Copper-catalyzed aerobic radical C-C bond cleavage of N-H ketimines

Article abstract of DOI:10.3762/bjoc.11.209

We report herein studies on copper-catalyzed aerobic radical C-C bond cleavage of N-H ketimines. Treatment of N-H ketimines having an α-sp³ hybridized carbon under Cu-catalyzed aerobic reaction conditions resulted in a radical fragmentation with C-C bond cleavage to give the corresponding carbonitrile and carbon radical intermediate. This radical process has been applied for the construction of oxaspirocyclohexadienones as well as in the electrophilic cyanation of Grignard reagents with pivalonitrile as a CN source.

Full text of DOI:10.3762/bjoc.11.209

Copper-catalyzed aerobic radical C–C bond cleavage
of N–H ketimines
Ya Lin Tnay, Gim Yean Ang and Shunsuke Chiba*§
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2015, 11, 1933–1943.
Division of Chemistry and Biological Chemistry, School of Physical
and Mathematical Sciences, Nanyang Technological University,
Singapore 637371, Singapore
doi:10.3762/bjoc.11.209
Received: 23 July 2015
Accepted: 23 September 2015
Published: 19 October 2015
Email:
Shunsuke Chiba* - shunsuke@ntu.edu.sg
This article is part of the Thematic Series "Copper catalysis in organic
synthesis".
*
Corresponding author
§
Fax: +65-67911961; Tel: +65-65138013
Guest Editor: S. R. Chemler
Keywords:
C–C bond cleavage; copper; ketimines; molecular oxygen; radical
© 2015 Tnay et al; licensee Beilstein-Institut.
License and terms: see end of document.
Abstract
We report herein studies on copper-catalyzed aerobic radical C–C bond cleavage of N–H ketimines. Treatment of N–H ketimines
having an α-sp3 hybridized carbon under Cu-catalyzed aerobic reaction conditions resulted in a radical fragmentation with C–C
bond cleavage to give the corresponding carbonitrile and carbon radical intermediate. This radical process has been applied for the
construction of oxaspirocyclohexadienones as well as in the electrophilic cyanation of Grignard reagents with pivalonitrile as a CN
source.
Introduction
Alkylideneaminyl radicals (iminyl radicals) have been utilized metals [28-32], electron-rich organic electron donors [33-38], or
for the synthesis of azaheterocycles through an intramolecular sensitized photolysis [39-42] (Scheme 1c). Although the oxida-
N–C bond formation with the unsaturated systems [1-6]. As tive generation of iminyl radicals has also been reported, only
precursors of iminyl radicals, readily available oximes and their iminooxyacetic acids have been used as the precursors when we
derivatives have commonly been utilized. The generation of started our studies on the oxidative reactions of N–H ketimines
iminyl radicals involves the homolysis of the N–O bond with [43-49] (Scheme 1d).
radical initiators [7-15] (Scheme 1a) or using thermal [16-20] or
photoreaction conditions [21-27] (Scheme 1b). An alternative The generation of iminyl radicals by single-electron oxidation
route to iminyl radicals is the single-electron reduction of oxime of N–H ketimines appears to be the most atom economical
derivatives mediated by the appropriate lower valent transition method, since only protons (H+) are produced along with the
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Beilstein J. Org. Chem. 2015, 11, 1933–1943.
Scheme 1: Generation of iminyl radicals from oxime derivatives.
iminyl radicals (Scheme 2). However, the instability of N–H Recently, we have studied the chemical reactivity of N–H
ketimines [50] limits their use as starting materials.
ketimines towards copper-catalyzed aerobic reaction conditions
51-53]. In these studies, we employed the nucleophilic addi-
[
tion of Grignard reagents to carbonitriles followed by protona-
tion as one of the methods for in situ generation of N–H
ketimines, which were directly subjected to Cu-catalyzed
aerobic reactions without further purification [54]. In this way,
biaryl N–H ketimines generated from biaryl-2-carbonitriles
were found to undergo copper-catalyzed aerobic aromatic C–H
amination (Scheme 3a) [52] or 1,4-aminooxygenation (spirocy-
clization) (Scheme 3b) [51], affording phenanthridine deriva-
Scheme 2: Oxidative generation of iminyl radicals from N–H
ketimines.
Scheme 3: Copper-catalyzed aerobic reactions of in situ generated biaryl N–H ketimines.
1934

