Copper-catalyzed ring-opening C(sp3)-N coupling of cycloketone oxime esters: Access to 1°, 2° and 3° alkyl amines

Article abstract of DOI:10.1039/c9cc02030f

A novel copper-catalyzed C(sp³)-N coupling of cycloketone oxime esters with nitrogen nucleophiles has been realized. All of the N-aryl/alkylanilines, anilines and benzophenone imine could be employed in this protocol to produce a variety of 1°, 2° and 3° alkyl amines in one or two steps. These resultant cyano-containing alkyl amines were proven to be versatile synthetic building blocks in a variety of chemical transformations.

Full text of DOI:10.1039/c9cc02030f

View Article Online
View Journal
ChemComm
Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: L. Tian, S. Gao, R.
Wang, Y. Li, C. Tang, L. Shi and J. Fu, Chem. Commun., 2019, DOI: 10.1039/C9CC02030F.
This is an Accepted Manuscript, which has been through the
Volume 52 Number
1 4 January 2016 Pages 1–216
Royal Society of Chemistry peer review process and has been
accepted for publication.
ChemComm
Accepted Manuscripts are published online shortly after
Chemical Communications
www.rsc.org/chemcomm
acceptance, before technical editing, formatting and proof reading.
Using this free service, authors can make their results available
to the community, in citable form, before we publish the edited
article. We will replace this Accepted Manuscript with the edited
and formatted Advance Article as soon as it is available.
You can find more information about Accepted Manuscripts in the
author guidelines.
Please note that technical editing may introduce minor changes
to the text and/or graphics, which may alter content. The journal’s
standard Terms & Conditions and the ethical guidelines, outlined
in our author and reviewer resource centre, still apply. In no
event shall the Royal Society of Chemistry be held responsible
for any errors or omissions in this Accepted Manuscript or any
consequences arising from the use of any information it contains.
ISSN 1359-7345
COMMUNICATION
Marilyn M. Olmstead, Alan L. Balch, Josep M. Poblet, Luis Echegoyenet al.
Reactivity differences of Sc3N@C2n (2n 68 and 80). Synthesis of the
first methanofullerene derivatives of Sc N@D5h-C80
=
3
rsc.li/chemcomm

Please do not adjust margins
Page 1 of 5
ChemComm
View Article Online
DOI: 10.1039/C9CC02030F
Journal Name
COMMUNICATION
Copper-catalyzed Ring-opening C(sp3)–N Coupling of Cycloketone
Oxime Esters: Access to 1º, 2º and 3º Alkyl Amines
Li Tian,a Shuangqiu Gao,a Rui Wang,a Yang Li,a Chunlin Tang,a Lili Shi,*b and Junkai Fu*a,b
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
A novel copper-catalyzed C(sp3)–N coupling of cycloketone oxime alkyl acids.12 These reactions are featured with a single-
esters with nitrogen nucleophiles has been realized. All of the N- electron transfer (SET) process of alkyl electrophiles to
aryl/alkylanilines, anilines and benzophenone imine could be produce the alkyl radical intermediates,13 which would
employed in this protocol to produce a variety of 1º, 2º and 3º recombine with the metal and undergo further reductive
alkyl amines through one or two steps. These resultant cyano- elimination. Considering the importance of alkyl amines in the
containing alkyl amines were proven to be versatile synthetic reportire of organic synthesis, searching for supplementary
building blocks in a variety of chemical transformations.
method to construct the C(sp3)–N bonds and ultimately obtain
different types of alkyl amines is deemed worthy of pursuit.
The C(sp3)–N formation plays an important role in organic
synthesis, as it could offer an efficient access to alkyl amines
that are frequently engaged motifs in alkaloids and bioactive
molecules.1 The most common method to construct these
bonds relies on direct substitution of alkyl electrophiles with
nitrogen nucleophiles (Figure 1a).2 However, such processes
suffer from some limitations including deactivation of nitrogen
nucleophiles under the acidic conditions in SN1 reactions;
difficult or even impossible for bulky secondary and tertiary
alkyl electrophiles; as well as concomitant elimination or
overalkylation. A renaissance was stimulated in exploring
effective protocols towards their facile preparations over the
past few years, such as reductive amination,3 C(sp3)–H
amination4 and olefin hydroamination5. Recently, transition
metal-catalyzed alkylation of nitrogen nucleophiles with alkyl
electrophiles has been a promising solution to directly forge
the C(sp3)–N bonds.6 Despite its success, this method poses
two distinct challenges simultaneously: β-hydride elimination
from metal alkyl intermediates7 and the difficulty in C(sp3)–N
reductive elimination8. The pioneering work have been
successively achieved by Fu & Peters,9 Hartwig10 and Hu11, in
which alkyl halides or N-hydroxyphthalimide esters were
coupled with carbazoles, amides, aryl/alkyl amines and
benzophenone-derived imines. Very recently, MacMillan and
co-workers disclosed a decarboxylative C(sp3)–N coupling via
dual copper and photoredox catalysis by using iodomesitylene
dicarboxylates that generated in situ from the corresponding
(a) Construction of C(sp3)–N bonds
+
Classic method:
alkyl
X
H
N



