Nucleophilic attack of α-aminoalkyl radicals on carbon-nitrogen triple bonds to construct α-amino nitriles: An experimental and computational study

Article abstract of DOI:10.1002/chem.201303296

A new reactivity pattern of α-aminoalkyl radicals, involving nucleophilic attack on Ci￡N triple bonds under thermal conditions, has been developed to construct α-amino nitriles. In contrast to previous C-H functionalization of tertiary amines involving α-aminoalkyl radicals, this methodology does not require the use of photocatalytic conditions or a transition-metal catalyst. Inexpensive and nontoxic phenylacetonitrile was chosen as cyano source for this α-aminonitrile forming reaction. A plausible mechanism is proposed based upon experimental and computational results. An α-aminoalkyl radical intermediate and benzoyl cyanide have been shown to be key intermediates in this Copyright

Full text of DOI:10.1002/chem.201303296

FULL PAPER
DOI: 10.1002/chem.201303296
À
Nucleophilic Attack of a-Aminoalkyl Radicals on Carbon Nitrogen
Triple Bonds to Construct a-Amino Nitriles: An Experimental and
Computational Study
Chao Zhang,[a] Chunmei Liu,[a] Ying Shao,[b] Xiaoguang Bao,*[a] and Xiaobing Wan*[a]
Abstract: A new reactivity pattern of
a-aminoalkyl radicals, involving nucle-
nylacetonitrile was chosen as cyano
source for this a-aminonitrile forming
reaction. A plausible mechanism is
proposed based upon experimental and
radical intermediate and benzoyl cya-
nide have been shown to be key inter-
mediates in this green and mild radical
process. Nucleophilic attack of the
ꢀ
ophilic attack on C N triple bonds
under thermal conditions, has been de-
ꢀ
veloped to construct a-amino nitriles.
computational results. An a-aminoalkyl
a-aminoalkyl radical on the C N bond
À
In contrast to previous C H function-
of PhCOCN followed by an elimina-
tion step forms the desired a-aminoni-
trile and an acyl radical.
alization of tertiary amines involving
a-aminoalkyl radicals, this methodolo-
gy does not require the use of photoca-
talytic conditions or a transition-metal
catalyst. Inexpensive and nontoxic phe-
Keywords: density functional calcu-
lations · radical reactions · reaction
mechanisms · reactive intermedi-
ates · synthetic methods
Introduction
[1]
À
C H functionalization of tertiary amines has drawn much
attention in recent years as a powerful strategy to construct
various a-substituted amines, which are important synthetic
intermediates for generating nitrogen-containing com-
pounds.[2] Currently, two methods are routinely employed to
synthesize a-functionalized tertiary amines. The first in-
volves generation of iminium ion intermediates through oxi-
dation of tertiary amines, which has been developed by the
groups of Murahashi,[3] Li,[4] and others[5] (Scheme 1a). Very
recently, an elegant functionalization of tertiary amines via
iminium ion intermediates formed in situ through visible-
light photoredox catalysis has also been reported.[6]
À
Scheme 1. a-C H bond functionalization of tertiary amines.
