A metal-free direct C (sp3)-H cyanation reaction with cyanobenziodoxolones

Article abstract of DOI:10.1039/c8ob00173a

A metal-free protocol of direct C(sp³)-H cyanation with cyanobenziodoxolones functioning as both cyanating reagents and oxidants was developed. Unactivated substrates, such as alkanes, ethers and tertiary amines, were thereby transformed to the corresponding nitriles in moderate to high yields. Mechanistic studies indicated that the cyanation proceeded with two potential pathways, which is highly dependent on the substrates: (1) a free radical case for alkanes and ethers and (2) an oxidative case for tertiary amines.

Full text of DOI:10.1039/c8ob00173a

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Takeharu Haino et al.
Solvent-induced emission of organogels based on tris(phenylisoxazolyl)
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Metal-Free Direct C (sp3)−H Cyanation Reaction with
Cyanobenziodoxolones
Received 00th January 2018,
Accepted 00th January 20xx
Ming-Xue Sun,a,b Yao-Feng Wang,b Bao-Hua Xu,b Xin-Qi Ma*a and Suo-Jiang Zhang*b
DOI: 10.1039/x0xx00000x
A metal-free protocol of direct C(sp3)−H cyanation with cyanobenziodoxolones functioning as both a cyanating reagent
and oxidant was developed. Unactivated substrates, such as alkanes, ethers and tertiary amines, were thereby
transformed to the corresponding nitriles in moderate to high yields. Mechanistic studies indicated that the cyanation
proceeded with two potential pathways, which is highly depend on the substrates: (1) a free radical case for alkanes and
ethers; (2) an oxidative case for tertiary amines.
www.rsc.org/
nucleophilic addition of cyanide anion (−CN). A series of metal
catalyst/peroxidant systems has been developed for such a
transformation. Although great progress has been achieved
Introduction
The cyano group is an important motif among natural
products, pharmaceuticals, functional materials, agrochemicals
and holds a critical position within synthetic chemistry.1
Various methodologies have been developed to introduce a
cyano group into different organic skeletons.2 In this regard,
with respect to the direct C(sp3)
−H cyanation of organic
substrates, development of novel methodology that operates
under metal-free conditions for a broad scope of substrates is
desirable.
the direct C(sp3)
−H cyanation reaction provides a concise,
Scheme 1 Direct C (sp3) -H cyanation.
efficient atom economy access to nitriles, and represents an
important research topic in this field. For instance, the
electrophilic cyanation was generally attained under strong
basic conditions, wherein the cyanating reagents containing a
heteroatom-CN bond serve as synthetic equivalents of [+CN]
synthon, such as cyanogen halides, p-toluenesulfonyl cyanide
(TsCN) or 1-cyanobenzotriazole.3a,3b By following such
stratage, α-C(sp3)
H cyanation of specific carbonyl compound
a
−
or silyl enol ethers was reached under mild conditions and the
enantioselective conversion was also investigated.3c-3j In
comparison, cyanation of hydrocarbons through a free radical
strategy was rarely reported and only few cases are available
up to now (Scheme 1B),4 which involves the formation of
carbon centred radical intermediates with excess oxidant or
under photoinduced conditions. Besides, transition metal-
catalyzed oxidative α-C(sp3)
−H cyanation of tertiary amines
represents the third case (Scheme 1C),5 which underwent the
formation of an iminium ion intermediate followed by
Cyclic hypervalent iodine reagents exhibited excellent
reactivity and enhanced stability, which have been widely
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employed in various functional-group transfer reactions,6 such proper extent. As a result, the yield of nitrile product was
as trifluoromethyl- increased up to 91% from 78% when the amount of solvent
trifluoromethylation,7 azidation,8
thiolation,9 and ethynylation.10 Electrophilic cyanation using was doubled (entry 9 vs. 10). It could be attributed to but not
cyanobenziodoxolones as the cyano-transfer reagent has been limited to the increased solubility of 2a in the reaction
extensively explored.3c,3i Interestingly, recent studies on the solution. Most importantly, a catalytic amount of TBPB is
photocatalyzed decarboxylative cyanation and cyanation of equally effective (entries 12∼16), suggesting it therein
thiols with cyanobenziodoxolones demonstrated a novel functions as an initiator rather than a terminal oxidant. It is
cyanation process,11 wherein the iodine centred radical species necessary to note that only traces of 3a could be detected in
was formed as a key intermediate. Noteworthily, Zhdankin and the absence of TBPB (entry 17). Under optimized conditions,
co-workers reported a metal-free case of direct azidation of 1a (10 equiv.) smoothly reacted with 2a (0.1 mmol) in the
organic substrates, such as dimethylanilines, alkanes, and presence of TBPB (20 mol%) at 110 oC for 16 h to provide 3a in
alkenes, with azidobenziodoxoles functioning as not only the a high yield of 90% (entry 14).