deactivation in SN1 reactions
sensitive to steric hindrance
elimination or overalkylation
substitution
R2
C-H
amination
hydro-
amination
alkyl
H
R1
3
N
+
C
+
(sp )
N
R
H
N
reductive
elimination
Fu, Peters, Hartwig
Hu, MacMillan
Challenges:
-hydride elimination from
metal alkyl intermediates
 the difficulty in C(sp3)-N
reductive elimination
[M]
SET
M
alkyl
X
+
H
N
alkyl
N
(b) C(sp3)–N formation via ring-opening of cycloketone oxime esters
previous
work
R
CN
n
O
R
N
[Cu], [Ni], [Fe]
or photoredox
R = C, O, S, Se, Te, N3, B
O
CN
n
R1
-
n
- RCO2
this work
N
R2
CN
n
n = 1, 2
R1, R2 = aryl, alkyl, H
earth-abundant copper salt
1°, 2° and 3° alkyl amines


Figure 1. C(sp3)–N coupling of alkyl electrophiles with nitrogen
nucleophiles.
Recent advance has demonstrated that the generation of
alkyl carbon radical containing a cyano group from C–C bond
cleavage of cycloketone oxime derivatives could be achieved
by transition metal catalysts (Cu, Ni and Fe)14 or photoredox
catalysis15 via a SET process. This strategy has implemented
the construction of C(sp3)–C and C(sp3)–Y (Y = O, S, Se, Te, N3,
or B) bonds (Figure 1b).16-18 In this context, we envisaged that
the cycloketone oxime esters might fulfill the engagement to
introduce alkyl radical intermediates for the coupling of
nitrogen nucleophiles. This idea ultimately led to the discovery
of a copper-catalyzed C(sp3)–N coupling of cycloketone oxime
a. Jilin Province Key Laboratory of Organic Functional Molecular Design & Synthesis,
Department of Chemistry, Northeast Normal University, Changchun 130024,
China. fujk109@nenu.edu.cn
b. Key Laboratory of Chemical Genomics, School of Chemical Biology and
Biotechnology, Peking University Shenzhen Graduate School, Shenzhen 518055,
China. shill@pkusz.edu.cn
Electronic Supplementary Information (ESI) available: [details of any supplementary
information available should be included here]. See DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
Please do not adjust margins

