Copper-Catalyzed Radical 1,4-Difunctionalization of 1,3-Enynes with Alkyl Diacyl Peroxides and N-Fluorobenzenesulfonimide

Article abstract of DOI:10.1021/jacs.8b11499

Many reactions involving allenyl ion species have been studied, but reactions involving allenyl radicals are less well understood, perhaps because of the inconvenience associated with the generation of short-lived allenyl radicals. We describe here a versatile method for the generation of allenyl radicals and their previously unreported applications in the intermolecular 1,4-carbocyanation and 1,4-sulfimidocyanation of 1,3-enynes. With the assistance of the trifunctional reagents, alkyl diacyl peroxides or N-fluorobenzenesulfonimide, a range of synthetically challenging multisubstituted allenes can be prepared with high regioselectivity. These multisubstituted allenes can be easily transformed into synthetically useful structures such as fluorinated vinyl cyanides, lactones, functionalized allenyl amides, 1-aminonaphthalenes, and pyridin-2(1H)-ones, and several novel transformations are reported. The results of radical scavenger and radical clock experiments are consistent with the proposed allenyl radical pathway. Density functional theory (DFT) and IR spectroscopy studies suggest the formation of an isocyanocopper(II) species in the ligand exchange step. On the basis of the results of IR, DFT, and diastereoselectivity studies, an isocyanocopper(II)/copper(I) catalytic cycle is proposed, which differs from the previously considered Cu(III) mechanism in cyanation reactions.

Full text of DOI:10.1021/jacs.8b11499

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Article
Copper-Catalyzed Radical 1,4-Difunctionalization of 1,3-Enynes
with Alkyl Diacyl Peroxides and N-fluorobenzenesulfonimide
Xiaotao Zhu, Weili Deng, Mong-Feng Chiou, Changqing Ye, Wujun Jian,
Yuehua Zeng, Yihang Jiao, Liang Ge, Yajun Li, Xinhao Zhang, and Hongli Bao
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b11499 • Publication Date (Web): 04 Dec 2018
Downloaded from http://pubs.acs.org on December 4, 2018
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Journal of the American Chemical Society
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Copper-Catalyzed Radical 1,4-Difunctionalization of 1,3-Enynes with
Alkyl Diacyl Peroxides and N-fluorobenzenesulfonimide
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Xiaotao Zhu,§,† Weili Deng,§,† Mong-Feng Chiou, §,† Changqing Ye,†,|| Wujun Jian,† Yuehua
Zeng,† Yihang Jiao,†,|| Liang Ge,†,|| Yajun Li,† Xinhao Zhang,*,‡ and Hongli Bao*,†,||
† State Key Laboratory of Structural Chemistry, Key Laboratory of Coal to Ethylene Glycol and Its Related
Technology, Center for Excellence in Molecular Synthesis. Fujian Institute of Research on the Structure of Matter,
University of Chinese Academy of Sciences, 155 Yangqiao Road West, Fuzhou, Fujian 350002, People's Republic of
China.
‡ Lab of Computational Chemistry and Drug Design, State Key Laboratory of Chemical Oncogenomics, Peking
University Shenzhen Graduate School, Shenzhen 518055, People’s Republic of China.
|| University of Chinese Academy of Sciences, Beijing, 100049, People’s Republic of China.
KEYWORDS. allenes, 1,4-carbocyanation, 1,4-sulfimidocyanation, 1,3-enynes, allenyl radical, radical relay, copper
catalysis
ABSTRACT: Many reactions involving allenyl ion species have been studied but reactions involving allenyl radicals are
less well understood, perhaps because of the inconvenience associated with the generation of short-lived allenyl radicals.
We describe here a versatile method for the generation of allenyl radicals and their previously unreported applications in
the intermolecular 1,4-carbocyanation and 1,4-sulfimidocyanation of 1,3-enynes. With the assistance of the trifunctional
reagents, alkyl diacyl peroxides or N-fluorobenzenesulfonimide, a range of synthetically challenging multi-substituted
allenes can be prepared with high regioselectivity. These multisubstituted allenes can be easily transformed into
synthetically useful structures such as fluorinated vinyl cyanides, lactones, functionalized allenyl amides, 1-
aminonaphthalenes and pyridin-2(1H)-ones, and several novel transformations are reported. The results of radical
scavenger and radical clock experiments are consistent with the proposed allenyl radical pathway. Density functional
theory (DFT) and IR spectroscopy studies suggest the formation of an isocyanocopper(II) species in the ligand exchange
step. Based on the results of IR, DFT and diastereoselectivity studies, an isocyanocopper(II)/copper(I) catalytic cycle is
proposed, which differs from the previously considered Cu(III) mechanism in cyanation reactions.
difunctionalization.12 This is probably due to the
INTRODUCTION
generation of short-lived allenyl radicals.13 1,4-Di-
functionalization of 1,3-enynes that proceeds via an
Allenes are important structural motifs found in natural
products and are key intermediates in the synthesis of
complex molecules (Scheme 1a).1,2 Classical methods for
the synthesis of allenes include prototropic re-
arrangements,3 sigmatropic rearrangements,4 nucleophilic
substitutions,5 1,4-additions to enynes6-8 and other
methods.9,10 While most of these methods usually
introduce only one functional group, 1,4-addition to 1,3-
enynes introduces two functional groups simultaneously
and has attracted increasing attention in recent years.
Groups led by Ma, Kambe, Yoshida and Kimura have
developed efficient 1,4-difunctionalization reactions of 1,3-
enynes using organometallic reagents, affording allenes
via allenyl anion intermediates (Scheme 1b).6 Compared to
the allenyl ionic intermediates, allenyl radicals have been
less utilized in organic synthesis.
allenyl radical pathway could be very useful. The allenyl
radical is very reactive and is susceptible to oxidation to
an allenyl cation, as an effective electrophile, or reduction,
forming a carbon-metal bond,12 to the allenyl anion, as a
nucleophile. Consequently, reactions which cannot
proceed by an allenyl anion pathway may take advantage
of a feasible allenyl radical pathway.