Beilstein J. Org. Chem. 2015, 11, 1933–1943.
tives and azaspirocyclohexadienones, respectively, depending trile 5a [55]. Thus, it is deduced that oxaspirocyclohexadienone
on the helical sense of the biaryl axis.
3a was formed through oxygenation of the putative C-radical.
Moreover, in this transformation, the cyano group of carboni-
Herein we report applications of the copper-catalyzed aerobic trile 1a is transferred to Grignard reagent 2a to afford p-toluni-
C–C bond fission of iminyl radical species for the synthesis of trile (5a). Considering the importance of carbonitriles in organic
oxaspirocyclohexadienones as well as the electrophilic cyana- synthesis [56], we postulated that the cyano group transfer from
tion of Grignard reagents using the readily available pivaloni- simple carbonitriles onto Grignard reagents could be realized
trile as a CN source.
using this strategy.
Results and Discussion
Based on these preliminary results (Scheme 4), we next started
We further explored the reactivity of biaryl N–H ketimines to investigate the synthesis of oxaspirocylohexadienones as the
under copper-catalyzed aerobic reaction conditions, aiming at target product. Using carbonitrile 1a and p-tolylmagnesium
the synthesis of 6-membered azaspirocycles such as 3a’ from bromide (2a), an optimization of the reaction conditions was
carbonitrile 1a having a quaternary sp3-hybridized carbon conducted (Table 1). Increasing the amount of the additive
center at its α-position. The reaction of p-tolylmagnesium bro- 1,10-phenanthroline to 40 mol % slightly improved the yield,
mide (2a) to carbonitrile 1a proceeded smoothly in Et2O at giving 3a in 40% yield (Table 1, entry 1). The use of
8
0 °C in a sealed tube, generating N–H ketimine 1aa after 2,2’-bipyridine (bpy) provided a comparable result (Table 1,
protonation with MeOH. Subsequently, Cu(OAc)2 (20 mol %), entry 2), while performing the reaction in the presence of
,10-phen (20 mol %) and DMF (to 0.1 M final concentration) 1,4-diazabicyclo[2.2.2]octane (DABCO) led to lower yields of
1
were added and stirred at room temperature under an air atmos- spirodienone 3a (Table 1, entry 3). We therefore decided to
phere (Scheme 4). Interestingly, no formation of the desired proceed with 1,10-phenanthroline as the optimal ligand and
6
-membered azaspirocycle 3a’ was observed, while oxaspirocy- subsequently tested different Cu(II) and Cu(I) salts (Table 1,
clohexadienone 3a, biaryl alkene 4a, and p-tolunitrile (5a) were entries 4–7). The best results were obtained using 40 mol % CuI
isolated in 29%, 32%, and 86% yields, respectively (Scheme 4). which provided 3a in 46% isolated yield (Table 1, entry 7). A
reduction of the catalyst loading to 20 mol % slightly lowered
Oxaspirocyclohexadienone 3a was formed through C–C bond the yield of 3a (Table 1, entry 9) and a stoichiometric amount of
cleavage from N–H ketimine intermediate 1aa most likely via catalyst did not significantly improve the yield of 3a (Table 1,
the corresponding iminyl radical, that undergoes radical frag- entry 10). Performing the reaction under an O2 atmosphere did
mentation to afford the corresponding C-radical and carboni- also not increase the yield of 3a (Table 1, entry 8).
Scheme 4: Copper-catalyzed aerobic C–C bond cleavage reactions of N–H ketimines.
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Beilstein J. Org. Chem. 2015, 11, 1933–1943.
Table 1: Optimization of reaction conditions: oxaspirocyclohexadienone synthesis.a
Entry
Cu salt
Additive
[mol %]
Atmosphere
Yield [%]b
[mol %]
3a
4a
5a
1
2
3
4
5
6
7
8
9
Cu(OAc)2 [20]
Cu(OAc)2 [20]
Cu(OAc)2 [20]
CuCl2 [20]
CuCl [20]