Please do not adjust margins
ChemComm
Page 2 of 5
COMMUNICATION
Journal Name
esters with different nitrogen nucleophiles, which provides an (entry 15). Thus, the standard reaction conditions were
efficient and general access to a variety of 1º, 2º and 3º alkyl submitting the substrates under circumstances conVieswisAtirnticgleoOfnl1in5e
DOI: 10.1039/C9CC02030F
amines, together with the assembly of synthetically useful mol% copper (II) triflate and 15 mol% 1,10-phen in toluene at
cyano moieties.19
80 °C.
Table 1. Reaction conditions screeninga
Table 2. Substrate Scope of Aryl Aminesa, b
O
Ph
Cu(OTf)2 (15 mol%)
1,10-phen (15 mol%)
O
Ph
R1
N
Ph
H
N
[Cu], solvent
ligand, 80 °C
N
H
N
N
Ph
CN
N
R2
CN
+
O
O
+
R1
R2
Ph
Ph
toluene, 80 o
C
1a
2
3
1a
2a
3a
Me
3° alkyl amines
MeO
Entry
Copper
CuI
Solvent
Ligand
Yield (%)b
Br
N
CN
1
2
toluene
toluene
toluene
toluene
toluene
toluene
THF
-
-
-
-
-
-
-
-
-
-
62
50
N
CN
N
CN
Cu(MeCN)4PF6
CuTC
Ph
Ph
3
trace
77
3b, 54%
3c, 60%
3d, 84%
Me
4
Cu(OTf)2
Cu(OAc)2
CuCl2
3f
R = H, , 68%
3g
R = 3-Me, , 65%
3h
R = 4-Me, , 66%
3i
R = 3-Br, , 62%
3j
R = 4-Br, , 63%
3k
R = 4-Cl, , 81%
R = 4-OMe, , 75%
Me
N
CN
N
CN
5
70
6
12
R
7
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
-
30
3e
, 78%
3l
8
dioxane
CH3CN
DCE
10
R
N
CN
Br
N
CN
N
CN
9
trace
45
Ph
Ph
Ph
3m
R = ethyl,
, 80%
10
11
12
13
14c
15
3n
R = n-butyl, , 62%
R = isopropyl, 3o, 60%
3p
3q
, 83%
, 71%
toluene
toluene
toluene
toluene
toluene
PMDTA
1,10-Phen
Bphen
74
N
CN
N
CN
81
N
CN
50
Ph
3r
3s
3t
, 80%
, 62%
, 60%
1,10-Phen
1,10-Phen
42
0
2° alkyl aminesc
R
a
The reactions were carried out with 1a (0.4 mmol), 2a (0.2 mmol),
3u
R = H, , 51%
3v
R = 2-Br, , 70%
R = 3-Cl,
R = 4-NO2, , 60%
copper salt (15 mol%) and ligand (15 mol%) in solvent (2.0 mL) at 80
N
H
CN
ºC. b Isolated yields. c With K2CO3 (1.0 equiv). PMDTA = N,N,N',N'',N''-
3w
3x
, 54%
N
H
CN
pentamethyldiethylenetriamine,
phenanthroline.
Bphen
=
4,7-diphenyl-1,10-
3y
, 33%
a
b
c
Standard reaction conditions. Isolated yields. Aryl amine 2 (2.0
equiv) and cyclobutanone oxime ester 1a (1.0 equiv) were used for
aniline and its derivatives.
With readily accessible cyclobutanone oxime ester (1a) and
diphenylamine (2a) as the model substrates, copper iodide
was initially evaluated as the catalyst. As expected, the desired
tertiary amine 3a was successfully isolated with 62% yield in
toluene at 80 °C (entry 1). A more ionic salt Cu(MeCN)4PF6
brought a lower yield (50%, entry 2). However, we observed
that copper(I) thiophene-2-carboxylate posed a deleterious
effect on the reaction, leading to only trace amount of product
(entry 3). Switching the catalyst to copper (II) triflate,
pleasingly, afforded the desired product in 77% yield, which
outperformed other common copper (II) catalysts (entries 4-6).
Concomitantly, solvent effect was shown to be fairly significant
in ensuring a satisfactory yield (entries 7-10). Toluene was the
best choice. Polar solvents such as acetonitrile completely
suppressed the desired reaction, while nonpolar solvent 1,2-
dichloroethane provided the product in just 45% isolated yield.
It merited attention that ligand also proved to be a parameter
to affect the developed sequence. The presence of 1,10-phen
increased the yield slightly up to 81% (entry 12). In
comparison, PMDTA and Bphen had no positive effect on the
outcome (entries 11 and 13). When base, such as K2CO3 was
added into the reaction, the yield was dramatically dropped to
42% (entry 14). In addition, control experiment in the absence
of copper catalyst failed to afford any desired product, which
showed the importance of copper salt for the transformation