Nitriles are versatile building blocks useful in the
synthesis of carboxylic acids, amines, amides, and
ketones,14 and are also an important class of organic
compounds, frequently found in pharmaceuticals and
other important chemicals.15 Due to the unique role of the
cyano group, its introduction into organic molecules is
important in synthetic chemistry. Difunctionalizations of
alkenes with
a cyanation reaction have been well
developed.16 In these difunctionalization cyanation
reactions, copper salts are frequently utilized either as
catalysts or as stoichiometric reagents. The copper(III)/-
1,4-Difunctionalization of 1,3-enynes11 via
pathway is unusual, as is intermolecular 1,4-
a
radical
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Page 2 of 14
copper(I) catalytic cycles proposed in other C-C bond and
group19 as alkylating reagents and internal oxidants,
C-N bond formation reactions,17 have also been frequently
proposed in cyanation reactions.16a-d,16g,16i Notwithstanding
these significant breakthroughs in difunctionalization
cyanation reactions, the 1,4-difunctionalization cyanation
of 1,3-enynes has been only reported once by Liu et al.18 in
work that uses Togni’s reagent. On the basis of our
previous work,19 we envisioned that the allenyl radical
pathway could offer a solution to this type of reaction. In
view of the fact that the structure and reactivity of allenyl
radicals differ from those of the conventional alkene
counterpart, the difunctionalization cyanation of 1,3-
enynes could proceed through some unique reaction
pathway (Scheme 1c). We report in this paper our recent
discovery of copper-catalyzed intermolecular 1,4-
carbocyanation and 1,4-sulfimidocyanation of 1,3-enynes,
reactions that proceed via allenyl radical intermediates
through a radical or radical relay pathway.
acting simultaneously. In addition to behaving as
alkylating reagents and internal oxidants, alkyl diacyl
peroxides can serve as a reagent that could safely release
the cyano group from trimethylsilyl cyanide (TMSCN) or
generate a new radical through a radical relay process.
1
2
3
4
5
6
7
8
Table 1. Optimization of conditions for 1,4-alkylcyanation with
lauroyl peroxide (LPO).a
9
Cat, 5 mol %
C6H13
NC
C11H23
C6H13
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
Ligand, 0-7 mol %
Solvent, 50 oC, 12 h, N2
C
+
+
TMSCN
LPO
OMe
1s
1
OMe
O
N
N
N
N
N
N
N
L3
L1
L2
N
N
N
Scheme 1. Allenyl intermediates and this work.
N
N
Cl
Cl
L4, Phen
L5
L6
a) Natural products containing allenyl skeleton
Me
entry cat.
solvent
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
THF
ligand
-
yield (%)
trace
trace
trace
trace
15%
40%
38%
45%
57%
52%
48%
50%
65%
1
2
Fe(OTf)3
Ni(acac)2
H
C
C
H
COOH
H
H
O
-
-
-
-
N
H
HO
C
H
H
O
3
4
Pd(OAc)2
CoCl2
H
Br
Phomallenic acid C
(-)-Histrionicotoxin 285A
(-)-Panacene
O
Cl
O
HO
C
5
CuTc
OH
H
C
O
6
CuTc
L1
H
OAc
HO
Peridinin
(+)-Scorodonin
7
CuTc
L2
L3
L4
L5
L6
L4
L4
L4
L4
L4
L4
L4
L4
L4
L4
b) Allenyl intermediates in organic synthesis
8
CuTc
9
CuTc
C
C
C
C
C
10
11
CuTc
CuTc
E
[Rad]
Rad
Nu
12
13
14
15
16
17
18
19c
20d
21e
CuI
C
Cu(OAc)2
Cu(OTf)2
CuBr2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
E
Nu
Allenyl cation
Previous arts
60%
62%
46%
Allenyl radical
Rare
Allenyl anion
DCM
Toluene
DCM
DCM
DCM
75%(73%b)
38%
c) This work: 1,4-Carbocyanation and 1,4-sulfimido-cyanation of 1,3-enynes
O
Alkyl
O
20%
55%
50%
Alkyl
O
R3
R3
O
R2
NC
[Cu]
R
+
C
R2
Rf-I
R1
R1
rac-
C
F
a
R = [C] and [N]
via
N
Reaction conditions: 1,3-Enyne (1s), (0.2 mmol), LPO (3 equiv),
PhO2S
SO2Ph
TMSCN (3 equiv), catalyst (5 mol %), and ligand (0 or 7.0 mol %) ,
b
c
solvent (1 mL), 50 oC, 12 h under N2. Yield of isolated product.
room temperature. d 70 oC. e LPO (1.5 equiv), TMSCN (1.5 equiv).
RESULTS AND DISCUSSION
1,4-Alkylcyanation of 1,3-enynes
Our investigation began with the reaction of a 1-(dec-1-en-
3-yn-2-yl)-4-methoxybenzene (1s) with the commercially
available LPO and TMSCN. Details of the optimization of
the conditions are provided in Table 1. The iron, nickel,
palladium and cobalt catalysts that were examined were
not active in this reaction (Table 1, entries 1-4). The
reaction with 5 mol% of copper(I)-thiophene-2-carboxy-
late (CuTc) forms the product in 15% yield (entry 5).
Studies of ligands (entries 6-11) revealed that
Carboxylic acids are inexpensive, stable and non-toxic
feedstock chemicals. An alkyl diacyl peroxide, readily
prepared from carboxylic acids, is a type of activated
carboxylic acid. Such peroxides usually serve as oxidants
and recently have been systematically studied by our
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phenanthroline (L4) improved the yield significantly, the reagents via a radical relay pathway only if the radical
1
2
3
4
5
6
7
8
product being obtained in 57% yield (entry 9).
Optimization of copper catalysts and solvents showed
that Cu(OAc)2 is the optimal metal catalyst and DCM is
the optimal solvent (entry 17). No 1,2-alkylcyanation
product was observed, the sole product being the 1,4-
alkylcyanation product, a tetrasubstituted allene (1)
which is produced exclusively in 73% yield.
relay step is faster than alkyl radical addition to 1,3-enynes.
Surprisingly, with 1.5 equivalents of LPO (entry 5), the
reaction reached essentially full conversion and the 1,4-
perfluoroalkylcyanation product (11) was isolated in 89%
yield. No 1,4-alkylcyanation product (11’) was observed in
this reaction.
