Reductive Cleavage of Unactivated Carbon-Cyano Bonds under Ammonia-Free Birch Conditions

Article abstract of DOI:10.1021/acs.joc.9b02028

A general protocol for the reductive cleavage of unactivated carbon-cyano bonds in aliphatic nitriles has been achieved under single-electron-transfer conditions using Na/15-crown-5/H₂O. Electron is supplied by the electride derived from bench-stable sodium dispersions and recoverable 15-crown-5. H₂O provides the proton source and suppresses the reduction of aromatic moieties. Compared with the Na/NH₃ electride system generated under traditional Birch conditions, this ammonia-free electride system is more practical and features better reactivity and chemoselectivity for the decyanations of a broad range of aliphatic nitriles.

Full text of DOI:10.1021/acs.joc.9b02028

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Article
Reductive Cleavage of Unactivated Carbon-Cyano
Bonds under Ammonia-Free Birch Conditions
Yuxuan Ding, Shihui Luo, Lifu Ma, and Jie An
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b02028 • Publication Date (Web): 05 Nov 2019
Downloaded from pubs.acs.org on November 9, 2019
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The Journal of Organic Chemistry
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Reductive Cleavage of Unactivated Carbon-Cyano Bonds under
Ammonia-Free Birch Conditions
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Yuxuan Ding‡, Shihui Luo‡, Lifu Ma*,† and Jie An*,‡
† School of Precision Instrument and Opto-Electronics Engineering, Tianjin University, Tianjin 300072, China
‡ College of Science, China Agricultural University, No. 2 Yuanmingyuan West Road, Beijing 100193, China
Supporting Information Placeholder
Na dispersion
Highly Practical
Broad Substrate Scope
Good Chemoselectivity





15-crown-5 H O
,
2
R
R
CN
R
H
THF, 0 o
62-98%
= functionalized alkyl, Ar, HetAr
C
H O as Proton Donor
2
Recyclable Crown Ether
ABSTRACT: A general protocol for the reductive cleavage of unactivated carbon-cyano bonds in aliphatic nitriles has been
achieved under single electron transfer conditions using Na/15-crown-5/H2O. Electron is supplied by the electride derived from
bench-stable sodium dispersions and recoverable 15-crown-5. H2O provides the proton source and suppresses the reduction of
aromatic moieties. Compared with the Na/NH3 electride system generated under traditional Birch conditions, this ammonia-free
electride system is more practical and features better reactivity and chemoselectivity for the decyanations of a broad range of
aliphatic
nitriles.
tolerance, formation of amine by-products and the problems
associated with the usage of liquid ammonia (A, Scheme 1).1
The electride is an ionic compound in which the positive
charge of the complexed alkali metal cation is balanced by a
solvated electron.7 It has a distinct dark blue color. While the
C−CN bond cleavage process of tertiary nitriles can be
accomplished by aryl radical anions, such as potassium
toluene radical anion1a and lithium naphthalenide8, electride
system is still required for the alkali metal mediated
decyanation process of unactivated primary and secondary
nitriles.
Recently, our group has developed a practical and ammonia
free method for the preparation of sodium electride using
sodium dispersions and 15-crown-5.9 Sodium dispersion (5-10
m) in mineral oil is a bench-stable and commercially
available reagent.10 The high specific surface area of sodium
particles is crucial for the successful preparation of sodium
electride. Previously, we have developed a practical and
chemoselective ammonia-free Birch reduction of aromatic
compounds using Na/15-crown-5/i-PrOH.8a Therefore, we
hypothesized that Na/15-crown-5 electride system might also
be suitable for the challenging reductive cleavage of
unactivated carbon-cyano bonds.