adjacent to the nitrogen atom by using Et3B/air.[7c] MacMil-
lan and co-workers described a photoredox-catalyzed a-
amino C H arylation reaction that proceeds through a radi-
À
The second type of a-C H bond functionalization of terti-
cal process.[7d] Recently, the groups of Nishibayashi,[7e–g]
Reiser and Pandey,[7h] and Yoon[7i] have independently re-
ported the visible-light-mediated addition of a-amino alkyl
radicals to various a,b-unsaturated systems. In 2012, tandem
a-alkylation/cyclization of N-benzyl carbamates with nonac-
tivated olefins was established by MancheÇo and co-work-
ers.[7j]
À
ary amines takes advantage of nucleophilic a-aminoalkyl
radicals (Scheme 1b).[7] Yoshida et al. reported the addition
of a-amino alkyl radicals to various double bonds bearing
an electron-withdrawing group based on the reduction of
a “cation pool”.[7a,b] Related studies by the group of Nagao-
À
ka revealed a radical hydroxyalkylation of the C H bond
Despite the remarkable success of the radical strategy
outlined above, its usual reliance on photocatalytic/electro-
chemical conditions and the requirement for C=C bonds
bearing electron-poor groups limit its utility in synthetic
chemistry. Therefore, a new process that can be applied to
a broader range of electrophiles under thermal conditions is
highly desirable. Herein, we report a mechanistically inter-
esting and metal-free[8,9] process to construct synthetically
important a-amino nitriles[10] (Scheme 1c). To the best of
our knowledge, this represents the first example of nucleo-
[a] C. Zhang, C. Liu, Prof. Dr. X. Bao, Prof. Dr. X. Wan
Key Laboratory of Organic Synthesis of Jiangsu Province
College of Chemistry, Chemical Engineering and Materials Science
Soochow (Suzhou) University, Suzhou 215123 (P.R. China)
Fax: (+86)512-6588-0334
E-mail: xgbao@suda.edu.cn
wanxb@suda.edu.cn
[b] Y. Shao
Key Laboratory of Fine Petrochemical Engineering
Changzhou University, Chanzhou 213164 (P. R. China)
ꢀ
philic attack of a-aminoalkyl radicals on C N bonds under
thermal conditions, although ketone-nitrile reductive cou-
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201303296.
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17917

pling mediated by SmI2 constitutes a valuable method with
phenyl ring of phenylacetonitrile was further investigated.
The use of 4-nitrophenylacetonitrile as cyano source led to
formation of the desired product 3a in 35% yield (Table 1,
entry 14). In sharp contrast, when 4-methoxyphenylacetoni-
trile was used as cyano source, product 3a was achieved in
high yield detected by GC (89%; Table 1, entry 15). Un-
fortunately, its purification was very difficult due to the
presence of some uncharacterized byproducts. Considering
the expense and operational simplicity, phenylacetonitrile
was chosen as cyano source in subsequent investigations.
Other cyano sources, such as TsCN and CCl3CN, did not
lead to the desired product (Table 1, entries 16 and 17). No-
tably, this a-amino nitrile formation reaction could be scaled
up to 10 mmol, generating the desired product 3a in 65%
yield (Table 1, entry 18).
which to form a-hydroxy ketone derivatives.[11,12]
Results and Discussion
The reaction conditions for oxidative cyanation[13] of N,N-di-
methylaniline (1a) was extensively screened with tetraACHTUNTRGNEUNGbutyl-
ACHTUNGTRENNUNGammonium iodide (TBAI) as catalyst and tert-butyl hydro-
peroxide (TBHP) as primary oxidant (Table 1).[14] When
Table 1. Optimization of reaction conditions.[a]
To ascertain the identity of the active intermediates that
result from TBAI/TBHP, we screened a series of iodine-con-
taining reagents to see whether they could similarly catalyze
the oxidative cyanation of N,N-dimethylaniline (1a). None
of the I(0)–I(V) species tested could drive the reaction
enough to produce substantial amounts of the a-amino ni-
trile product 3a (Table 2). In particular, we found no evi-
Entry
Catalyst
Cyano source
Oxidant
Yield [%][b]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
TBAI
TBAI
TBAI
TBAI
–
PhCH2CN
NaCN
TMSCN
TBHP
TBHP
TBHP
TBHP
TBHP
–
TBHP
TBHP
TBHP
TBHP
Oxone
TBP
84
10
10
MeCN
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
<10
n.d.
35
PhCH2CN
PhCH2CN
PhCH2CN
PhCH2CN
PhCH2CN
PhCH2CN
PhCH2CN
PhCH2CN
PhCH2CN
4-NO2-PhCH2CN
4-OMe-PhCH2CN
TsCN
TBAI
KI
Bu4NBr
PdCl2
CuBr2
TBAI
TBAI
TBAI
TBAI
TBAI
TBAI
TBAI
TBAI
Table 2. Investigations on the reaction mechanism by screening various
iodine reagents.[a]
H2O2
TBHP
TBHP
TBHP
TBHP
TBHP
89[c]
<5
<5
65[d]
Entry
Catalyst
Yield [%][b]
CCl3CN
PhCH2CN
1
2
3
4
5
6
I2
IBr
NIS
PhIACTHNUTRGENUG(N OAc)2
NaIO3
<5
<5
<5
<5
<5
<5[c]
[a] Reaction conditions: 1a (0.5 mmol), 2 (1.25 mmol), TBAI (0.01 mol),
oxidant (2.5 mmol), H2O (1.5 mL), tBuOH (0.5 mL), 608C, 36 h. [b] Iso-
lated yield; n.d.=not detected. [c] Detected by GC. [d] 1a (10 mmol)
was used.