Table 3. Optimization of conditions for 1,4-alkylcyanation with n-
C4F9I.a
Table 2. Substrate scope of alkyl diacyl peroxides for 1,4-
9
alkylcyanations.a
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
CuTc, 5 mol %
Phen, 7 mol %
C4F9
C6H13
NC
C11H23
C6H13
NC
R
C6H13
NC
C6H13
C4F9I
C
O
+
Cu(OAc)2, 5 mol %
R
Phen, 7 mol %
DCM, 50 oC, 12 h
TMSCN
C
C
C6H13
+
CH3CN, 50 oC, 12 h
TMSCN
O
+
R
O
O
Additive
11'
Cl
1s
2-10
OMe
Ad
Cl
11s
OMe
Cl
11
not observed
C4H9
OMe
C6H13
C6H13
C6H13
NC
C
entry
additive
/
11, yield (%)b
C
C
NC
NC
1
/
OMe
OMe
3
, 74%
2
3
4
5
6
TBHP(in H2O)
TBHP(in decane)
TBPB
27
15
10
4
7
, 76%
2
, 72%
O
OMe
C6H13
NC
C6H13
NC
C6H13
NC
C
C
C
O
LPO
90 (89, dr=13.5:1) c
80
OMe
, 65%
LPO (1.0 equiv)
OMe
OMe
, 84%
6
5
, 45%
aReaction conditions: 1,3-Enyne (11s, 0.2 mmol), n-C4F9I (1.5 equiv),
C6H13
C6H13
C6H13
C
C
C
additive (1.5 equiv), TMSCN (1.5 equiv), in CH3CN (1 mL), 50 oC.
b
NC
NC
NC
Br
1
c
yields are determined by H NMR. Yield of isolated product in
parentheses.
OMe
OMe
, 55%
OMe
8
, 77%
10
, 76%
9
a Reaction conditions: 1,3-Enyne (1s, 0.2 mmol), alkyl diacyl peroxide
(3 equiv), TMSCN (3 equiv), in DCM (1 mL), 50 oC, yields of isolated
products.
Table 4. Substrate scope of alkyl iodides in 1,4-alkylcyanations.a,b
CuTc, 5 mol %
Phen, 7 mol %
R
C6H13
NC
C6H13
C
The scope of diacyl peroxides as the alkylating reagent
was studied under the optimized reaction conditions and
the results are shown in Table 2. Simple alkyl diacyl
peroxides afford the desired products (2-5) in good (45-
76%) yields. Alkyl diacyl peroxides with additional
functionality such as bromo, alkenyl or ester groups are
well tolerated in this reaction, delivering the
corresponding products (6-10) in 55-84% yield.
+
RI
LPO, 1.5 equiv
TMSCN, 1.5 equiv
CH3CN, 50 oC, 12 h
11s
Cl
Cl
12-18
F
C6H13
NC
C8F17
C6H13
NC
C6H13
NC
CF2CF2OCF2CF2SO2F
CF3
CF3
C
C
C
Cl
, 88%, dr = 18:1
Cl
Cl
13
, 85%, dr = 16:1
12
, 85%, dr > 99:1
14
1,4-Fluoroalkylcyanation of 1,3-enynes
F
F
C6H13
NC
C6H13
CF3
C6H13
NC
C6H13
NC
C3F7
C
CO2Et
C
CO2Et
Cl
C
C
NC
Introduction of fluoroalkyl moieties into commonly used
building blocks has recently been attracting increasing
attention.20 Notwithstanding the recent significant
progress in the fluoroalkylation of unsaturated
hydrocarbons,21 efficient methods for the production of
fluoroalkylated allenes from 1,3-enynes are not known.
We questioned if fluoroalkylated iodides could serve as a
reagent with which to generate fluoroalkylated allenes.
Unfortunately, under the previously defined standard
conditions, no product was observed (Table 3, entry 1)
and in view of the oxidative nature of this reaction,
oxidative additives were studied. t-Butyl hydroperoxide
(TBHP) and t-butyl peroxybenzoate (TBPB) enabled the
reactions, which give the desired products in 10-27% yield
(Table 3, entries 2-4). It was surmised that alkyl diacyl
peroxides could promote this reaction as trifunctional
Cl
Cl
, 75%, dr = 5.3:1
Cl
, 94%, dr = 12:1
18
, 88%, dr = 11:1
15
16
17
, 51%, dr > 99:1
Unsuccessful substrates
O
BocN
CH3I
PhI
I
I
I
21s'
22s'
23s'
19s'
20s'
a
Reaction conditions: 1,3-Enyne (11s, 0.2 mmol), RI (1.5 equiv), LPO
(1.5 equiv) in CH3CN (1 mL), 50 oC, 12 h under nitrogen atmosphere. b
Yield of isolated product.
The scope of fluoroalkylated iodides under the optimized
reaction conditions was studied and the results are shown
in Table 4. Perfluoroalkyl iodides afford products 12-15 in
85-94% yield with diastereoisomeric ratios ranging from
12:1 to 99:1. Interestingly, trifluoromethyl iodide (CF3I) can
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noe
C10H21
be used to introduce a CF3 group into the 1,3-enyne and
the product (16) can be isolated in 75% yield with a dr
value of 5.3:1. Iodoacetates can also participate in this
reaction, giving products 17 and 18 in 51% and 86% yield,
respectively. Other alkyl iodides (19s’-23s’) are not
reactive under these conditions.
With these conditions in hand, we investigated the scope
of 1,3-enynes and the results are shown in Table 5. The
substrate scope of the reactants is broad, producing the
corresponding products 24-36 in up to 94% yield. Many
functional groups, including -OH and -NHBoc are
tolerated, giving products 35-36. Double 1,4-fluoro-
alkylcyanation of 37s occurred and the product (37) was
isolated in 68% yield as a single isomer.