azide reagent but also an oxidant.8a A free radical chain
Table
1 Conditions optimization for the cyanation of
a
mechanism was proposed by their priliminary studies, wherein
the propagation steps after initiation stage involves the azide
abstraction of azidobenziodoxoles by alkyl radicals and the
hydrogen abstraction of substrates by the in-situ generated 2-
iodobenzoate radical (a kind of iodine centred radical species).
We, therefore, speculated that this protocol could also be
cyclohexane (1a
H
)
CN
3a
oxidant
+
CN sources
solvent, time
2
1a
CN
CN
CN
employed for the direct C(sp3)
with cyanobenziodoxolones, which has not been studied yet.
Herein, we report a metal-free case of direct C(sp3)
−H cyanation of hydrocarbons
I
I
I
O
S
O
O
O
O
Me
CN
tBu
F3C
O
O
O
−
H
2a
2b
2c
2d
cyanation of organic substrates with cyanobenziodoxolones
using catalytic amount of tert-butyl-peroxybenzoate (TBPB) as
the initiator. It shows a wide substrates tolerance. Not only
alkanes and tertiary amines but also ethers were transformed
to the corresponding nitriles under mild conditions with
satisfactory yields. Most importantly, mechanistic studies
indicated that the functionalization of tertiary amines
proceeded with an oxidative pathway rather than the
supposed free radical pathway.
Oxidant
(equiv.)
Time
Yield
(%)
Entry
2
Solvent
(h)
12
12
12
12
12
12
12
12
12
12
12
12
12
16
16
16
16
1
2
2a
2b
2c
2d
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
TBPB (1)
TBPB (1)
TBPB (1)
TBPB (1)
DTBP (1)
TBHP (1)
DDQ (1)
BPO (1)
PhCF3
PhCF3
PhCF3
PhCF3
PhCF3
PhCF3
PhCF3
PhCF3
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
64
44
3
41
4
30
5
17
6
8
Results and discussion
7
trace
49
We started with a model reaction of 1-cyano-1,2-benziodoxole
8
(
2a, 0.1 mmol) with cyclohexane (1a, 10.0 equiv.), which was
o
conducted in PhCF3 (0.3 mL) at 110 C in the presence of
stochiometric amount of tert-butyl-peroxybenzoate (TBPB, 1.0
equiv.). The desired product cyclohexanecarbonitrile (3a) was
directly formed with 64% yield (Table 1, entry 1).
Consequently, reaction conditions varing the cyano reagents,
solvents and amounts of oxidant were examined. Hypervalent
iodine(III) reagents other than 2a exhibited reduced activity
9
TBPB (1)
TBPB (1)
TBPB (1)
TBPB (0.5)
TBPB (0.2)
TBPB (0.2)
TBPB (0.1)
TBPB (0.05)
−
78
10b
11c
12b
13b
14b
15b
16b
17b
91
86
84
82
(entries 1∼3). Besides, the highly reactive p-toluenesulfonyl
90
cyanide (TsCN, 2d) was also employed, but leading to 3a with a
poor yield of 30% under identical conditions (entry 4). We also
found the performance of TBPB is the best as compared with
those of the other four oxidants screened (entry 1 vs. entries
79
63
trace
5∼8). Inspection of the reaction solvents (Table S1) suggested
a General conditions: 1a (1.0 mmol, 10 equiv.), 2 (0.1 mmol), oxidant
(1.0 equiv.), solvent (0.3 mL), 110 oC, under argon, Yield determined
by GC using cyclohexanone as the internal standard; b solvent (0.6 mL);
c solvent (1.0 mL).