INTRODUCTION
Cleavage of the carbon-cyano bond is
a
useful
transformation in organic synthesis.1 The α-C−H acidity,
ortho-directing effect and electron withdrawing ability of the
cyano group have made it an important functional handle and
directing group in many C−C bond forming reactions.2
However, after the cyano group has fulfilled its obligation, a
reductive decyanation process is required to generate the
desired final product, which has been exemplified in the
synthesis of many natural products.1b-c
Scheme 1. Reductive Decyanations of Nitriles
A. Decyanation Under Classic Birch Conditions
R
N
R
R
R
NH2
N
Na/NH3
<-33 o
N
H
H
+
R
R
C
by products
R
 Not Tolerate Aromatic Moieties  Formation of Complicated By-products
 Hazardous Liquid Ammonia  Tedious Experimental Procedure
B. This Work:
 Ammonia Free
Na/15-crown-5/H2O
THF, 0 o
= functionalized alkyl, Ar, HetAr
 H2O as Proton Donor
 Good Chemoselectivity
 Recyclable Crown Ether
R
CN
R
H
C
R
The removal of cyano groups can be achieved by recently
RESULTS AND DISCUSSION
developed [Fe]3, [Ni]4 or [Rh]5 catalyzed reductive
decyanations.6 However, the problems associated with β-
hydride elimination, the usage of water- and air- sensitive
reagents and/or harsh reaction conditions have made reactions
of this type less practical.3-5 Therefore, classic Birch
conditions using electride derived from alkali metal and liquid
ammonia are still commonly employed in the reductive
decyanation reactions, despite its poor functional group
Scheme 2 Proton Donor-Dependent Chemoselectivity of
the Na/15-crown-5 Electride System
i-PrOH
Na/15-crown-5/
complicated mixture
CN
1a
H O
Na/15-crown-5/
42%
2
H
2a
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The initial trail with 4-phenylbutanenitrile using 6 equiv of
Page 2 of 7
influence of addition order was also studied. Compared with
the reaction in which sodium dispersions were added after the
addition of 1b and 15-crown-5 (entry 5, Table 1), higher yield
was obtained if the substrate was added after the formation of
the electride (entry 7, Table 1). Finally, the usage of less
amount of reagents was tested, while yields dropped from 75%
to 47% by decreasing the amount of Na/15-crown-5/H2O from
10 equiv to 6 equiv (entries 7-9). Therefore, the reaction
conditions illustrated in entry 7 (Table 1) were used for the
substrate scope investigation. Of note, 15-crown-5 was not
consumed under the reaction conditions, which can be easily
recovered after the reaction by reported method.9a
1
2
3
4
5
6
7
8
Na/15-crown-5/i-PrOH resulted in the formation of
complicated mixture. 74% of the aromatic moiety was reduced
to the corresponding cyclohexadiene. Only trace amount of the
desired decyanation product 2a was formed (Scheme 2).
Surprisingly, we then discovered that the chemoselectivity of
the Na/15-crown-5 electride system can be significantly
influenced by the nature of the proton donor. By using 6 equiv
of Na/15-crown-5/H2O, the reduction of aromatic moieties
was suppressed, and the selective cleavage of C−CN bond was
achieved (Scheme 2). Furthermore, amine by-products derived
from the nitrile reduction was not detected under Na/15-
crown-5/H2O conditions. It is noteworthy that Na/15-crown-5
electride is reasonably stable with H2O. After H2O was added
to a solution of Na/15-crown-5 electride in THF, the dark blue
color of electride can persist for longer than 1 hour.
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Table 2. Reductive Cleavage of Carbon-Cyano Bonds
Using Na/15-crown-5/H2Oa
Na/15-crown-5/H2O
R
H
R
CN
THF, 0 oC, Ar
Table 1. Optimization of the Reductive Decyanation
2
1
substrate
product (yield)b
O
O
O
O
Na/15-crown-5/H2O
solvent, 0 oC, Ar
H
O
O
O
N
CN
CN
H
c
1b
1c
1d
2b
(75%)
O
1b
2b
H
entry Na/15-crown-5/H2O
(equiv)
solvent
addition
order
yield
(%)a
2c
(85%)
(83%)
1
2
3
4
5
6
7
8
9
10/0/10
10/10/10
10/10/10
10/10/10
10/10/10
10/10/10
10/10/10
8/8/8
hexane
hexane
Et2O
A
A
A
A
A
A
B
B
B
<5
<5
<5
<5
55
40
75
58
47
CN
H
2d
2e
O
O
CN
CN
CN
H
H
H
toluene
THF
1e
(98%)
O
O
2-MeTHF
THF
1f
2f
(98%)
(91%)
THF
1g
2g
O
O
O
O
6/6/6
THF
CN
CN
H
H
1h
1i
2h
(84%)
(70%)
Method A: sodium dispersions in oil (10.0 equiv), 1b (1.0
equiv), 15-crown-5 (0-10.0 equiv), H2O (10.0 equiv), 0 ℃.
Addition order: 1b, 15-crown-5, Na, H2O. Method B: sodium
dispersions in oil (6.0-10.0 equiv), 1b (1.0 equiv), 15-crown-5
(6.0-10.0 equiv), H2O (6.0-10.0 equiv), 0 ℃. Addition order: Na,
15-crown-5, 1b, H2O. aYields were determined by 1H NMR.
HO
HO
2i
N
H
N
H
CN
H
O
O
With the preliminary results in hand, we started the
optimization of reaction conditions using nitrile 1b as the
model compound (Table 1). As expected, no reaction was
observed using 10 equiv of Na and H2O in hexane (entry 1,
Table 1), which demonstrated that the existence of electride
was crucial for the cleavage of C−CN bond. Therefore, 15-
crown-5 was added to facilitate the formation of electride.