I2 (20 mol%), Bu4NOH (1.0 equiv)
[a] Reaction conditions: 1a (0.5 mmol), 2a (1.25 mmol), catalyst (0.01
mol), TBHP (2.5 mmol), H2O (1.5 mL), tBuOH (0.5 mL), 608C, 36 h.
[b] Isolated yield. [c] [Bu4N]+[IO]À generated in situ.
phenylacetonitrile (2a) was used as cyano source, the de-
sired a-amino nitrile 3a was obtained in high yield (84%;
Table 1, entry 1). In contrast to previous oxidative cyanation
of tertiary amines,[15] the methodology was distinguished by
the fact that it did not require photocatalytic conditions, ex-
pensive transition-metal catalysts, or toxic cyano sources. In
fact, cyanide anions such as NaCN and TMSCN (Table 1,
entries 2 and 3), which are frequently used as nucleophiles
to attack iminium ion intermediates in a-amino nitrile syn-
thesis, were found to be poor cyano donors for 1a, suggest-
ing that a different mechanism was involved in this TBAI/
TBHP system. Both TBAI and TBHP were essential for a-
amino nitrile formation under our conditions (Table 1, en-
tries 5 and 6). Replacement of TBAI by other catalysts, in-
cluding organocatalysts and transition-metal catalysts, did
not lead to the desired product (Table 1, entries 7–10). Nota-
bly, when other common oxidants were used for this trans-
formation, again, no significant amount of product 3a was
detected (Table 1, entries 11–13). Substituent effect on the
dence that hypoiodite, which Ishihara et al.[16] showed could
be generated in situ from iodine and Bu4NOH, had any ap-
preciable impact on the yield of 3a (Table 2, entry 6). These
findings implied that this cyanation reaction likely involved
C
C
a tBuO and/or tBuOO radical intermediate that was gener-
ated from TBHP[14] rather than an oxidizing iodine species.
Further mechanistic studies revealed that adding 2,2,6,6-
tetramethylpiperidine-1-oxyl (TEMPO) as a radical scaveng-
er resulted in a sharp decrease in the yield of 3a and gave
rise to small amounts of a-aminoalkyl radical adduct 4 and
C
PhC(O) radical adduct 5, which not only confirmed our ear-
lier speculation of the involvement of radical intermediates,
but also hinted at benzoyl cyanide as the cyano donor
(Scheme 2a). Substituting benzoyl cyanide for phenylaceto-
nitrile led to the identical product 3a in high yield
(Scheme 2b). In addition, no significant amount of a-amino
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À
Radical Attack on C N Triple Bonds
FULL PAPER
these processes generally entail
an a-amino perACTHNUTRGENUGNoxide precursor
that can subsequently convert
into an iminium ion intermedi-
ate when aided by a transition-
metal catalyst. However, imini-
um ions might not play
a major role in the formation
of 3a due to the absence of
any metal ions in our catalytic
system. This was confirmed by
the finding that a-amino per-
AHCTUNGTERGoNNUN xide derivative 8 fared poorly
as a substrate in our reaction
(Scheme 2 f).
Scheme 3 provides an over-
view of our proposed radical-
mediated mechanism for the a-
cyanation of tertiary amines. A
catalytic redox cycle involving
TBHP and TBAI first gave
C
rise to both tBuO (A) and
tBuOO (B; Scheme 3a),[19,20]
C
which could then abstract the
a-hydrogen of the tertiary
amine to afford a-amino
radical intermediate
(Scheme 3b). In addition to C,
benzoyl cy nide (D) could also
be formed in situ due to the
oxidative environment in-
ACHTUNGTRENNUNGalkyl
C
ACTHUNGTRENNUGaAHCTUNGTRENNNUG
volved (Scheme 3c). Finally,
nucleophilic attack of a-amino-
ꢀ
Scheme 2. Investigations on the reaction mechanism.