that nonpolar ones, such as PhCF3, 1,2-dichloroethane (DCE)
and ethyl acetate (EtOAc), are more efficient than polar ones,
such as CH3OH, CH3CN and acetone, wherein EtOAc provided a
relatively good yield of 3a (78%). On the other hand, the
reactivity is highly thermo-dependent, which was found
remarkably dropped when the temperature was reduced to 90
oC (48%, Table S1). Suprisingly, further improvement of the
reactivity was achieved upon diluting the reaction solution to a
The scope of alkane substrates tolerance was next
examined (Scheme 2). Alkanes (1a∼1f) were successfully
converted into the corresponding nitriles with yields ranging
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from 20% to 90% under the optimized conditions. For instance, position underwent quite well with leading to the desired cyno
3b originated from cyclooctane (1b) was obtained with products in high yields. In comparison, the corresponding
satisfactory 75% yield. The reaction involving adamantane (1c
was conducted under a modified ratio of two substrates (1c
2a = 2) because of the poor solubility of 1c in the reaction lower yields. However, the situation for N,N-dimethylaniline
solution. The oxidative cyanation proceeded well and provided bearing electron-withdrawing aldehyde group 4d is
3c with 76% yield. Alkanes with benzyl substutents were also complicated: a low yield of 5d (72%) was detected by H NMR
examined (1d H at the benzylic analysis along with a multitude of unrecognizable products,
1f), which bears active C(sp3)
)
cyano products substituted with a methoxyl (5e) and methyl
:
(
5f) group at the para-position were obtained with relatively
(
1
)
∼
−
position towards oxidation in principle. However, the yield of which may be attributed to the high reactivity of aldehyde
each cyanation product was remarkably decreased, especially group under oxidative conditions. Additionally, it exhibited
in the case of an acyclic case (1f). Besides, varied products equally effective when the phenyl group in 4a was replaced
including the corresponding dimers and those upon with a naphthalenyl one (4g). When two otho-positions in 5f
dehydrogenation were detected by GC-MS analysis.
This newly developed system can also be extended to the corresponding nitrile (5h) was decreased, suggesting a
oxidative C(sp3)
H cyanation of ether at oxygen-ortho-position negative effect of steric hindrance. In addition, we found that
was further blocked by methyl group, the yield of the
−
(Scheme 2), which was sporadically reported so far.4b,4c,12 We 6-membered cyclic tertiary amines (4i) were well tolerated,
found that 5-membered cyclic ether (1g) was well tolerated, and the desired nitrile product was obtained with moderate
thus leading to the desired product (3g) with 90% yield. In 40% yield. No regioisometric product with cyano group at the
comparison, reduced reactivity was observed for 6-membered methyl position has been observed. The yield was not
ones (1h
in the case of reaction involving 1k, only one nitrile product electron-deficient groups, such as phenyl (Ph, 4j) and (tert-
3k) with functionalization at the benzylic position was butoxy)carbonyl (BOC, 4k). And it led to a slightly increased
obtained. Besides the cyclic ethers, two acyclic ones (1l and performance by introducing benzo group to the 6-membered
1m) were also employed as the substrates in the reaction with ring (4l vs. 4k). Unexpectedly, the reaction of 4m bearing an
2a, each leading to the corresponding nitrile with a moderate C(sp3)
H locating at the benzyl position gave the desired nitrile
5m in a very high yield of 88%, which is different with the
observation for alkanes (3d 3f vs. 3a) and ethers (3k vs. 3h).
∼1k) under standard reaction conditions. Specifically, decreased by replacing the methyl group in 4i with more
(
α
-
−
yield.
∼
Scheme 2 Substrate scope of alkanes and ethers.c
Finally, the performance of 5-membered tertiary amines (4n
and 4o) was also studied, thereby offering the corresponding
nitriles with satisfactory yields.
CN
TBPB (20 mol%)
X
I
X
R1
R1
CN
H
O
+
EtOAc (0.6 mL)
110 oC, 16 h
under Ar
Scheme 3 Substrate scope of tertiary amines.a
O
1 (X = C, O)
(10 equiv.)