This reaction was then found to be highly solvent-dependent
(entries 2-5, Table 1). Complicated byproducts were formed in
the reaction with hexane or Et2O as the solvent and only trace
amount of the desired product was formed (entries 2-3, Table
1), whereas in THF, a solvent with higher dielectric constant, a
promising 55% yield was obtained (entry 5, Table 1). 2-
Methyltetrahydrofuran (2-MeTHF) is a green alternative to
THF with a slightly lower dielectric constant. The reaction
using 2-MeTHF (entry 6, Table 1) resulted in a lower yield
than that using THF (entry 5, Table 1). Hence, we determined
that THF was an optimal solvent for this reaction. Of note, the
low yield obtained in the reaction with toluene as solvent
revealed that aromatic radical anion was not a viable reagent
for the cleavage of cyano group in 1b (entry 4, Table 1). The
1j
2j
(70%)
(73%)
N
H
N
H
N
N
1k
2k
N
H
CN
N
H
H
N
CN
N
H
1l
2l
(62%)
CN
H
N
1m
2m
2n
(72%)
(65%)
CN
H
1n
1o
N
2o
(74%)
CN
CN
H
complicated products
complicated products
1p
1q
CN
Cl
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aConditions: 1 (0.50 mmol, 1.0 equiv) was added to a
Figure 1. Variation of Relative Energy in kcal/mol Associated
with the C−CN Bond Stretching for 6 Å with 0.1 Å per Step in
60 Steps in 3 (a) and 6 (b) in Scheme 3 (R = CH3).
1
2
3
4
5
6
7
8
suspension of sodium dispersions in hexane (5.00 mmol, 10.0
equiv) and 15-crown-5 (5.00 mmol, 10.0 equiv) in THF (3.0 mL)
under Ar at 0 ℃, and stirred vigorously. Then H2O (5.00 mmol,
In a parallel computational study (Figure 1), kinetics of the
homolysis of the radical anion 3 and neutral radical 6 derived
from MeCN was investigated by semi-empirical method and
DFT calculations. The most stable structures for 3 and 6 were
optimized using uB3LYP functional,12 with a 6-31+G(d,p)
basis set.13 A rigid scan conducted along the C−CN coordinate
in the optimized structure of 3 and 6 for 6 Å (0.1 Å/step, in 60
steps) gave the potential energies of 19.84 and 49.78 kcal/mol
for the C−CN homolysis process of 3 and 6, respectively.
Those results indicated that the energy barrier of C−CN bond
cleavage in 6 was higher than that of 3, which was in
agreement with the experimental results.
b
c
10.0 equiv) was added and stirred for 1 h. Isolated yields. 1b
(1.0 mmol).
The optimal conditions were applied to the reductive
decyanation of different classes of aliphatic nitriles (Table 2).
In general, this method is amenable to a broad range of
primary, secondary, and tertiary aliphatic nitriles, with high
yields and good functional group tolerance. The reduction of
aromatic moieties and amines derived from the reduction of
nitriles were not observed. Benzonitriles with electron-
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donating groups (1d−1h) were converted to the corresponding
alkanes smoothly. In the case of aryl ethers (1e−1h), partial
Scheme 4. Synthetic Applications
loss of the alkoxy or methyl groups was not detected. No
impact on the yield was observed with hydroxyl group (1h).
Aliphatic amines (1l, 1n) did not interfere with the reaction
conditions. Moreover, this reaction could be readily extended
to substrates containing heterocycles, such as indoles (1i, 1j)
and benzimidazole (1k), which could expand its synthetic
utility in the synthesis of bioactive molecules. Significantly,
substrate with sterically hindered substituents (1o) was
tolerated well in the decyanation reaction. However, partial
reductions of conjugated alkyne (1p) and halide (1q) were
observed and resulted in complicated products. In addition,
scaling up the reaction to 1.0 mmol did not have a detrimental
effect on the yield (1b).
R
1) base
2) RX
CN
R
14
2m
(72%)
R = Me
1m
(68%)
RX = MeI
Na/15-crown-5
H2O
1) base
Ph
CN
O
N
O
1c
2)
P
N
N
O
N
(65%)
CN
15
2n
1n
(62%)
This reductive decyanation reaction under ammonia-free
Birch conditions provides various applications in organic
synthesis. For example, upon the base treatment of 1c, the
corresponding nitrile-stabilized carbanion can be alkylated or
aminated with a variety of reagents (Scheme 4). The
subsequent removal of cyano group in the resulting products
has allowed the utility of nitriles as traceless functional
handles.
In summary, a practical and chemoselective protocol for the
reductive cleavage of unactivated C−CN bond in aliphatic
nitriles has been developed under modified Birch conditions
using Na/15-crown-5/H2O. Electride system derived from
sodium dispersions and 15-crown-5 can selectively promote
the homolysis of C−CN bond in nitriles and suppress the
formation of amine by-products derived from the nitrile
reduction. Using H2O to replace i-PrOH as the proton donor is
the key to the success of this reaction, which dramatically
switches the chemoselectivity from dearomatization to
decyanation. Excellent yields were obtained across a broad
range of primary, secondary, and tertiary nitriles. Compared
with transition metal catalyzed C−CN bond cleavage
processes and decyanations under traditional Birch conditions,
this protocol is more practical. Only inexpensive,
commercially available and stable reagents are used, and
strictly inert atmosphere is not necessary. New reactions and
selectivity with the Na/15-crown-5 electride system will be the
subject of our future research.