AHCTUNGERTGaNNUN lkyl radical C on the C N
bond of PhCOCN (D) and
nitrile 3a was achieved when a,a-dimethylphenylacetonitrile
was used as the cyano source (Scheme 2c).
subsequent elimination leads to the desired product and
C
a PhC(O) radical (E; Scheme 3d). It is noteworthy that the
C
C
One could argue that nucleophilic substitution of acyl cya-
PhC(O) radical (E) could be trapped by tBuOO (B), pro-
viding the tert-butyl peroxybenzoate as a byproduct, which
was verified by experiment.
nide by TEMPO,[17] instead of direct coupling between
G
E
R
G
G
G
ACHTUNGTRENNUNG
C
PhC(O) radical and TEMPO, could also reasonably form
adduct 5. To offer more compelling evidence, further experi-
ments were carried out to test the involvement of acyl radi-
cals in this a-amino nitrile formation reaction. Employing 3-
phenylpropanoyl cyanide as a cyano source led to formation
of product 3a in moderate yield (Scheme 2d). When the re-
The complexity of the above mechanism and the many re-
active species it involves renders the reaction system suscep-
tible to multiple alternative pathways contributing to poten-
tial side reactions. To explore these possibilities, (U)B3LYP
calculations[21] were performed on the a-amino nitrile for-
mation reaction by using the Gaussian 09 suite.[22] The 6-31+
action of 1a with 3-phenyl
ACHTUNGTRNEpNUNG ropanoyl cyanide was performed
in the presence of TEMPO, in addition to the expected
GACHTUNGTRENNUG
C
PhCH2CH2C(O) radical adduct 6, we also detected adduct
ACHTUNGTRENNUNG
C
C
7, which was formed from PhCH2CH2 radical and TEMPO
(Scheme 2e). These results suggest that the
PhCH2CH2C(O) radical generated in situ and subsequent
decarbonyl tion pro
cess[18] is involved in this transforma-
tion.
C
AHCTUNGTRENNUNG
G
E
T
N
N
G
sition, were assessed and compared (Scheme 4). Calculations
indicated that the former reaction pathway is much more fa-
vorable than the latter in terms of both kinetic and thermo-
dynamic profiles (Figure 1). Therefore, a-aminoACTHNUTRGNEaUNG lkyl radical
C, resulting from H-atom abstraction, would be expected to
À
Transition-metal-catalyzed a-C H functionalization of ter-
tiary amines by using TBHP as oxidant has been elegantly
investigated by several groups.[3a,f,4a–d,5c–e,h,j–l] According to
pioneering studies by Klussmann et al.[5j] and Doyle et al.,[5l]
participate in the subsequent reactions. In addition, the cal-
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17919

X. Bao, X. Wan et al.
C
Figure 1. Energy profiles of the two reaction pathways between tBuO
and PhN(CH3)2 calculated at the (U)B3LYP/6-311+ +G(d,p)//
(U)B3LYP/6-31+G(d,p) level of theory (DH
(0 K), in kcalmolÀ1). Bond
lengths are shown in ꢁ.
A
ACHTUNGTRENNUNG
A
ACHTUNGTRENNUNG
Scheme 3. Proposed reaction mechanism.
C
Scheme 5. Three possible reaction pathways between tBuO and
PhCH2CN.
C
Scheme 4. Two reaction pathways between tBuO and PhNACHTNUGTRNEG(UN CH3)2.
culated energy barrier for abstraction of an a-H from PhN-
C
ACHTUNGTRENNUNG(CH3)2 by tBuOO (B) was revealed to be much higher than
C
for tBuO (A; see Scheme S1 and Figure S1 in the Support-
ing Information), which is at least partially attributable to
the lower spin density of the former species around its ter-
minal oxygen (0.68 vs. 0.87 e).