H2SO4, 1 mL
CH3CH2OH, 0.1 mL
C6H13
NC
C11H23
H
1
2
3
4
5
6
7
8
C
H
H
H
noe
noe
30 oC, 1 h
H
HO
NC
OMe
C5H11
1
38
, 43%
O
C6H13
CN
O
CF3COOH, 3 equiv
DCM, 6 mL
rt, overnight
C5H11
H
1s
H
OMe
O
9
noe
O
As for Table 5
55%, 4.7 mmol
I
40
, 83 %, Z/E = 2.5:1
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
OH
O
O
OH
C6H13
NC
O
C6H13
NC
I2, 1.5 equiv
K2CO3, 1.0 equiv
C
I
cyclohexane/DCM (2/1, 1 mL)
rt, overnight
O
39
41
, 93 %
C4F9
OMe
Table 5. Substrate scope of 1,3-enynes for 1,4-fluoroalkylcyanation.a,b
O
CuTc, 5 mol %
Phen, 7 mol %
CO2Et
F
F
R2
F
F
H
H
H2SO4, 2 mL
rt, 1 h
C4F9
O
+
R2
C
C
C
I
LPO, 1,5 equiv
TMSCN, 1.5 equiv
R1
Me
NC
R1
H2N
NC
Me
O
1 equiv
1.5 equiv
42
43
, 61%
CO2Et
F
F
CO2Et
F
F
C4F9
F
CO2Et
F
F
CO2Et
F
F
Et
Ph
H2SO4, 1 mL
C
C
C
C
CH3CH2OH
rt, 10 min
NC
Me
NC
Ph
NC
Ph
NC
Ph
27
, 85%
C6H13
C6H13
CN
45
24
25
26
, 94%
, 54%
, 71%
Ph
, 55%
CO2Et
F
F
CO2Et
F
F
CO2Et
F
F
CO2Et
F
F
CuCl, 10 mol %
dppbz, 12 mol %
B2pin2, 3 equiv
As for Table 5
85%, 7 mmol
C6H13
C6H13
C6H13
NC
C6H13
NC
Bpin
C4F9
C4F9I
C6H13
NC
C
C
C
C
NC
NC
LiOtBu, 3 equiv
DMA, rt, 12 h
OMe
Ph
C6H13
NC
C4F9
Ph
O
C
46
, 42%
OMe
MeO
Ph
28
29
, 83%
, 70%
31
, 79%
30
, 86%
I
C6H13
NC
44
C4F9
CO2Et
F
F
NIS, 3 equiv
C6H13
NC
CO2Et
F
F
CH3CN, 80 oC, 36 h
Ph
47
, 81%
CO2Et
F
F
C
C6H13
CO2Et
F
F
C6H13
NC
C
Ph
C
NC
C
NC
OH
S
32
33
34
35
, 73%
, 43%
, 31%
, 69%
EtO2
C
F
CO2Et
F
F
1,4-Sulfimidocyanation of 1,3-enynes
CO2Et
F
F
F
Ph
C
C
NC
C
C6H13
NC
NHBoc
C6H13
C6H13
C6H13
CN
C-C and C−N bonds are two of the most ubiquitous
natural chemical bonds.23,24 The introduction of both
carbon and nitrogen functionalities into 1,3-enynes,
generating allenes is unprecedented. We envisioned that
the allenyl radical pathway could lead to amine-
containing allene motifs. N-fluorobenzenesulfonimide
(NFSI) has been shown by Zhang and others16a,25 to be a
very useful amination reagent. Accordingly, we studied
the 1,4-sulfimido-cyanation of 1,3-enynes with NFSI and
TMSCN.
After comprehensive optimization of conditions, the
optimal reaction conditions were confirmed and the 1,4-
sulfimidocyanation product (48) was obtained in 73%
yield in presence of CuTc (for details, see Table S1 in
Supporting Information - SI). With these conditions in
hand, we investigated the scope of 1,3-enynes (Table 6).
Reactions of disubstituted 1,3-enynes afford tri- and tetra-
substituted allenes (48-54) in moderate yields. Both R1
and R2 can be alkyl or aryl groups. Hydroxyl and amino
groups are tolerated (53 and 54). Reactions of
trisubstituted 1,3-enynes can deliver tetrasubstituted
allenes (55-83), whose synthesis otherwise could be
challenging. When both R1 and R2 are aryl groups and R3
is an alkyl group, the corresponding products (55-60) are
c
36
37s
, 68%
37
, 68%
a
Reaction conditions: 1,3-Enyne (0.2 mmol), RI (1.5 equiv), LPO (1.5
equiv) in CH3CN (1 mL), 50 oC, 12 h under N2. Yield of isolated
b
product. c 6 equiv of LPO and 6 equiv of TMSCN were used.
Synthetic applications of this methodology for
carbocyanation of 1,3-enynes have been demonstrated and
are shown in Scheme 2. Under acidic conditions, the
allene (1) was isomerized to the diene (38) in 43% yield.
Lactones 40 and 4122 were prepared in high yields from
allene 39 which is generated from the 1,3-enyne (1s) in
one step with iodoacetic acid. Interestingly, the allene (42)
with a perfluoroalkyl group selectively produced the
allenyl amide (43) in 61% yield under similar acidic
conditions, while phenyl allene (44) delivered a fused ring
compound (45). The allene (44) could also be easily
transformed into vinyl-Bpin (46) and conjugated vinyl
iodide (47) in 42% and 81% yield, respectively.
Scheme 2. Synthetic applications for carbocyanation products.
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Page 5 of 14
Journal of the American Chemical Society
obtained in moderate to high yields. Heteroaromatic chloro (61, 66-79), cyclopropyl (62), alkynyl (74), bromo
1
2
3
4
5
6
7
8
compounds such as thiophene can be used in the reaction
(58). Reactions of electron-deficient 1,3-enynes tend to
give the desired products in better yields (55, 56 vs. 57-63).
All the reactions deliver the corresponding products with
high diastereoisomeric selectivity, single diastereoisomers
being obtained in most cases. Subsequently, we
investigated the cases in which R1 is an aryl group, and R2
and R3 are alkyl groups. Additional functionalities such as
(76), ester (77), or alkenyl (78) are well tolerated in the
reaction. The diastereoselectivity of these reactions is
excellent and products are isolated in most cases as a
single diastereoisomer. Interestingly, when R1 of the
trisubstituted 1,3-enynes is an alkyl group (80-83) the dr
values drop dramatically. The structures of products 49,
62, 76, 83, and 83’ were confirmed by X-ray
crystallographic analysis.
9
Table 6. Substrate scope of 1,3-enynes for 1,4-sulfimido-cyanations.