Scheme 3. Proposed Mechanism
N
fast
Na/15-crown-5
Na/15-crown-5
Na
R
4
R
5
R
N
R
1
3
H+
+
Na
+ H
slow
Na
R
R
H
R
NH2
R
NNa
R
NNa
4
6
7
8
2
nitrile reduction by Na/EtOH
Nitriles can be converted to the corresponding primary
amines in high yields using Na/EtOH in hexane via an inner
11
sphere electron transfer process (1  8, Scheme 3).10b,
While, by using the electride derived from Na and 15-crown-
5, the decyanation product was formed exclusively (Table 2).
We hypothesize that, under Na/15-crown-5 conditions, the
radical anion 3 derived from the first electron transfer (1  3,
Scheme 3) will undergo a fast C−CN homolysis and lead to
the formation of radical 4, which will be ultimately converted
into the desired product 2. In contrast, in the absence of crown
ether, neutral radical 6 formed from the first electron transfer
(1  6, Scheme 3) is more susceptible to the second electron
transfer (6  7, Scheme 3) and, as a result, converted into the
amine product 8.
EXPERIMENTAL SECTION
General Information. Glassware was dried in an oven
overnight before use. Thin layer chromatography was carried
out on SIL G/UV254 silica-aluminum plates and plates were
visualized using ultra-violet light (254 nm) and KMnO4
solution. For flash column chromatography, silica gel 60, 35-
70 μm was used. NMR data was collected at 300 MHz. Data
was manipulated directly from the spectrometer or via a
networked PC with appropriate software. All samples were
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analyzed in CDCl3 unless otherwise stated. Reference values
for residual solvent were taken as δ = 7.27 (CDCl3) for H
oil by centrifuging, draining mineral oil and redispersing in
1
1
2
3
4
5
6
7
8
hexane under argon. The concentration of sodium dispersions
NMR; δ = 77.1 (CDCl3) for 13C NMR. Multiplicities for
coupled signals were designated using the following
abbreviations: s = singlet, d = doublet, t = triplet, q = quartet,
quin = quintet, br = broad signal, and J value are given in Hz.
All compounds used in this study have been described in the
literature or are commercially available. All solvents and
reagents were used as supplied. Sodium dispersion in oil was
purchased from Alfa Aesar.
in hexane was titrated before use.16
Warning Statement. Sodium cyanide may form during the
reaction or quench process. The aqueous phase obtained
during the workup process should be treated with a saturated
aqueous solution of FeSO4 before disposal, and avoid contact
with any acids.
1,2-Dimethoxy-4-methylbenzene17 (2b, Table 2). According
to the general procedure, the reaction of 2-(3,4-
dimethoxyphenyl)acetonitrile (88.6 mg, 0.500 mmol), Na
dispersion in hexane (19.5 wt %; 590 mg, 5.00 mmol ), 15-
crown-5 (0.989 mL, 5.00 mmol) and H2O (90.0 mg, 5.00
mmol), after chromatography (0-20% EtOAc/hexane),
9
Optimization Studies (Table 1). Method A: To a solution
of 2-(3,4-dimethoxyphenyl)acetonitrile (88.6 mg, 0.500 mmol,
1.00 equiv) in anhydrous solvent (3.0 mL), 15-crown-5 (0-
0.989 mL, 0-5.00 mmol, 0-10.0 equiv) was added, followed by
Na dispersion in oil (30.8 wt %; 373 mg, 5.00 mmol, 10.0
10
11
12
13
14
15
16
17
18
19
20
21
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1
afforded 57.1 mg of 2b in 75% yield as a colorless oil. H
o
equiv) under Ar at 0 C and stirred vigorously. After 20 min,
NMR (300 MHz, CDCl3) δ 6.78 (m, 1H), 6.74 – 6.69 (m, 2H),
3.88 (s, 3H), 3.86 (s, 3H), 2.32 (s, 3H); 13C{1H} NMR (75
MHz, CDCl3) δ 148.9, 147.0, 130.5, 120.9, 112.6, 111.4, 56.1,
55.9, 21.0.
H2O (90.0 mg, 5.00 mmol, 10.0 equiv) was added and stirred
for 1 h at 0 oC. The reaction was then quenched by a saturated
aqueous solution of NaHCO3 (2.0 mL) and the reaction
mixture was diluted with Et2O (10 mL) and brine (10 mL).
1,2-Dimethoxy-4-methylbenzene17 (2b, Table 2). According
to the general procedure, the reaction of 2-(3,4-
dimethoxyphenyl)acetonitrile (177 mg, 1.00 mmol), Na
dispersion in hexane (19.5 wt %; 1.18 mg, 10.0 mmol), 15-
crown-5 (1.98 mL, 10.0 mmol) and H2O (180 mg, 10.0 mmol),
after chromatography (0-20% EtOAc/hexane), afforded 99.0
mg of 2b in 65% yield as a colorless oil. 1H NMR and 13C{1H}
NMR data were same as previously descripted.