We then similarly analyzed three possible reaction routes
C
between tBuO (A) and another reactant, PhCH2CN (2a),
which were a) H-atom abstraction from the methylene
C
group, b) the addition of tBuO to the cyano group, and
C
Figure 2. Energy profiles of three reaction pathways between tBuO and
PhCH2CN calculated at the (U)B3LYP/6-311+ +G(d,p)//(U)B3LYP/6-
31+G(d,p) level of theory (DH
(0 K), in kcalmolÀ1). Bond lengths are
shown in ꢁ.
C
c) the addition of tBuO to the benzene ring (Scheme 5).
AHCTUNGTRENNUNG
The energy profiles of these three reaction pathways are
summarized in Figure 2. Calculations indicated that hydro-
gen abstraction was exothermic by 26.1 kcalmolÀ1 and had
the smallest activation energy demand of the three reaction
pathways at only 1.5 kcalmolÀ1.[24] The two alternative addi-
tion reaction pathways could therefore not compete with
the H-atom abstraction reaction pathway.
G
ACHTUNGTRENNUNG
Computational studies also provided a rather convenient
but nevertheless convincing explanation for the generation
of PhCOCN (D), an experimentally verified intermediate
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À
Radical Attack on C N Triple Bonds
FULL PAPER
that proved crucial for both product formation and mecha-
nistic deduction. Following a-H abstraction, radical G might
C
combine with tBuOO (B) to afford a closed-shell intermedi-
ate J, which could then undergo a second a-H abstraction,
C
this time by tBuO (A), to eventually give D (Scheme 6).
Scheme 6. In situ generation of PhCOCN (D) through a radical process.
C
Scheme 7. Two possible reaction pathways between PhNCH3CH2 radical
(C) and PhCOCN (D).
The calculated energy barrier of the a-H abstraction from J
À1
induced by tBuO was shown to be only 0.8 kcalmol , sug-
group) would be more favorable,[25] because it requires
3.6 kcalmolÀ1 less energy than the latter (Figure 4).
C
gesting that the formation of the PhCOCN intermediate (D)
was plausible (Figure 3).
Although both experimental and computational results
present convincing evidence that supports a radical mecha-
nism, we found that the use of Na
of up to 10% of 3a (Table 3, entry 1), suggesting that an im-
in um ion mechanism seemed at least feasible under some
conditions. In contrast to 1a, when cyan tion of 1-phenyl-
pyrrol dine was performed by using PhCH2CN as cyano
ACHTUNGERTNCNUNG N could result in a yield
AHCTUNGTRENNUNG ACHTUNREGTNNUNGiACTUHNGTRENNUGN
A
N
ACHTUNGTRENNUNG
A
R
ACTHUNGTRENNUNiG ACHTUNGTRENNNUG
source, the yield of product 3b decreased remarkably (50 vs.
84%; Table 3), perhaps due to increased steric hindrance. It
should be noted that the ionization energy (IE) of radical O
is 9.8 kcalmolÀ1 lower than that of radical C, indicating that
it is much easier for radical O to be oxidized to the corre-
C
Figure 3. Energy profiles of the H-abstraction reaction between tBuO
and J calculated at the (U)B3LYP/6-311+ +G
(d,p) level of theory (DH
(0 K), in kcalmolÀ1). Bond lengths are shown in
ꢁ.
ACHTUNGERTN(NUNG d,p)//(U)B3LYP/6-31+G-
A
ACHTUNGTRENNUNG
sponding imCAHUTGNERTNiUNG nAHCTUNTGERNNUNGiACTHNUGTRENuGUNN m ion intermediates P in the presence of
TBHP. Consequently, the yield of product 3b through an
ionic process increases in comparison with 3a (40 vs. 10%).
The calculated IE of radical Q is 15.3 kcalmolÀ1 lower
than that of radical C (116.6 vs. 131.9 kcalmolÀ1), suggesting
that radical Q could be easily oxidized to the corresponding
iminium ion intermediate. As anticipated, the ionic cyana-
tion reaction proceeds smoothly, leading to the desired
product 3c in 54% yield (Table 3, entry 3).