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
R3
R3
CuTc
, 5 mol %
R2
NC
[N]
Phen,
7 mol %
CN
+ TMS
NFSI
+
R2
C
CH3CN, 12 h
R1
R1
[N] = N(SO2Ph)2
rac-(48-83)
R3 = H
C5H11
C5H11
H
[N]
Cl
Et
[N]
Ph
[N]
Ph
NC
[N]
[N]
[N]
[N]
C
C
C
C
C
C
C
, 53%
NC
Me
NC
Me
NC
NHBoc
OH
NC
Ph
56%
NC
Cy
X-ray
NC
50
Me
a
48
49
52,
53
54
, 36%
, 73%
, 65%
, 60%
51
, 54%
R1 = Aryl; R2 = Aryl; R3 = Alkyl
Ph
Cl
Me
S
Me
Me
Me
Me
Me
[N]
[N]
Ph
[N]
[N]
Me
[N]
F
Cl
C
C
C
[N]
C
C
NC
NC
NC
Ph
C
NC
NC
NC
Ph
F
Cl
F
55
56
57
58
59
60
, 82%, dr > 99:1
, 80%, dr > 99:1
, 63%, dr > 99:1
, 50%, dr > 99:1
Me
, 48%, dr > 99:1
, 75%, dr > 99:1
R1 = Aryl; R2 = Alkyl; R3 = Alkyl
Me
[N]
C
Cl
Me
Cl
Me
Me
[N]
C
C5H11
[N]
F
Me
Cy
NC
[N]
[N]
C5H11
C
[N]
C
C
NC
NC
C
Ph
NC
Ph
NC
Ph
NC
Ph
X-ray
F
61
62
63
64
65
66
, 84%, dr > 99:1
, 74%, dr > 99:1
, 50%, dr > 99:1
, 76%, dr > 99:1
, 70%, dr > 99:1
, 75%, dr > 99:1
R1 = Aryl; R2 = Alkyl; R3 = Alkyl
Cl
Cl
Cl
Cl
Et
Me
Cl
Me
Me
Et
Et
C5H11
[N]
Cl
Cl
[N]
[N]
[N]
[N]
C
[N]
C
C
C
C
NC
C
NC
NC
NC
Ph
NC
Ph
NC
Ph
CF3
Me
70
, 71%, dr > 99:1
69
Cl
72
, 72%, dr > 99:1
, 70%, dr > 99:1
68
71
67
, 80%, dr > 99:1
, 64%, dr > 95:5
Cl
, 75%, dr > 99:1
Cl
CO2Me
Cl
Me
Br
[N]
Cl
C10H21
[N]
7
[N]
Cl
2
[N]
[N]
C
[N]
C
C
C
NC
C
NC
C
NC
NC
NC
Ph
NC
Ph
5 mmol, 78%
75
X-ray
Cl
, 81%, dr > 99:1
Cl
Cl
Cl
, 60%, dr > 99:1
74
76
, 81%, dr > 99:1
, 55%, dr > 99:1
77
, 69%, dr > 99:1
73
, 65%, dr > 99:1
78
R1 = Alkyl; R2 = Alkyl or Aryl; R3 = Alkyl
Cl
C10H21
[N]
ClC3H6
Et
C5H11
NC
Et
Ph
Me
[N]
Ph
C
NC
[N]
C
Ph
[N]
C
C
NC
C
C
NC
and
Two X-ray
NC
Me
Pr
NC
Pr
[N]
[N]
80
81
82
83
83'
and , 64%, dr = 1.1:1
, 76% dr = 2.2:1
, 50%, dr = 3:1
, 77%, dr = 2.2:1
79
, 30%, dr > 99:1
ACS Paragon Plus Environment

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o
Reaction conditions: 1,3-Enyne (0.5 mmol), NFSI (1.5 equiv), TMSCN (1.5 equiv), in CH3CN (2 mL), rt-50 C, 12 h under N2. Yield of isolated
product. a Reaction was performed at 80 oC.
1
2
3
Scheme 3. Synthetic applications of nitrogen-containing allenes.
Mechanism studies
4
5
6
7
8
9
Et
NHSO2Ph
Et
[N]
(i)
C
C
Scheme 4. Plausible catalytic cycle for the 1,4-alkylcyanation of 1,3-
enynes.
H2N
Me
X-ray
NC
Me
O
48
84
, 65%
O
H
NHSO2Ph
H
NHSO2Ph
(iii)
(ii)
R3
H
[N]
O
R
R2
C
C
R3
R
O
C
R
H2N
NC
Me
Me
LCu(I)
C
NC
Me
O
R3
R1
Product
O
R2
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
NC
R
A
86
49
85
, 72%
, 52%
R2
R1
CO2
R1
R
C
Radical addition
R3
CN
L(III)Cu
R1
R
Cl
R1
O
LCu(II)OCOR
Tautomerism
C
[N]
B
R2
R1
C
conditions
R3
F
NC
TMSCN
Cl
R2
R
R3
R
O
R2
C
NH2
LCu(II)CN
R2
R
Si
R1
R2
C
O
E
R1
D
, allenyl radical
D
Me
O
Me
O
Et
O
Based on previous findings in cyanation reactions,16
a
Cl
Cl
Cl
Me
plausible mechanism for this reaction is proposed in
Scheme 4. The reaction is initiated by a single electron
transfer from the copper(I) catalyst (A) to an alkyl diacyl
peroxide generating an alkyl radical (R•) and a copper(II)
complex (B). The alkyl radical (R•) generated in this way
adds to the 1,3-enyne, giving the allenyl radical (D).
Similar to previous reported cyanation reactions,16f,16g the
copper complex B can exchange the ligand with TMSCN
to generate the Cu(II)CN complex (E). E subsequently
couples with the allenyl radical (D) to generate the
copper(III) intermediate (F), which readily undergoes
reductive elimination. Finally, the product is released and
the copper (I) catalyst is regenerated. This mechanism is
straightforward, but the observed high diastereo-
selectivity raises the question as to how a remote chiral
center at allenyl group of D or F can control the
stereoselectivity of the C-C coupling in these cyanation
reactions. Mechanistic studies were undertaken to obtain
an answer to this question.
First, radical scavenger and radical clock studies were
conducted in an effort to find evidence of allenyl radicals.
As shown in Scheme 5, the 1,4-carbocyanation reaction
was chosen as the example. Upon addition of three
equivalents of the radical scavenger TEMPO (2,2,6,6-
tetramethylpiperidine-1-oxyl) into a standard reaction, no
reaction ensues and no desired product is observed
(Scheme 5a), indicating involvement of a radical pathway
in the reaction. Further verification of the existence of the
radical C using a radical clock experiment was initiated
with an 1,3-enyne (92) in which R1 is a cyclopropyl group
(Scheme 5b). Under the standard conditions, no ring-
opening product (93’) is observed and the cyclic product
(93) was isolated in 40% yield. We suspected that the
ring-opening of this specialized cyclopropane is not fast
because the neighboring phenyl group (R2) may stabilize
the allenyl radical D by resonance. We then prepared
substrate 94 and examined it in the ring-closing reaction
which was expected to be faster.27 With a catalytic
amount of Cu(OAc)2, products 95 and 96 were isolated in
NH2
NH2
NH2
87
61
88
69
89
70
, 47%, from
, 61%, from
with condition (iv)
, 50%, from
with condition (v)
with condition (v)
Cl
Me
H
Me
N
O
[N]
(vi)
C
Cl
NC
X-ray
61
90
, 41%
Cl
Me
NC
CN
[N]
Me
Cl
(vii)
C
NC
61
91
, 90%
Reaction conditions: (i) 1 mL of conc. H2SO4, rt, 2 h. (ii) 1 mL of conc.
o
o
H2SO4, 10 C, 2 h.(iii) 0.5 mmol, 2 mL conc. H2SO4, -10 C, 8 h. (iv) 1
mL of conc. H2SO4, -16 oC, 12 h. (v) 1 mL of conc. H2SO4, 0 oC, 12 h. (vi)
o
1 mL of conc. H2SO4, 0.5 mL of H2O, 90 C, 12 h. (vii) 5 mol % of
Pd(PPh3)4, 1.5 equiv of TMSCN, THF, 80 oC, 5 h.