×
The aqueous layer was extracted with Et2O (2
10 mL), the
organic layers were combined, dried over MgSO4, filtered and
concentrated. Then the sample was analyzed by 1H NMR
(CDCl3, 300 MHz) to obtain the yield using internal standard
(1,1,2,2-tetrachlorethan) and comparison with corresponding
samples. Method B: To a suspension of Na dispersion in oil
(30.8 wt %; 224-373 mg, 3.00-5.00 mmol, 6.00-10.0 equiv) in
anhydrous THF (1.0 mL), 15-crown-5 (0.594-0.989 mL, 3.00-
Toluene18 (2c, Table 2). According to the general procedure,
the reaction of 2-phenylacetonitrile (58.6 mg, 0.500 mmol),
Na dispersion in hexane (19.5 wt %; 590 mg, 5.00 mmol), 15-
crown-5 (0.989 mL, 5.00 mmol) and H2O (90.0 mg, 5.00
mmol), after chromatography (hexanes), afforded 39.2 mg of
2c in 85% yield as a colorless oil. 1H NMR (300 MHz, CDCl3)
δ 7.29 – 7.22 (m, 2H), 7.21 – 7.12 (m, 3H), 2.35 (s, 3H);
13C{1H} NMR (75 MHz, CDCl3) δ 137.9, 129.1, 128.3, 125.4,
21.5.
o
5.00 mmol, 6.00-10.0 equiv) was added under Ar at 0 C and
stirred vigorously for 5 min. The color of the solution tuned
dark blue rapidly, indicating the formation of electride. A
solution of 2-(3,4-dimethoxyphenyl)acetonitrile (88.6 mg,
0.500 mmol, 1.00 equiv) in THF (2.0 mL) was then added at
the same temperature and stirred vigorously. After 20 min,
H2O (54.0-90.0 mg, 3.00-5.00 mmol, 6.00-10.0 equiv) was
o
added and stirred for 1 h at 0 C. The reaction was then
1,2,3,5-Tetramethylbenzene19 (2d, Table 2). According to
the general procedure, the reaction of 2-mesitylacetonitrile
(79.6 mg, 0.500 mmol), Na dispersion in hexane (19.5 wt %;
590 mg, 5.00 mmol), 15-crown-5 (0.989 mL, 5.00 mmol) and
H2O (90.0 mg, 5.00 mmol), after chromatography (hexanes),
quenched by a saturated aqueous solution of NaHCO3 (2.0 mL)
and the reaction mixture was diluted with Et2O (10 mL) and
brine (10 mL). The aqueous layer was extracted with Et2O (2
×
10 mL), the organic layers were combined, dried over
MgSO4, filtered and concentrated. Then the sample was
1
1
afforded 55.7 mg of 2d in 83% yield as a colorless oil. H
analyzed by H NMR (CDCl3, 300 MHz) to obtain the yield
NMR (300 MHz, CDCl3) δ 6.93 (s, 2H), 2.36 – 2.33 (m, 9H),
2.23 (s, 3H); 13C NMR{1H} (75 MHz, CDCl3) δ 136.3, 134.6,
131.8, 128.4, 20.8, 20.5, 14.9.
using internal standard (1,1,2,2-tetrachlorethan) and
comparison with corresponding samples.
General Procedure for the Reductive Decyanation of
Nitriles by Na/15-crown-5/H2O. To a suspension of Na
dispersion in hexane (19.5 wt %; 590 mg, 5.00 mmol, 10.0
equiv) in anhydrous THF (1.0 mL), 15-crown-5 (0.989 mL,
5.00 mmol, 10.0 equiv) was added under Ar at 0 oC and stirred
vigorously for 5 min. The color of the solution tuned dark blue
rapidly, indicating the formation of electride. A solution of
nitrile (0.500 mmol, 1.00 equiv) in THF (2.0 mL) was then
added at the same temperature and stirred vigorously. After 20
min, H2O (90.0 mg, 5.00 mmol, 10.0 equiv) was added and
1-Methoxy-2-methylbenzene20 (2e, Table 2). According to
the
general
procedure,
the
reaction
of
2-(2-
methoxyphenyl)acetonitrile (73.6 mg, 0.500 mmol), Na
dispersion in hexane (19.5 wt %; 590 mg, 5.00 mmol), 15-
crown-5 (0.989 mL, 5.00 mmol) and H2O (90.0 mg, 5.00
mmol), after chromatography (0-10% EtOAc/hexane),
1
afforded 59.9 mg of 2e in 98% yield as a colorless oil. H
NMR (300 MHz, CDCl3) δ 7.23 – 7.13 (m, 2H), 6.92 – 6.82
(m, 2H), 3.85 (s, 3H), 2.25 (s, 3H); 13C{1H} NMR (75 MHz,
CDCl3) δ 157.8, 130.7, 126.9, 126.7, 120.4, 110.0, 55.3, 16.2.