The final phase of our proposed mechanism begins with
attack of the a-aminoalkyl radical C on the cyano group in
PhCOCN to give imine radical intermediate L (Scheme 7),
the activation energy of which was estimated to be 4.7 kcal
molÀ1. Inspection of the spin density of L revealed the un-
paired electron to be mainly localize around the terminal ni-
trogen site. The adduct L can then undergo elimination re-
action to form the final a-amino nitrile product and the
PhC(O) radical. The energy of
One noteworthy finding was that substituting PhCH2CN
for NaCN as the cyano donor in the above reaction pro-
the transition state (TS) in the
elimination step is 2.8 kcal
molÀ1 higher than that of the
TS in the first addition step,
which indicates that elimina-
tion is the rate-limiting step in
the production of a-amino ni-
trile (Figure 4).
Another complicating factor
that needs to be considered is
the competition between the
cyano group and the benzene
ring as the site of radical addi-
tion. Computational studies re-
vealed that the former (cyano
C
Figure 4. Energy profile of two reaction pathways between PhNCH3CH2 radical and PhCOCN calculated at
(0 K), in kcalmolÀ1). Bond
the (U)B3LYP/6-311+ +GACHTUGNTREN(NNUG d,p)//(U)B3LYP/6-31+GACHTUNRTEGG(NNUN d,p) level of theory (DHCAHTNUGTRENNGUN
lengths are shown in ꢁ.
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X. Bao, X. Wan et al.
Table 3. Calculated ionization energies (IE) of radicals at the (U)B3LYP/6-311+ +G-
(d,p)//(U)B3LYP/6-31+G(d,p) level of theory and the implication of the yield in radi-
cal and ionic processes.[a]
ary amines to the niACTHNUTRGENNtGU rile-formACHTUGNTRENiNNGU ng reaction by using
the optimized set of conditions, to explore the
scope of the approach. The reactions all provided
G
ACHTUNGTRENNUNG
the corresponding a-amino ni
erate to high yields as summarized in Table 4. No-
tably, cyanation of tertiary amines containing two
ACHTUNGTRENtNUNG rile products in mod-
AHCTUNGTRENNUNG
À
chemically unequivalent a-C H bonds was found
À
to occur selectively on the primary C H (products
3d–h). Furthermore, halo
gen substituents on the
aromatic ring did not appear to interfere with the
À
C H functionalization (products 3k, 3m, and 3n),
allowing further synthetic manipulations such as
transition-metal-catalyzed cross-coupling reactions.
When N,N-diACTHNUGRTENNUGbutylCAHUTNGTRENNaUGN niline was used as reaction
Entry a-Amino-
alkyl
IE
Iminium
cation
Product
Yield
Yield
G
[kcalmolÀ1
]
(PhCH2CN)
(NaCN)
[%][b]
[%][b]
partner, no significant amount of a-amino nitrile
3o was observed, perhaps due to increased steric
interference.
1
2
3
131.9
84
10
Conclusion
122.1
116.6
50
–
40
54
A novel reactivity pattern of a-aminoalkyl radicals,
involving nucleoACHTUNGTRENpNGNU hilic attack on the carbon–nitro-
gen triple bond of PhCOCN and subsequent elimi-
C
nation of PhC(O) radical, has been realized for
the first time under thermal conditions.
À
In contrast to previous C H functionalization of
4
–
–
55
–
ter
A
photocatalytic conditions or transition-metal cata-
lysts. Inexpensive and nontoxic PhCH2CN was
[a] Reaction conditions: 1a (0.5 mmol), TBAI (0.01 mol), TBHP (2.5 mmol), H2O
(1.5 mL), tBuOH (0.5 mL), 608C, 36 h. [b] PhCH2CN (1.25 mmol) was used. [c] NaCN
(1.25 mmol) was used.