[20]
1,10-phen [40]
bpy [40]
air
air
air
air
air
air
air
O2
air
air
35 (40)
32
32 (31)
36
85 (86)
80
DABCO [40]
10
21
87
1,10-phen [40]
1,10-phen [40]
1,10-phen [40]
1,10-phen [40]
1,10-phen [40]
1,10-phen [20]
1,10-phen [100]
27
22
78
37
28
96
40 (40)c
42 (46)c
43
34 (27)c
34 (28)c
37
95 (90)c
92 (78)c
99
CuI [20]
CuI [20]
CuI [10]
37
34
95
10
CuI [100]
46
30
93
aAll reactions were carried out using 0.5 mmol of biaryl carbonitrile 1a with 1.3 equiv of Grignard reagent 2a in Et2O (0.5 mL) at 80 °C (sealed tube)
for 4 h followed by the addition of MeOH (60 μL, 3.0 equiv), DMF (5 mL), Cu catalyst and additive and subsequent stirring for 4 h at rt:
1
1
,10-phen = 1,10-phenanthroline; bpy = 2,2’-bipyridine; DABCO = 1,4-diazabicyclo[2.2.2]octane. bCrude yields determined by 1H NMR based on
,1,2,2-tetrachloroethane as an internal standard. cIsolated yields are given in parentheses.
A proposed reaction mechanism for the formation of oxaspiro- While formation of biaryl alkene 4a could not be avoided at this
cyclohexadienone 3a, alkene 4a, and p-tolunitrile (5a) are moment, it is still appealing to probe the potential utility of the
depicted in Scheme 5. Single-electron oxidation of N–H current transformation toward the synthesis of oxaspirocyclo-
ketimine 1aa with higher valent Cu(II) species generated under hexadienones 3. Therefore, the reactions of carbonitriles 1b–d
the aerobic reaction conditions forms iminyl radical species A, were examined under the current best reaction conditions
that undergoes β-carbon fragmentation to give p-tolunitrile (5a) (Table 1, entry 8) using p-tolyl Grignard reagent 2a (Table 2).
and biaryl-2-isopropyl radical B (Scheme 5a). The aerobic Carbonitrile 1b, having methyl groups in ortho-positions on
oxygenation of C-radical B affords peroxy radical C, that is both aryl rings of the biaryl moiety, underwent the C–C bond
presumably reduced by Cu(I) species through the Fenton-type fission process smoothly to afford oxaspirocyclized product 3b
mechanism [57] to give alkoxy radical D [58]. Subsequent and biaryl alkene 4b in 48% and 35% yields, respectively, along
spirocyclization of the alkoxy radical D onto the benzene ring with p-tolunitrile (5a) in 90% yield (Table 2, entry 1). The reac-
affords cyclohexadienyl radical F, oxygenation of which fol- tions of N–H ketimines having cyclopentyl and tetrahydropy-
lowed by C=O bond formation finally provides the oxaspiro- ranyl rings derived from nitriles 1c and 1d, respectively,
cyclohexadienone product 3a. Whereas, the oxidation of the afforded tricyclic oxaspirocyclohexadienones 3c and 3d in
benzylic radical B by the existing Cu(II) species to carbocation moderate yields along with the corresponding alkenes 4c and 4d
G and subsequent E1-type elimination of a proton provides as well as p-tolunitrile (5a) (Table 2, entries 2 and 3).
biaryl alkene 4a (Scheme 5b). The presence of alkoxy radical D
in the reaction process could be further supported by the reac- On the other hand, the reaction starting from carbonitrile 1e
tion of biaryl hydroperoxide 6, which could be converted into having a strained cyclobutane ring did not form the desired
the alkoxy radical D under copper-catalyzed aerobic reaction oxaspirocyclohexadienone (Scheme 6). Instead, γ-bromoketone
conditions [58]. Indeed treatment of hydroperoxide 6 under the 8e was isolated in 44% yield along with nitrile 5a in 80% yield.
standard reaction conditions afforded 3a in 24% yield along The formation of γ-bromoketone 8e is most likely caused by
with biaryl alcohol 7 in 25% yield (Scheme 5c).
radical ring opening from the transient cyclobutoxy radical I,
1936