Synthetic applications of nitrogen-containing tri- or tetra-
substituted allenes have been demonstrated and are
shown in Scheme 3. A tetrasubstituted allene (48) and a
trisubstituted allene (49) can be successfully converted
into the corresponding amides (84, 85) in the presence of
H2SO4. One of the sulfonyl groups of N(SO2Ph)2 is
simultaneously deprotected. When the temperature was
decreased to -10 oC, the cyano group remained untouched,
affording the cyano allene 86 in 52% yield. Under similar
reaction conditions, substrates 61, 69, and 70 with a
phenyl group attached to the allene molecule, produces 1-
naphthylamines (87-89) in moderate yields. This type of
transformation has not been published previously. When
the reaction is performed in aqueous H2SO4, the
tetrasubstituted allene (61) produces a pyridin-2(1H)-one
(90) in 41% yield. With palladium as the catalyst, the
allene (61) produces compound 91 in 90% yield.26 The
structures of products 84 and 90 were confirmed by X-ray
crystallographic analysis.
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Reaction conditions
as for Table 2
C6H13
NC
C11H23
C6H13
O
C11H23
C6H13
C11H23
50% and 25% yield, respectively (Table 7, entry 1). This
C
C
1s
MeO
1
2
3
4
5
6
7
8
suggests that allenyl radicals are indeed generated in situ.
The reaction rate of the coupling of allenyl radical with
Cu(II) complex is comparable to that of the radical
cyclization. To assess the presence of the copper cyanide
complex (E), CuCN was utilized as the source of both the
copper and the cyano source. Interestingly, the
uncyclized product (96) was isolated or observed as the
only or the dominant product in most cases when a
stoichiometric quantity of CuCN was added (Table 7,
+
+
additive, 5 equiv
OMe
OMe
OMe
1'
1''
1
entry
additive
none
1
1’
/
1’’
/
1
73%
71%
69%
2
3
H2O
0
/
/
MeOH
0
9
entries 2,
4
and 6). Control experiments with
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
Table 9. Probe experiments for the allenyl cation with NFSI
Cu(OAc)2/TMSCN were also conducted (Table 7, entries 3
and 5). Different product ratios are observed for the two
copper complexes. On the basis of the results in Table 7,
it is probable that the catalytic reaction with
Cu(OAc)2/TMSCN proceeds through a different pathway
compared with the reaction that starts with CuCN. To
further confirm that this reaction goes through an allenyl
radical rather than an allenyl cation, ten allenyl cation
trapping experiments were done with two different 1,3-
enyne substrates 1s and 48s. No water or CH3OH adduct,
which could prove the formation of the allenyl cation was
ever observed (Tables 8, 9 and SI). Considering all of
these results together, the allenyl radical pathway is
preferred over the allenyl cation pathway.
Reaction conditions
as for Table 6
Et
[N]
Et
[N]
Et
[N]
48s
+
+
C
C
additive
NC
Me
O
Me
MeO
Me
[N] = N(SO2Ph)2
48
48'
48''
entry
additive
none
48
48’
/
48’’
/
1
73%
71%
71%
69%
64%
2
3
4
5
H2O, 10 equiv
H2O, 0.5 mL
0
/
0
/
MeOH, 10 equiv
MeOH, 0.5 mL
/
0
/
0
Scheme 5. Radical trapping and ring-opening experiments
Density functional theory (DFT) calculations on the 1,4-
alkylcyanation of 1,3-enynes were performed in an effort
to understand the mechanism at the atomic level. Figure 1
depicts the overall potential energy surface of the Cu-
catalyzed reaction.28 The copper catalyst, Cu-1, a complex
a) With TEMPO
C6H13
NC
C11H23
C6H13
Reaction conditions as for Table 2
TEMPO, 3 equiv
C
1
OMe
1s
OMe
of CuTc with
a ligand, 1,10-phenanthroline (L), is
not observed
b) Ring-opening experiment
considered to be the active catalyst, since 30 min pre-
coordination was conducted in the experiment. Initially,
oxidation of Cu-1 with hexanoic peroxyanhydride (HPO),
results in a hexanoyloxyl radical (INT1) and a Cu(II)
complex (INT2) appended to a hexanoate. A high
exergonicity (23.7 kcal/mol) indicates that the oxidation
MeOOC
Ph
O
O
Cu(OAc)2, 5 mol %
Phen, 7 mol %
Ph
Ph
OMe
O
+
MeO
C
2
DCM, 50 oC, 6 h
TMSCN
O
NC
NC
92
93
93', not observed
, 40%
process
is
thermodynamically
favorable.
The
Table 7. Ring-closing experiments
transformation of radical INT1 to an allenyl radical INT5
is shown in the SI (Figure S9). The generated
hexanoyloxyl radical (INT1) undergoes decarboxylation
(TS5), leading to an alkyl radical (INT7) with a quite low
barrier (3.4 kcal/mol). Subsequently the alkyl radical
reacts with a 1,3-enyne to form an allenyl radical, INT5, in
a step which is exergonic by 24.4 kcal/mol and has a free
energy barrier of 11.0 kcal/mol. The potential energy
surface for the formation of the allenyl radical is similar to
that reported in our previous publication.19a On the basis
of the calculation concerning the oxidation process, the
presence of A, B, C and D in the proposed mechanism
(Scheme 4) are reasonable.
Next, we focused on the cyanide exchange step.