AHCTUNGTRENNUNG
duced ring-contraction product 3b in 55% yield (Table 3,
entry 4). We proposed a plausible mechanism for this unex-
pected product as shown in Scheme 8. Basically, the radical
intermediate Q that was generated from TBAI/TBHP-pro-
moted a-H abstraction of 1c (step a) could be oxidized to
form a cyclic im
hydrolysis and ring opening, could be converted into al
hyde S. The terminal hydrogen of S could be abstracted to
produce acyl radical T, which then leads to the formation of
radical U through decarbonyl tion (step e). The latter radi-
cal undergoes cyclization (step f), hydrogen abstraction
ACHTUNGTRENNUNGinACHTUNGTRENNUNGiACHTUNGTRENNUNG
G
E
E
ACHTUNGTRENNUNG
G
ACHTUNGTRENNUNG
R
U
ACHTUNGTRNENUNG ACHTNUREGTNNUNGaACTUHNGTRENNUGN
A
E
G
G
ACHTUNGTRENNUNG
Scheme 8. Proposed mechanism for the cyanation of 1-phenylpiperidine
by using PhCH2CN.
(step g), and eventually reacts with PhCOCN (step h) to
afford 3b. To verify our hy-
pothesis, we capatured the re-
action
TEMPO and generated a varie-
ty of a-aminoalkyl, acyl, and
intermediates
with
A
ACHTUNGTRENNUNG
alkyl radical adducts, which
could all be easily derived
from intermediates at different
stages of the proposed mecha-
nism (Scheme 9).
We then subjected a series
of differently substituted terti-
Scheme 9. Detection of reaction intermediates.
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Radical Attack on C N Triple Bonds
FULL PAPER
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d) K. R. Campos, Chem. Soc. Rev. 2007, 36, 1069–1084; e) C.-J. Li,
Acc. Chem. Res. 2009, 42, 335–344; f) X. Chen, K. M. Engle, D.-H.
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used as cyano source for the construction of a-amino ni-
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
C
ACHUTNGRENzNUG oAHCTUNGTRNENyUGN l cya-
AHCTUNGTRENNUNG
ꢀ
C
the PhC(O) radical (E) provided the desired a-amino ni-
trile. It is noteworthy that ring-contraction product 3b was
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achieved when 1-phenyl
action conditions using PhCH2CN as cyano donor. The un-
usual characteristics of the a-aminoalkyl radical will be fur-
ther explored in our laboratory, especially with respect to its
use with electrophiles other than PhCOCN.
ACHTUNGTERNNpUNG ipACHUTNGTERNNGUerACHTUNGERTNNUNGiACHNUTTGREGdNNUN ine was submitted to the re-
AHCTUNGTRENNUNG
ACHTUNGTRENNUNG
Experimental Section
General procedure: Bu4NI (0.01 mmol) and tertiary amine (0.5 mmol)
were added to a test tube and H2O (1.5 mL), tBuOH (0.5 mL), phenyl-
ACHTUNGTRENNUNGacetonitrile (1.25 mmol, 142 mL), and TBHP (70% in H2O, 2.5 mmol,
342 mL) were added by using a syringe. The reaction mixture was stirred
at 608C for 36 h, then the reaction was quenched (consumption of residu-
al TBHP) by the addition of saturated Na2SO3 solution and extracted
with ethyl acetate. The organic layer was combined and dried with
Na2SO4. Removal of solvent followed by flash column chromatographic
purification afforded products.
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Acknowledgements
This project was funded by the Priority Academic Program Development
of Jiangsu Higher Education Institutions (PAPD) and NSFC (21072142,
21272165).
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M. Ishida, T. Nakajima, Y. Honda, O. Kitao, H. Nakai, T. Vreven,
J. A. Montgomery, Jr., J. E. Peralta, F. Ogliaro, M. Bearpark, J. J.
Heyd, E. Brothers, K. N. Kudin, V. N. Staroverov, T. Keith, R. Ko-
bayashi, J. Normand, K. Raghavachari, A. Rendell, J. C. Burant,
of theory, which is much higher in energy than the studied intermo-
lecular H-abstraction reactions.
[25] The X3LYP[26] functional gives nearly the same energies for these
two reaction pathways as B3LYP (Figure S2, see the Supporting In-
formation).
[26] X. Xu, W. A. Goddard III, Proc. Natl. Acad. Sci. USA 2004, 101,
2673.
Received: August 22, 2013
Published online: November 22, 2013
Chem. Eur. J. 2013, 19, 17917 – 17925
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
17925