2a
3
(0.1 mmol)
CN
CN
CN
CN
CN
3a 90%a
3c 76%b
3b 75%
3d 54% (50%) 3e 45% (41%)
CN
O
CN
O
CN
O
CN
O
CN
Me
O
O
3j 51% (47%)
3f 20%
3g 90%
3i 68%
3h 60%
CN
O
O
Me
O
CN
CN
3l 47% (42%)
3k 60% (55%)
3m 30%
a Yield determined by GC using cyclohexanone as the internal standard, b 1c
(2 equiv.); c Yield determined by 1H NMR using CH2Br2 as internal standard;
Isolated yield is shown in the parentheses.
With the success in cyanation of both alkanes and ethers,
we turned our attention to tertiary amines bearing reactive
C(sp3)
−H bonds adjacent to the nitrogen (Scheme 3). It was
a
Yield determined by 1H NMR using CH2Br2 as internal standard
;
observed that electronic variation of the substituents at the
phenyl moiety of N,N-dimethylaniline significantly affected the
reaction efficiency. The cyanation of non-substituted N,N-
dimethylaniline (4a) and thoes substituted with electron-
withdrawing groups (–CN (4b) and –COOMe (4c)) at the para
Isolated yield is shown in parentheses.
To elucidate the oxidative cyanation pathway with
respect to different R-H substrate, the spin-trapping technique
was introduced to detect the involved but short-lived radicals,
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wherein the N-tert-butyl-α-(4-pyridyl-1-oxide) nitrone (4-POBN) a free radical pathway for cyanation of alkanes and ethers;
was used as the spin-trap reagent (Scheme 4). The cyanation while denotes an oxidative cyanation pathway for tertiary
reaction involving either alkane (1a) or ether (1k) was amines. All reactions started with the generation of oxygen-
completely supressed in the presence of 1.5 molar equivalent centered radicals, such as tert-butoxy radical (tBuO ), from
of 4-POBN. Meanwhile, the positive mode ESI-MS analysis of initiator TBPB (this step was ommitted from Scheme 5 for
the reaction solution shows peaks at m/z 277.1946 (assigned clarity). For the radical pathway , hydrogen atom abstraction
to 4-POBN-1a) and 327.1776 (assigned to 4-POBN-1k), each (HAA) of an R H bond in a substrate by tBuO occurred
being assigned to the corresponding radical adduct with 4- directly to provide the transiency carbon radical . Subsequent
POBN (Scheme S2 and S3), suggesting a radical pathway. To trapping by 2a will lead to both nitrile and iodine centred
our surprise, a moderate yield of cyanide product (5m) was radical II similar step involving the formation of
obtained from the reaction of tertiary amine 4m with 2a in the thiocyanates and decarboxylative cyanation has been reported
presence of 4-POBN (1.5 equiv.) with no radical adduct (6m
by Waser.11 It was assumed that II should be reactive enough
being detected by ESI-MS analysis, thus disfavoring a similar to undergo HAA of substrate in a metal-free catalysis, thus
radical pathway as that of alkanes and ethers. Instead, it raises being regenerated and affording 2-iodobenzoic acid ( ) at the
another parallel mechanistic possibility of an oxidative same time. In the case of pathway involving tertiary amines
cyanation progress, wherein iminium cations were mainly as the substrates, a single electron transfer (SET) from nitrogen
formed rather than readily happens rather thsqan the direct HAA of
-C(sp3) radicals followed by neucleophic to tBuO
addition by the in-situ generated cyanide anion.13 To clarify C(sp3)
H bond, with affording nitrogen-centered cation radical
this hypothesis, a competition experiment between the III and tert-butoxy anion (tBuO−). The -C(sp3) radical IV can be
B
•
A
−
•
I
I
3
.
A
)
I
8
B
α
•
α-
−
α
present cyanation and oxidative trifluoromethylation14 formed from III upon deprotonation by a proper base, which
towards tertiary amine was consequently designed (Scheme quickly undergo SET oxidation by 2a to afford iminium cations
4
D
). The cyanation of 4m with 2a was conducted in the
pesence of excess TMSCF3 (3.0 equiv.) and CsF (2.0 equiv.), Nucleophilic addition of cyanide anion to
wherein not only nitrile (5m, 42%) but also trifluoromethylated the desired nitrile ; while III was regenerated through SET
7m, 9%) product was obtained. In addition, further oxidative oxidation of substrate with II
V
and coincidentally release II together with cyanide anion.