Complexation of TMSCN with INT2 to form intermediate
INT3, was calculated to be endergonic (5.1 kcal/mol
uphill), suggesting that the approach of TMSCN may be
hindered due to the bulk of the trimethylsilyl group of
TMSCN. Interestingly, a cyanide exchange transition state,
TS1, is located with a free energy barrier of 26.6 kcal/mol
[Cu], X mol %
Phen, Y mol %
C11H23
+
Ph
C11H23
C
CN
95
C
Me
LPO, 3 equiv
Me
Me
NC
Ph
DCM, 50 oC, 12 h
Ph
94
96
entry [Cu]
Phen
(mol %)
7
TMSCN 95
96
1
Cu(OAc)2,
5 mol %
3 equiv
50% 25%
2
3
CuCN, 3 equiv
420
420
/
0
0
33%
0
Cu(OAc)2,
3 equiv
3 equiv
4
5
6
CuCN,
140
42
/
0
23%
100 mol %
Cu(OAc)2,
30 mol %
CuCN,
3 equiv
/
28% 36%
1% 4%
42
30 mol %
Table 8. Probe experiments for the allenyl cation with LPO
ACS Paragon Plus Environment

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leading to an isocyanocopper complex INT4.29 The
formation of INT6 in which the exergonicity of INT6 is
1
2
3
4
5
6
7
8
linearity of Si-C-N and the bulk of TMS forces the
exchange to occur via a seven-membered ring transition
state TS1, in which ring strain is relaxed (Figure S10).
Moreover, transition state TS1-F, is also identified, further
confirming the generation of isocyanocopper complex
INT4 as well as the generation from TS1. It is noteworthy
that an isocyanocopper complex is still delivered via the
cyanide exchange transition state, TS1-F, when the other
radical initiator, NFSI, is employed (See Figure S10 and
Figure S11 in SI for more details).
The reaction pathway in which the allenyl radical couples
directly with the terminal carbon atom of isocyanide in
INT4 was then considered. A triplet transition state TS2 is
found for the cyanation of the allenyl radical with a 22.0
kcal/mol barrier. Unlike the Cu(III) mechanism proposed
in the literature,16a-d,16f,16i the linear allenyl radical in TS2
couples directly with the terminal carbon of the
isocyanocopper(II) complex.30 In this manner, Cu(II)
accepts one electron from isocyanide, forming Cu(I)31 via
an outer-sphere pathway.32 As an alternative, the other
cyanation processes originating from an accepted
cyanocopper complex should also be considered. A
transition state TS3 corresponding to the CN flipping is
also located with an 11.4 kcal/mol barrier leading to
5.7 kcal/mol relative to INT4. Although the cyanocopper
complex (INT6) is more thermodynamically favored than
the isocyanocopper complex (INT4), TS4 faces a much
higher barrier (35.5 kcal/mol) to access the cyano-
substituted allene.
On the basis of DFT studies, an alternative reaction
mechanism, involving isocyanocopper, for the 1,4-
alkylcyanation of 1,3-enynes is revealed.
To support the results from DFT studies, further control
experiments were conducted. First, in order to verify the
ligand exchange step between the copper(II) species
(INT2) and TMSCN, the reaction solution was examined
by GC-MS. As predicted by the DFT calculation in Figure 1,
the trimethylsilyl carboxylate (C11H23COOSiMe3) was
observed in GC-MS when LPO was used, supporting the
hypothesis that the cyanide arises from TMSCN exchange
with the carboxylate. Second, because the DFT studies
predict the formation of the isocyanocopper species, a
series of infrared spectroscopy studies were carried out to
examine the existence of an isocyanocopper species. A
regular solution in DCM, with the same concentration in
the reaction conditions, and a 10 times more concentrated
solution of 1,10-Phen ligand and Cu(OAc)2 treated with 10
equivalents of TMSCN was examined by IR spectroscopy
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
C5H11
)
e
M
(
3
i
S
C5H11
C
O
Ar
N
C
C6H13
N
C
Ar
O
N
N
C5H11
C6H13
N
N
Cu
O
C
N
C
O
Cu
N
Cu
O
N
O
O
2-th
TS1
N
N
O
2-th
Cu
O
2-th
2-th
TS4
O
TS2
TS1
2.9
TS4
-0.5
Cu-1
0.0
N
OSi(Me)3
C5H11
N
C
O
Cu
O
TS2
-8.3
O
N
O
C5H11
O
2-th
INT3
2
TS3
-18.6
INT5
TMSCN
INT5
O
TS3
-18.9
C5H11
INT1
O
INT4
-30.3
INT2
-23.7
Cu-1
INT6
)
e 3
M
(
i
S
-36.0
C
N
C5H11
C5H11
C
N
O
N
O
O
Cu
O
N
N
O
N
N
O
C
N
Cu
N
Cu
Cu
O
O
N
N
O
O
O
O
2-th
2-th
Cu-1
2-th
P
2-th
INT3
INT2
-61.0
INT4
INT6
C6H13
C5H11
Ar
C
C
O-
O-
2-th
N
N
N
Ar
N
N
O
=
P
O
C6H13
C
INT5
=
=
S
C5H11
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Figure 1. The Gibbs free energy profile for the Cu-catalyzed alkylcyanation. A simplified hexanoic peroxyanhydride is employed in place of LPO
to reduce the computational demand and the complexity of the conformational space. Relative free energies are in kcal/mol.
1
2
3
4
5
6
7
8
9
(Figure 2). Two peaks at 2154 and 2132 cm-1 were observed
in the solution and remained unchanged for 60 min.
However, in the 10 times more concentrated solution, a
new peak at 2088 cm-1 was observed in the first few
minutes, and then subsequently decreased to a much
smaller peak. According to reported works,33 we
tentatively assigned the peak of 2088 cm-1 to an
isocyanocopper species,29c,34 and those at 2154/2132 cm-1 to
a cyanocopper species, which arise from tautomerization
of the isocyanocopper species. More details of the
computational predictions for CN stretching frequencies
are discussed in the Computational Method and Details
section in the SI.
selected as the models with which to study the
diastereoselectivity, because of their dramatically
different dr selectivity.35 Figure 3(a) and (b) shows the
four transition states TS2-nS and TS2-nR (n = 63 and 81),
which determine the diastereoselectivity. The free energy
difference between TS2-63S and TS2-63R is 5.8 kcal/mol,
and between TS2-81S and TS2-81R is 2.0 kcal/mol. The
trend is consistent with the experimental observation that
much higher dr selectivity is achieved when R1 is an aryl
group. Interestingly, in TS2-63S and TS2-63R, an apparent
π-π stacking interaction was found between the phenyl
group and the 1,10-phenanthroline ligand. Such stacking
forces the linear allenyl radical to adopt a pose in which
the remote chiral center is close to the ligand. The energy
of TS2-63R is therefore greater because of the repulsion
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16
17
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O
TMSCN, 10 equiv
rt
+
?
Cu(OAc)2
N
Si
between
the
substituents,
R1
and
R3.
