanshan Kong,a Lingqiong Zhang,a Xiaoli Dai,a Lianzhi Tao,a Chunsong Xie,a
Lei Shi,b,* and Min Wanga,*
a
College of Material, Chemistry and Chemical Engineering, Hangzhou Normal University, Hangzhou 310036, Peopleꢀs
Republic of China
Fax: (+86) 571-28867899; e-mail: mwang@hznu.edu.cn
The Academy of Fundamental and Interdisciplinary Sciences, Harbin Institute of Technology, Harbin 150080, Peopleꢀs
b
Republic of China
E-mail: lshi@hit.edu.cn
Received: January 31, 2015; Revised: April 15, 2015; Published online: June 18, 2015
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201500096.
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Abstract: A direct cyanation of benzyl ethers and
1,3-diarylpropenes with TMSCN was performed
under solvent- and metal-free conditions. This oxi-
dative cross dehydrative coupling (CDC) reaction
was promoted by 2,3-dichloro-5,6-dicyano-1,4-ben-
zoquinone (DDQ) and provided rapid access to
a broad range of nitriles in good to excellent yields.
sp sp C C bond formation via coupling with termi-
nal alkynes has been reported by Li and Jiao using
DDQ as an oxidant with catalytic amounts of either
AgOTf or Fe(OTf)2. A trityl ion was also used recent-
ly by Liu as an oxidative reagent for the coupling of
ether with potassium alkynyltrifluoroborate to form
3
[6]
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sp sp C C bond. Inoue also demonstrated that
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photoexcited benzophenone can act as a C H activa-
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Keywords: 1,3-diarylpropene; benzyl ether; C(sp )
tor and generate carbon radicals that are subsequently
trapped by tosyl cyanide to afford the corresponding
nitriles using excess amounts of several different sub-
strates including ethers, alcohols, amines, alkanes and
alkylbenzenes (Scheme 1).[7] It is well established that
the cyano group serves as a versatile functional group
H functionalization; cyanation; DDQ
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Direct functionalization of C(sp ) H bonds is a rapid in organic synthesis since it can be easily converted
and effective method for constructing structurally into a variety of different functionalities and branched
complex molecules, especially those with interesting carbon skeletons. Furthermore, cyano groups are
biological activities. For this reason, significant re-
search efforts have been directed towards the devel-
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opment of new synthetic methods for C(sp ) H bond
3
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functionalization, in particular C(sp ) H bonds that
are adjacent to heteroatoms.[1] Several recent studies
have reported the development of powerful methods
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for the functionalization of C(sp ) H bonds using
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metals or other oxidative reagents to afford C C and
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C X bonds, which can be useful for the synthesis of
tetrahydroquinoline derivatives.[2] However, reports
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studying the functionalization of O C(sp ) H bonds
using cross dehydrative coupling (CDC) methods
have been relatively scarce until recently. This may be
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due to the fact that O C(sp ) H bonds are less reac-
tive and generally possess less biological relevance
compared to C(sp ) H bonds adjacent to nitrogen.
Among these reports concerning the functionaliza-
tion of O C(sp ) H bonds, direct sp sp and sp sp
3
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3
3
3
3
2
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Scheme 1. Synthesis of cyanide derivatives of 1,3-diarylpro-
[3]
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C C bond formations are well studied. In addition, penes and benzylic ethers.
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Shanshan Kong et al.
found in numerous natural products and synthetic ma- were also investigated, including O2/DDQ (0.1 equiv),
terials with interesting biological activities.[8] While 1- MnO2/DDQ
(0.1 equiv) and t-BuOOH/DDQ
cyano isochroman compounds are traditionally syn- (0.1 equiv). However, all of these systems gave lower
thesized by reacting cyclic acetals with a metal cya- yields of the desired product. Other cyanide sources,
nide, this strategy requires an additional step when including
K3Fe(CN)6,
NH4HCO3/DMSO
and
isochroman is used as a starting material.[9] As part of CH2(CN)2, failed to provide any of the desired prod-
our ongoing work towards the development of new uct.
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methods for the functionalization of C(sp ) H bonds
Using our optimized conditions, we proceeded to
adjacent to heteroatoms,[10] we herein report the cyan- investigate the substrate scope of this cyanation reac-
ation reaction of benzyl ethers and 1,3-diarylpropenes tion using various benzyl ethers (Table 2). First, the
with TMSCN using a CDC approach under solvent- effect of different substituents on the phenyl ring was
and metal-free conditions.[11,12]
investigated. Our results showed that the substituent
DDQ was initially evaluated as an oxidative dehy- at the C-7 position of the isochroman ring has a signif-
drogenating reagent for the coupling of isochroman icant effect on the cyanation reaction (2b–f). For ex-
(1a) with TMSCN under metal-free conditions and ample, the presence of a halogenated substituent at
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proved to be a very efficient reagent for the C(sp ) H this position resulted in reduced yields (70–74%) of
functionalization of tetrahydroisoquinolines and iso- the corresponding nitriles, compared to that of elec-
chromans.[13] The desired product (2a) was obtained tron-donating and sterically bulky groups such as
when the reaction was refluxed in dichloromethane methyl and tert-butyl groups. Furthermore, the 6,7-di-
and 1,2-dichloroethane in 51% and 20% yields, re- methoxy substrate bearing, two electron-donating
spectively (Table 1, entries 1–2). Several other sol- groups, generated the highest yield, with the corre-
vents were evaluated and found to give higher yields, sponding nitrile 2g being isolated in 91% yield. Iso-
including benzene, toluene, THF and CH3CN chromans with substituents at the C-8 or C-6,8 posi-
(Table 1, entries 3–6). Interestingly, the reaction did
not proceed at all when water or DMF were used as
Table 2. DDQ mediated direct cyanation of benzylic
the solvent (Table 1, entries 7–8). Notably, highest
yield of the desired product (2a) was achieved when
the reaction was conducted neat at 808C (Table 1,
entry 9). These conditions appeared to be optimal,
with further decreases or increases in the reaction
temperature and time leading to reduced yields
(Table 1, entries 10–13). In addition, decreasing the
amount of TMSCN added to the reaction resulted in
a slight decrease in yield. Several co-oxidative systems
ethers.[a,b]
Table 1. Optimization of reaction conditions for the synthe-
sis of nitrile 2a from isochroman (1a).[a]
Entry
Solvent
Temp [8C]
Time
Yield[%][b]
1
2
3
4
5
6
7
8
DCM
DCE
PhH
PhCH3
THF
CH3CN
H2O
DMF
neat
neat
reflux
reflux
reflux
reflux
reflux
reflux
reflux
80
80
r.t.