Beilstein J. Org. Chem. 2015, 11, 1933–1943.
Scheme 5: Proposed reaction mechanisms for the formation of 3a, 4a and 5a, and the reaction of hydroperoxide 6.
which is driven by releasing ring strain of the cyclobutyl ring. cyanation of Grignard reagents. As carbonitriles are omni-
The resulting γ-keto radical J subsequently undergoes radical present components in various natural products, dyes and
bromination to form 8e [59]. This result unambiguously potent pharmaceutical drugs [60-62], new and versatile routes
supports the presence of the alkoxy radical intermediate during towards this substance class are always desirable. Conventional
oxaspirocyclohexadienone formation in our mechanistic methods to install the cyano group on aryl rings such as the
proposal.
Rosenmund–von Braun reaction [63] or the Sandmeyer reac-
tion [64] require the use of stoichiometric amounts of toxic
Next, we turned our attention to apply the present copper- metal cyanides (such as CuCN) as the “CN” anion source [65].
catalyzed aerobic C–C bond fission process in the electrophilic Therefore, an employment of aliphatic carbonitriles which are
1937

Beilstein J. Org. Chem. 2015, 11, 1933–1943.
Table 2: Substrate scope: oxaspirocyclohexadienone synthesis.a
Entry
Substrate
Productsb
1
5a 90%c
5a 76%c
5a 90%c
1b
1c
1d
3b 48%
3c 36%
3d 48%
4b 35%
4c 27%
4d 40%
2
3
aAll reactions were carried out using 0.5 mmol of biaryl carbonitrile 1 with 1.3 equiv of Grignard reagents 2a in Et2O (0.5 mL) at 80 °C (sealed tube)
for 4 h followed by the addition of MeOH (60 μL , 3.0 equiv), DMF (5 mL), CuI (20 mol %) and 1,10-phen (40 mol %) under ambient air at rt:
1,10-phen = 1,10-phenanthroline. bIsolated yields. c1H NMR crude yields based on 1,1,2,2-tetrachloroethane as an internal standard.
less toxic and easier to handle (such as acetonitrile [66-70], Ar atmosphere) provided only 2-pivaloylnaphthalene (9b) in
benzyl cyanide [71-76], and malononitrile [77,78]) for the “CN” 83% yield formed through hydrolysis of unreacted N–H imine
surrogates has been developed more recently [79]. We envi- 1fb during the aqueous work-up. Therefore molecular oxygen is
sioned that the readily available pivalonitrile (1f) could be a indispensable to achieve the present cyanation through the C–C
potential CN source for the electrophilic cyanation [80-86] of bond cleavage of the N–H ketimine. It was found that use of
Grignard reagents using the present protocol (Scheme 7).
CuBr2 as the catalyst resulted in formation of 5b in higher yield
86%).
(
Thus pivalonitrile (1f) was reacted with 2-naphthylmagnesium
bromide (2b) for formation of the corresponding N–H ketimine We next examined the substrate scope using different Grignard
fb, which was subsequently treated with 10 mol % of reagents (Table 3). The electrophilic cyanation proceeded
1
Cu(OAc)2 under an O2 atmosphere (Scheme 8). As expected, smoothly even with sterically bulky Grignard reagents such as
formation of 2-naphthonitrile (5b) was observed in 79% yield. 1-naphthyl- and 2,4,6-trimethylphenyl Grignard reagents (for 5c
On the other hand, the reaction in the absence of O2 (under an and 5d) (Table 3, entries 1 and 2). Electron-rich aryl Grignard
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Beilstein J. Org. Chem. 2015, 11, 1933–1943.
Scheme 6: Formation of bromoketone 6e.
Scheme 7: Electrophilic cyanation of Grignard reagents with pivalonitrile (1f).
Scheme 8: Electrophilic cyanation with pivalonitrile (1e).
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Beilstein J. Org. Chem. 2015, 11, 1933–1943.
Table 3: Scope of the reaction using different Grignard reagents.a
Entry
1
R–MgBr (2)
Time x/y (h)
12/18
Product 5b
2c
5c 76%
2
c
c
56/19
2
d
e
5d 81%
5e 67%
5f 74%
5g 81%
3
50/18
22/10
48/24
48/55
2
4
2
f
5
6
2
g
h
2
5h 70%
5i 63%d
7
8
48/24
48/48
2i
2j
5j 47%
aUnless otherwise noted, the reactions were carried out using 1 mmol of pivalonitrile (1f) with 1.3 equiv of Grignard reagents 2 in Et2O (1 mL) at 60 °C
sealed tube) for the time x followed by the addition of MeOH (120 μL), DMF (10 mL), and CuBr2 (10 mol %), and the mixture was stirred at 80 °C for
(
time y under an O2 atmosphere. bIsolated yields. cThe reaction was conducted using Cu(OAc)2 (10 mol %) as the catalyst. d1H NMR yield.
reagents could also be used to give the corresponding benzoni- carbonitrile (5i) was also prepared in 63% yield. The present
triles 5e, 5f and 5g in good yields (Table 3, entries 3–5). The method could also be applied for the cyanation of the primary
reaction also proceeded with chlorinated substrates leaving the alkyl Grignard reagent, phenethylmagnesium bromide (for 5j),
C–Cl bond intact (for 5h) (Table 3, entry 6). Thiophen-2- albeit the product yield was moderate.
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Beilstein J. Org. Chem. 2015, 11, 1933–1943.
1
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Conclusion
doi:10.1016/S0040-4020(01)80849-8
In summary, we have demonstrated a copper-catalyzed aerobic
generation of iminyl radicals from the corresponding N–H
ketimines and their radical C–C bond fission. These processes
could be applied for synthesis of oxaspirocyclohexadienones
through spirocylization of the transient alkoxy radicals gener-
ated by aerobic oxygenation of the resulting carbon radicals.
With the present protocol, the electrophilic cyanation of Grig-
nard reagents was also established using readily available pival-
onitrile as a simple CN source.
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