+
O
N
Observed by GC-MS
Distortion/interaction analysis (Figure S12) was also
investigated to determine the contributive factor of the
energy difference. The examination reveals that the
repulsion between R1 and R3 causes the distortion of
radical and reduces the π-π interaction between the
ligand and the phenyl group (R1). On the other hand,
when R1 is an alkyl group, the allenyl group may adopt
more orientations in TS2-81 due to the absence of the π-π
stacking interaction. The lowest energy transition states
for S and R are shown in Figure 3(b). The flexibility of the
allenyl radical may orient the remote chiral center away
from the copper complex and consequently decrease the
discriminatory effect. So far, the pathway through
isocyanocopper intermediate without a chiral ligand
explains the diastereoselectivity well while the substituent
R1 is an aryl group and the initial radical is bulky.
Calculation of the 1,4-fluoroalkylcyanation of 16 and 17
based on the π-π stacking model is also consistent with
the experimental observations (Figure S13).
2088 cm-1
New peak
(a) 0 min
10 times concentrated
2088 cm-1
(b) 60 min
10 times concentrated
Disappearing
(c) 0-60 min
Standard concentration
Figure 2. IR studies for the ligand exchange step.
(a)
1.99
2.22
2.26
[N]
1.95
1.98
*
*
[N]
R2
TS2-63R
R2
TS2-63S
0.0
5.8
Scheme 6. Revised plausible catalytic cycle for the 1,4-alkylcyanation
of 1,3-enynes.
(b)
O
R3
O
R
R2
R
R
R
O
C
[N]
LCu(I)
O
[N]
R1
NC
A
*
CO2
*
R3
R3
R
2.06
2.06
N
N
R2
R2
R2
R
LCu(II)OCOR
C
Cu(II)
=
B
R1
LCu(II)
F'
TS2-81S
TS2-81R
C
H
C
X
N
C
N
0.0
2.0
R1
TMSCN
R3
R2
Figure 3. Optimized structures of (a) TS2-63S and TS2-63R and (b)
TS2-81S and TS2-81R with relative free energies in kcal/mol. For
clarity, the majority of the hydrogen atoms are omitted. N(SO2Ph)2
and n-pentyl groups are simply depicted as a blue ball with symbol
[N] or a gray ball with symbol R2, respectively. Distances shown in
Figure are in Ǻ.
DFT
R
O
NC
LCu(II)
E'
TS accounts for the high
diastereoselectivity
controlled by the remote
chiral center
Si
R3
R2
O
R
GC-MS
DFT, IR
R2
C
R1
, allenyl radical
radical scavenger &
radical clock
D
With these encouraging results from the IR spectroscopy
studies that suggest the presence of the isocyanocopper,
we next investigated whether this isocyanocopper
Based on these mechanistic studies,
a revised
mechanism is proposed in Scheme 6.31-32 The
isocyanocopper species (E’) was predicted and observed.
More interestingly, a novel cyanation transition state (F’),
in which the linear allenyl radical couples with the
mechanism
can
account
for
the
observed
diastereoselectivity of the reactions. Substrates 63 and 81,
in which R1 is a phenyl or propyl group, respectively, were
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Page 10 of 14
XDB20000000), the Haixi Institute of CAS (CXZX-2017-P01),
the Shenzhen Basic Research Program
(JCYJ20170412150343516) for financial support. We thank
Professor Weiping Su, Daqiang Yuan and Gang Xu from our
institute for X-ray structural analysis. We thank Dr. G. W. A.
Milne for his writing suggestions.
terminal carbon of isocyanocopper, was revealed. This
transition state accounts for the high diastereoselectivity
controlled by the remote chiral center.
1
2
3
4
CONCLUSION
5
6
7
8
9
REFERENCES
Copper-catalyzed 1,4-alkylcyanation, 1,4-fluoroalkylcyan-
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trifunctional reagents which are the key to the 1,4-
carbocyanation while N-fluorobenzenesulfonimide is the
key to the 1,4-sulfimidocyanation. Broad substrate scope
and excellent functional group tolerance are observed in
this reaction. Many synthetically challenging allenes are
readily available from these methods and diverse
transformations of allene products are being pursued for
the synthesis of a variety of complex molecules. Distinct
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formation of an isocyano-copper(II) species which is
responsible for the next diastereoselective cyanation step.
This study should shed some light on the study of copper
catalyzed cyanation reactions.
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ASSOCIATED CONTENT
Supporting Information
Data for the crystal structures reported in this paper have
been deposited at the Cambridge Crystallographic Data
Centre (CCDC). 49 (CIF, CCDC 1588172), 62 (CIF CCDC
1587985), 76 (CIF, CCDC 1588594), 83 (CIF, CCDC 1588011),
83’ (CIF, CCDC 1588174), 84 (CIF, CCDC 1588171), and 90
(CIF, CCDC 1588173). Copies of these data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif. All
other data are available within the paper and its
Supplementary Information files, or from the corresponding
authors upon request.
Supplementary information and chemical compound
information are available free of charge on the ACS
Publications website. Correspondence and requests for
materials should be addressed to H. B.
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AUTHOR INFORMATION
Corresponding Author
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Rearrangement
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* E-mail: hlbao@fjirsm.ac.cn;
* E-mail: zhangxh@pkusz.edu.cn
Author Contributions
§X. Zhu, W. Deng and M. Chiou contributed equally.
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
We thank the National Key R&D Program of China (Grant
No. 2017YFA0700103), the NSFC (Grant Nos. 21502191,
21672213, and 21871258), the Strategic Priority Research
Program of the Chinese Academy of Sciences (Grant No.
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mechanism are shown in Figure S7 and discussed in the Si. For
the sake of clarity, only the most relevant part is shown in Figure
1.
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of
Alkenes
to
Versatile
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or Lower Order Lithium Cyanide (LiCN) Modified Gilman
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Amination of Unactivated Terminal Olefins Via an Ene
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Cu(II) and Ni(II) Complexes: Synthesis, Structure, Magnetism,
and Density Functional Theoretical Study. Inorg. Chem. 2001, 40,
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1
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4
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Spectroscopic and Theoretical Studies of Group
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(35) For comparison, methyl group is taken as the substituent R3
7
instead of ethyl to mimic the product 81.
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Allenyl radical
R3
O
R3
Alkyl
1
O
R3
Alkyl
O
R1
C
R2
NC
R2
R
O
2
3
4
R2
+
C
N
C
R1
Rf-I
R1
or
N
Cu
rac-
N
Functional groups:
OH, NHBoc, Br, Cl,
O
F
O
or
PhO2S
R = [C] and [N]
N
R'
alkenyl, alkynyl, ester,
ketone, etc.
SO2Ph
Versatile model for the
synthesis of allenes
Cyano or isocyano,
that is a question!
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