1-Methoxy-3-methylbenzene20 (2f, Table 2). According to
o
stirred for 1 h at 0 C. The reaction was then quenched by a
saturated aqueous solution of NaHCO3 (2.0 mL) and the
reaction mixture was diluted with Et2O (10 mL) and brine (10
the
general
procedure,
the
reaction
of
2-(3-
methoxyphenyl)acetonitrile (73.6 mg, 0.500 mmol), Na
dispersion in hexane (19.5 wt %; 590 mg, 5.00 mmol), 15-
crown-5 (0.989 mL, 5.00 mmol) and H2O (90.0 mg, 5.00
mmol), after chromatography (0-10% EtOAc/hexane),
×
mL). The aqueous layer was extracted with Et2O (2
10
mL), the organic layers were combined, dried over MgSO4,
filtered and concentrated. The crude product was purified by
flash chromatography (silica, 0-50% EtOAc/hexane).
The Preparation of Sodium Dispersions in Hexane. Sodium
dispersion in hexane was prepared from sodium dispersion in
1
afforded 59.9 mg of 2f in 98% yield as a colorless oil. H
NMR (300 MHz, CDCl3) δ 7.21 (m, 1H), 6.83 – 6.72 (m, 3H),
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The Journal of Organic Chemistry
3.82 (s, 3H), 2.37 (s, 3H); 13C{1H} NMR (75 MHz, CDCl3) δ
mmol), without chromatography, afforded the crude product.
The crude product was treated with a 3 M solution of HCl in
cyclopentylmethyl ether and filtered. The solid was then
washed with diethyl ether and dried under vacuum, afforded
1
2
3
4
5
6
7
8
159.7, 139.5, 129.3, 121.6, 114.8, 110.9, 55.2, 21.6.
1-Methoxy-4-methylbenzene20 (2g, Table 2). According to
the
general
procedure,
the
reaction
of
2-(4-
1
methoxyphenyl)acetonitrile (73.6 mg, 0.500 mmol), Na
dispersion in hexane (19.5 wt %; 590 mg, 5.00 mmol), 15-
crown-5 (0.989 mL, 5.00 mmol) and H2O (90.0 mg, 5.00
mmol), after chromatography (0-10% EtOAc/hexane),
61.5 mg of 2k in 73% yield as a white solid. H NMR (300
MHz, DMSO-d6) δ 7.72 (m, 2H), 7.47 (m, 2H), 2.81 (s, 3H);
13C{1H} NMR (75 MHz, DMSO-d6) δ 151.0, 130.6, 125.2,
113.4, 12.1.
1
afforded 55.6 mg of 2g in 91% yield as a colorless oil. H
1-Propylpyrrolidine Hydrochloride24 (2l, Table 2).
According to the general procedure, the reaction of 4-
(pyrrolidin-1-yl)butanenitrile (69.1 mg, 0.500 mmol), Na
dispersion in hexane (19.5 wt %; 590 mg, 5.00 mmol), 15-
crown-5 (0.989 mL, 5.00 mmol) and H2O (90.0 mg, 5.00
mmol), without chromatography, afforded the crude product.
The crude product was treated with a 3 M solution of HCl in
cyclopentylmethyl ether and filtered. The solid was then
washed with diethyl ether and dried under vacuum, afforded
NMR (300 MHz, CDCl3) δ 7.11 (m, 2H), 6.83 (m, 2H), 3.80
(s, 3H), 2.31 (s, 3H); 13C{1H} NMR (75 MHz, CDCl3) δ
157.6, 129.9 × 2, 113.8, 55.3, 20.5.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2-Methoxy-4-methylphenol21 (2h, Table 2). To a suspension
of Na dispersion in hexane (19.5 wt %; 590 mg, 5.00 mmol) in
anhydrous THF (1.0 mL), 15-crown-5 (0.989 mL, 5.00 mmol)
was added under Ar at 0 oC and stirred vigorously for 5 min. A
solution of 2-(4-hydroxy-3-methoxyphenyl)acetonitrile (81.6
mg, 0.500 mmol) was then added at 0 oC and stirred
vigorously. After 20 min, H2O (90.0 mg, 5.00 mmol) was
1
46.3 mg of 2l in 62% yield as a white solid. H NMR (300
MHz, DMSO-d6) δ 11.19 (br, 1H), 3.43 (m, 2H), 3.15 – 2.84
(m, 4H), 2.01 – 1.78 (m, 4H), 1.67 (m, 2H), 0.88 (t, J = 7.4
Hz, 3H); 13C{1H} NMR (75 MHz, DMSO-d6) δ 55.7, 53.1,
22.8, 18.9, 11.2.