V
finally produced
5
(
4
.
dehydrogenation was detected towards 7m, thereby offering
7m with 21% yield. These results demonstrated the iminium
Scheme 5 Plausible mechanisms.
′
I
cation was indeed formed during the oxidation, thereby
rendering nucleophilic addition of trifluoromethyl anion
possible.
•
I
O
CO2H
8
O
II
Scheme 4 Investigation of the reaction mechanism.
1 (X = C, O)
A
CN
R2
R2
R2
R
CN
2a
I
4-POBN (1.5 equiv.)
+
O
+
+ tBuO•
− tBuOH
A
B
C
X
X
X
TBPB (1.0 equiv.)
R1
R1
•
R1
H
CN
O
1a (10.0 equiv.) 2a (0.1 mmol)
3a trace
6a detected by ESI-MS
1 (X = C, O)
4 (X = N)
I
R
CN
CN
3 (X = C, O)
5 (X = N)
I
X = C, O
4-POBN (1.5 equiv.)
TBPB (1.0 equiv.)
O
O
O
O
+
+
tBuO•
tBuO
4 (X = N)
R2
CN
R2
O
1k (10.0 equiv.)
2a (0.1 mmol)
3k trace
CN
6k detected by ESI-MS
R2
2a
R
CN
tBuO
or 9
Ph
N
Ph
N
•
•
N
Ph
I
4-POBN (1.5 equiv.)
TBPB (20 mol%)
N
N
N
O
R1
+
R1
R1
+
H
O
V
CN
4m (1.0 equiv.) 2a (0.1 mmol)
5m (20%)
6m not detected
III
IV
tBuOH or 8
II
B
tBu
tBu
•
•
O
N
O
N
4-POBN
•
O
R =
N
O
N
I
4 (X = N)
CN
CF3
CN
COO
Ph
Ph
TBPB (20 mol%)
Ph
N
I
N
9
N
D
O
+
+
TMSCF3 (3.0 equiv.)
CsF (2.0 equiv.)
O
4m (1.0 equiv.)
5m 42%
7m (9%) + 7m' (21%)
2a (0.1 mmol)
Conclusions
On the basis of literatures11 and our experimental results,
In conclusion, we have developed a metal-free cyanation
method for the direct transformation of unactivated alkanes,
ethers and tertiary amines with cyanobenziodoxolones
functioning as both cyanating reagent and oxidant. A range of
nitrile products could be obtained thereby in moderate to high
a mechanistic proposal for the direct cyanation of alkanes,
ethers and tertiary amines with cyanobenziodoxolone (2a) is
presented in Scheme 5. The reaction pathway is highly
dependent on the structure of substrates launched, which was
categorized into two types (A and B). Specifically, A represents
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2015, 13, 881; (j) B. Ma, X. Lin, L. Lin, X. Feng and X. Liu, J.
Org. Chem., 2017, 82, 701.
yields under mild conditions. Mechanistic studies indicated
that the cyanation proceeded with two potential pathways,
which is highly depend on the substrates: (1) a free radical
case for alkanes and ethers; (2) an oxidative case for tertiary
amines. The present results may hold promise for further
development of novel structures of hypervalent iodine(III)
reagents in the functional group transfer reactions under
metal-free conditions.
4. Free radical cyanation: (a) Wen Zhang, Fei Wang, Scott D.
McCann, Dinghai Wang, Pinhong Chen, Shannon S. Stahl
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Conflicts of interest
There are no conflicts to declare.
Acknowledgements
Financial supports by National Science Foundation of China
(No. 21606328, 21476240 and Petrochemical Joint Fund
U1662133), Instrument Developing Project of the Chinese
Academy of Sciences (No. YZ201521) and CAS 100-Talent
Program (2014) are gratefully acknowledged. The authors are
grateful for the assistance from teacher Ling Wang of Analysis
and Test Centre, Institute of Process Engineering, Chinese
Academy of Sciences in ESI-MS (electrospray ionization mass
spectrometry).
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Organic & Biomolecular Chemistry
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DOI: 10.1039/C8OB00173A
Metal-Free Direct C (sp3)−H Cyanation Reaction:
Cyanobenziodoxolones as a Cyanating Reagent and Oxidant
Ming-Xue Sun,a,b Yao-Feng Wang,b Bao-Hua Xu,b Xin-Qi Ma*a and Suo-Jiang Zhang*b