60
100
2.5 h
5 h
2.5 h
2 h
4 h
5 h
51
20
84
75
76
72
0
2 h
2.5 h
1.5 h
8 h
4.5 h
85 min
1 h
0
9
88
33
79
53
78
66[c]
10
11
12
13
14
neat
neat
neat
neat
80
80
1.5 h
[a]
0.5 mmol of 1a, 0.6 mmol of DDQ and 1.5 mmol of
TMSCN in 2 mL of solvent under an atmosphere of Ar.
Isolated yield.
[a]
0.5 mmol of 1, 0.6 mmol of DDQ and 1.5 mmol of
[b]
[c]
TMSCN under Ar.
Isolated yield.
[b]
1.5 equivalent of TMSCN (0.75 mmol) was used.
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DDQ-mediated Direct C(sp ) H Cyanation
tions afforded similar results to 2a. However, substi- a methyl group at this position gave a reduced yield
tuting a bromo or trifluoromethyl group at the C-5 of 50% for the desired product 4e. In addition, when
position resulted in significantly reduced yields of 1,3-(4’-tert-butyl)diphenylpropene was subjected to
58% and 39%, respectively. The presence of a methyl the same optimized cyanation conditions, the reaction
substituent at the C-3 position of the pyrane ring (2l) proceeded smoothly to give the nitrile product 4 f in
led to the yield of 83%, whereas the introduction of 68% yield. No product was observed when 1-phenyl-
an ester substituent at the same position (2m) led to propene was submitted to these reaction conditions.
an even more drop in the yield to 57%. However, 4-
In conclusion, we have developed an efficient reac-
methylisochroman yielded the nitrile 2n in 84% tion for the coupling of benzylic ethers and 1,3-diaryl-
yield. We were pleased to find that applying the opti- propenes with TMSCN in the presence of DDQ
mized conditions to the symmetrical benzylic ether, under metal- and solvent-free conditions. This method
phthalane, afforded the corresponding mono-cyano provides rapid access to benzylic nitriles in good to
product 2o in 72% yield. Furthermore, the acyclic excellent yields. Further research efforts aimed to-
benzylic ether also reacted smoothly under the opti- wards exploring the application of CDC and tandem
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mized conditions to give the desired nitrile 2p in reactions to C(sp ) H bonds of benzylic ethers and
80% yield. Unfortunately, the use of benzyl phenyl other substrates are currently underway.
ether as a substrate failed to provide any of the de-
sired coupling products.
Encouraged by these results, we further explored Experimental Section
the scope of this transformation using several other
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substrates bearing a benzylic C(sp ) H bond. Based General Procedure
on previous literature concerning the CDC reaction
of compounds containing C(sp ) H bonds, we select-
To a mixture of trimethylsilyl cyanide (1.5 mmol) and DDQ
(0.6 mmol) was added isochroman (0.5 mmol). The resulting
mixture was stirred at 808C under argon for about 1.5 h and
then cooled to room temperature. The resulting suspension
was diluted with diethyl ether. The combined organics was
washed with NaHCO3 and brine, dried over Na2SO4 and
then, filtered and concentrated. The crude product was then
purified by silica gel chromatography (petroleum ether/ethyl
acetate=10:1) to give the desired nitrile 2a as a white solid
in 89% yield.
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ed 1,3-diarylpropenes as suitable substrates for our
new cyanation conditions.[14] To the best of our knowl-
edge, our work is the first report of an oxidative cou-
pling using 3 to give the corresponding 1-cyano-1,3-di-
3
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arylpropene 4 through direct C(sp ) H functionaliza-
tion.[15] As shown in Table 3, treatment of 3a under
our standard conditions provided 4a in 74% yield.
This result indicates that this new cyanation reaction
can be applied to the direct functionalization of
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C(sp ) H bonds adjacent to 1-phenylallylic carbon
atoms as well as heteroatoms. Halogenated groups
were also well tolerated at the C-4 position of the
phenylpropenyl ring of the substrates investigated,
giving the corresponding nitriles 4b–d in moderate
yields (57–62%). However, the substrate bearing
Acknowledgements
We gratefully acknowledge the Nature National Science
Foundation of China (21372056, 21202027, 21102057,
91127010), Changjiang Scholars and Innovative Research
Team in Chinese University (IRT 1231) and the Scientific Re-
search Foundation of Hangzhou Normal University for
Young Teachers (2012QDL001) for their financial support.
Table 3. DDQ mediated direct cyanation of 1,3-diarylpro-
penes.[a]
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