o
added and stirred for 1 h at 0 C. The reaction was then
quenched by a saturated aqueous solution of NaHCO3 (2.0
mL) and the reaction mixture was diluted with CH2Cl2 (10
mL) and brine (10 mL). The aqueous layer was extracted with
Ethylbenzene18 (2m, Table 2). According to the general
procedure, the reaction of 2-phenylpropanenitrile (65.6 mg,
0.500 mmol), Na dispersion in hexane (19.5 wt %; 590 mg,
5.00 mmol), 15-crown-5 (0.989 mL, 5.00 mmol) and H2O
(90.0 mg, 5.00 mmol), after chromatography (hexanes),
×
CH2Cl2 (2
10 mL), the organic layers were combined and
concentrated. The crude product was redissolved in Et2O (10
mL) and brine (10 mL). The aqueous phase was acidified to
pH = 1 by adding 3M aqueous solution of HCl, and extracted
1
afforded 38.2 mg of 2m in 72% yield as a colorless oil. H
×
with Et2O (2
10 mL), the organic layers were combined,
NMR (300 MHz, CDCl3) δ 7.36 – 7.28 (m, 2H), 7.26 – 7.18
(m, 3H), 2.69 (q, J = 7.6 Hz, 2H), 1.28 (t, J = 7.6 Hz, 3H);
13C{1H} NMR (75 MHz, CDCl3) δ 144.3, 128.4, 127.9, 125.7,
29.0, 15.7.
dried over MgSO4, filtered and concentrated. The crude
product was purified by flash chromatography (0-30%
EtOAc/hexane), afforded 58.0 mg of 2h in 84% yield as a
colorless oil. 1H NMR (300 MHz, CDCl3) δ 6.83 (m, 1H), 6.71
– 6.65 (m, 2H), 5.47 (br, 1H), 3.88 (s, 3H), 2.31 (s, 3H);
13C{1H} NMR (75 MHz, CDCl3) δ 146.4, 143.5, 129.7, 121.6,
114.2, 111.8, 55.9, 21.1.
N,N-dimethyl-1-phenylmethanamine Hydrochloride25 (2n,
Table 2). According to the general procedure, the reaction of
2-(dimethylamino)-2-phenylacetonitrile (80.1 mg, 0.500
mmol), Na dispersion in hexane (19.5 wt %; 590 mg, 5.00
mmol), 15-crown-5 (0.989 mL, 5.00 mmol) and H2O (90.0 mg,
5.00 mmol), without chromatography, afforded the crude
product. The crude product was then treated with a 3 M
solution of HCl in cyclopentylmethyl ether and filtered. The
solid was then washed with diethyl ether and dried under
vacuum, afforded 55.8 mg of 2n in 65% yield as a white solid.
1H NMR (300 MHz, DMSO-d6) δ 11.42 (br, 1H), 7.66 – 7.59
(m, 2H), 7.46 – 7.39 (m, 3H), 4.28 (s, 2H), 2.64 (s, 6H);
13C{1H} NMR (75 MHz, DMSO-d6) δ 131.0, 130.5, 129.2,
128.6, 59.1, 41.2.
3-Methyl-1H-indole22 (2i, Table 2). According to the
general procedure, the reaction of 2-(1H-indol-3-
yl)acetonitrile (78.1 mg, 0.500 mmol), Na dispersion in
hexane (19.5 wt %; 590 mg, 5.00 mmol), 15-crown-5 (0.989
mL, 5.00 mmol) and H2O (90.0 mg, 5.00 mmol), after
chromatography (0-50% EtOAc/hexane), afforded 45.9 mg of
2i in 70% yield as a colorless oil. 1H NMR (300 MHz, CDCl3)
δ 7.74 (br, 1H), 7.58 (d, J = 7.7 Hz, 1H), 7.29 (d, J = 7.8 Hz,
1H), 7.18 (m, 1H), 7.12 (m, 1H), 6.90 (m, 1H), 2.32 (d, J = 1.0
Hz, 3H); 13C{1H} NMR (75 MHz, CDCl3) δ 136.3, 128.3,
121.9, 121.6, 119.2, 118.9, 111.7, 111.0, 9.7.
Adamantane26 (2o, Table 2). According to the general
procedure, the reaction of (3r,5r,7r)-adamantane-1-carbonitrile
(80.6 mg, 0.500 mmol), Na dispersion in hexane (19.5 wt %;
590 mg, 5.00 mmol), 15-crown-5 (0.989 mL, 5.00 mmol) and
H2O (90.0 mg, 5.00 mmol), after chromatography (hexanes),
5-Methoxy-3-methyl-1H-indole22 (2j, Table 2). According to
the general procedure, the reaction of 2-(5-methoxy-1H-indol-
3-yl)acetonitrile (93.1 mg, 0.500 mmol), Na dispersion in
hexane (19.5 wt %; 590 mg, 5.00 mmol), 15-crown-5 (0.989
mL, 5.00 mmol) and H2O (90.0 mg, 5.00 mmol), after
chromatography (0-50% EtOAc/hexane), afforded 56.4 mg of
2j in 70% yield as a colorless oil. 1H NMR (300 MHz, CDCl3)
δ 7.79 (br, 1H), 7.25 (d, J = 8.8 Hz, 1H), 7.05 (d, J = 2.4 Hz,
1H), 6.97 (m, 1H), 6.88 (dd, J = 8.8, 2.4 Hz, 1H), 3.91 (s, 3H),
2.34 (d, J = 1.0 Hz, 3H); 13C{1H} NMR (75 MHz, CDCl3) δ
154.0, 131.5, 128.7, 122.6, 112.1, 111.7, 111.5, 100.8, 56.0,
9.8.
1
afforded 50.4 mg of 2o in 74% yield as a colorless oil. H
NMR (300 MHz, CDCl3) δ 1.89 (m, 4H), 1.77 (m, 12H);
13C{1H} NMR (75 MHz, CDCl3) δ 37.9, 28.5.
Computational Study. To investigate the kinetic of C-C
bond cleavage in [CH3−CN]-• radical anion (3 in Scheme 3)
and CH3−CNNa• neutral radical (6 in Scheme 3) in solvents,
starting geometries of 3 and 6 were initially generated using
the function of “gentor” implemented in the software of
molclus (molclus program). All rotating available chemical
bonds, such as C3-C1 σ bond in CH3−CNNa•, were rotated in
30 degrees per step for 360 degrees to cover as many as
possible structures in the gas phase. Formed structures were
2-Methyl-1H-benzo[d]imidazole Hydrochloride23 (2k, Table
2). According to the general procedure, the reaction of 2-(1H-
benzo[d]imidazol-2-yl)acetonitrile (78.6 mg, 0.500 mmol), Na
dispersion in hexane (19.5 wt %; 590 mg, 5.00 mmol), 15-
crown-5 (0.989 mL, 5.00 mmol) and H2O (90.0 mg, 5.00
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Page 6 of 7
then optimized by semi-empirical method PM727 using the
software MOPAC.28-31 To verify the accuracy of the calculated
energies by semi-empirical method, the top four most stable
structures were selected to calculated their single point energy
using the hybrid DFT functional M06-2X32 with a triple zeta
basis set of TZVP. 33,34 The DFT calculations were carried out
using the Gaussian 09D01 program. SMD solvation model
with tetrahydrofuran (THF) and cyclohexane as solvent were
applied to examine the solvation effects. Next, the most stable
structure with the lowest energy of 3 and 6 were re-optimized
using uB3LYP12 functional with a 6-31+G(d,p) basis set13,35
and SMD solvation model. Stable minima on potential surface
were confirmed by the frequency calculations with no
imaginary frequencies. A rigid scan was conducted along the
C−C coordinate of interest in 3 and 6 for 6 Å, with 0.1 Å per
step in 60 steps. 61 single point energies were obtained via this
C−C bond stretching. Calculated energy of the starting
structure was considered as zero. By subtracting calculated
single point energy in each step with the energy of the starting
structure, relative energies (ΔE) were calculated for 3 and 6,
respectively (see Tables S1 and S2). The entry with the
highest value of Δ E was labelled in bold to signify. The
calculated ΔEs were plotted against the “scan coordinates” to
construct Figure 1.
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ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website. 1H and 13C NMR spectra, and
computational data (PDF).
Neutral Organic Electron Donors:
A Tetra(Iminophosphorano)-
Substituted Bispyridinylidene. Angew. Chem. Int. Ed. 2015, 54,
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AUTHOR INFORMATION
Corresponding Author
*E-mail: lifuma@tju.edu.cn; jie_an@cau.edu.cn.
during Decyanation of Alkylcyano α,ω-Dienes:
A Deuterium
ORCID
Labeling and Structural Study of Mechanism. J. Org. Chem. 2008, 73,
4962–4970.
Yuxuan Ding: 0000-0002-4201-2689
Shihui Luo: 0000-0002-5661-4082
Jie An: 0000-0002-1521-009X
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Electrons as Anions. Science 2003, 301, 607. (d) Edwards, P. P.
Electrons in Cement. Science 2011, 333, 49.
(8) Amancha, P. K.; Lai, Y.-C.; Chen, I.-C.; Liu, H.-J.; Zhu, J.-L.
Diels–Alder Reactions of Acyclic α-Cyano α,β-Alkenones: A New
Approach to Highly Substituted Cyclohexene System. Tetrahedron
2010, 66, 871–877.
ACKNOWLEDGMENT
We thank National Natural Science Foundation of China (No.
21602248 and No. 11704280), and the Natural Science
Foundation of Beijing Municipality (No. 2192026) for financial
support.
(9) (a) Lei, P.; Ding, Y.; Zhang, X.; Adijiang, A.; Li, H.; Ling, Y.;
An, J.
A Practical and Chemoselective Ammonia-Free Birch
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