Having established the standard reaction conditions, we
explored the substrate scope with a variety of aryl amines 2.
As compiled in Table 2, diphenylamine derivatives with
electronic diverse substituents (MeO-, Br- and Me-) on the
phenyl rings could all react with cyclobutanone oxime ester 1a
to give the desired 3º alkyl amines 3b-3d in moderate to good
yields, while iminostilbene led to the formation of 3e in 78%
yield. This transformation was also compatible with a range of
N-alkylanilines, including various N-methylaniline derivatives
to produce 3f-3o, and the electronic features on the phenyl
ring showed little effect on reactivity. In addition, entities with
potentially intractable functional groups, such as bromo,
alkene and alkyne moieties (3p-3r) were shown to be well
accommodated in this process. Moreover, the cyclic 1,2,3,4-
tetrahydroquinoline and indoline could also suffer the reaction
conditions to give 3º alkyl amines 3s and 3t in 62% and 60%
yields, respectively. Similarly, the aniline and its derivatives
with electron-deficient phenyl rings were all suitable for the
current transformation, and 2º alkyl amines 3u-3x were
obtained in good yields. 1-Aminonaphthalene was also tested,
which gave product 3y in an acceptable yield of 33%.
Table 3. Substrate Scope of Cycloketone Oxime Estersa, b
2 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 3 of 5
ChemComm
Please do not adjust margins
Journal Name
COMMUNICATION
O
Ph
Cu(OTf)2 (15 mol%)
Bphen (15 mol%)
R
Scheme 2. Representative Derivatizations
N
H
N
View Article Online
Ph
N
CN
+
n
O
DOI: 10.1039/C9CC02030F
Ph
Ph
Ph
Cs2CO3 (1.0 equiv)
toluene, 80 °C
Me
Me
Me
n
R
n = 1, 2
N
CN
N
CN
N
CN
1
2a
4
S
Me
Ph
, 70%
O
O
Ph
Ph
7
8
9
, 62%
Ph
, 93%
Ph
N
CN
N
CN
N
CN
, 50%
Ph
Ph
Ph
a)
Me
CN
Me
4a
4b
4c
, 55%
, 53%
N
CN
Me
Me
N
CN
N
c)
b)
95%
Ph
Ph
N
CN
N
CN
O
N
CN
65%
Ph
Ph
B
O
Ph
Br
Br
11
3i
10
45% for
2 steps
f)
R
X
d), e)
72%
c
c
c
c
4e
R = Me, , 62%
R = Bu, , 60%
4g
X = Cl, , 70%
4d
N
, 71%
t
c
Me
NHBoc
Me
Me
4f
4h
X = Br, , 52%
N
N
O
Ph
Ph
R
d
4j
R = H, , 51%
Br
Br
CN
12
13
d
4k
R = 4-Cl, , 53%
Ph Ph
Ph
CN
Reaction conditions: a) For 7: PhB(OH)2 (1.2 equiv), Pd(PPh3)4 (5 mol%),
K2CO3 (10 equiv), toluene/H2O, refux, overnight; For 8 and 9: ArB(OH)2
(1.5 equiv), Pd(PPh3)4 (7.5 mol%), K2CO3 (3.0 equiv), DMF/H2O, 90 ºC,
overnight; b) B2(pin)2 (1.5 equiv), CH3CO2K (2.0 equiv), Pd(PPh3)4 (0.1
equiv), DMSO, 85 ºC; c) CH3I (1.1 equiv), LDA (1.5 equiv), THF, -78 ºC to
rt; d) LiAlH4 (3.0 equiv), Et2O, reflux; e) (Boc)2O (1.1 equiv), Et3N (3.0
equiv), DMAP (5 mol%), DCM, rt; f) CH3MgBr (6.0 equiv), Et2O, reflux,
overnight.
N
d
4l
R = 3-OMe, , 55%
c
Ph
4i
, 83%
a
The reaction were carried out with 1 (0.4 mmol), 2a (0.2 mmol),
Cu(OTf)2 (15 mol%), Bphen (15 mol%) and Cs2CO3 (1.0 equiv) in toluene
b
c
(2.0 mL) at 80 ºC. Isolated yields. In the absence of Bphen and
Cs2CO3. d Standard reaction conditions.
Pressing forward, a range of cycloketone oxime esters were
tested to react with diphenylamine (Table 3). The α-
substituted cyclobutanone oxime esters with diverse
functional groups, such as methyl (4a), olefin (4b) and
methoxy (4c), could all undergo the desired pathway to deliver
the corresponding products under modified reaction
conditions. When the cyclobutanone oxime esters with
electronic diverse phenyl rings (substituted with alkyl and
halides) at para-position were subjected to a simplified
procedure with only copper salt, 3º alkyl amines 4d-4h could
be obtained. The oxime ester with bis-phenyl installed at para-
position of the cyclic skeleton was shown to be suitable
substrate for this transformation, which afforded 4i in 83%
isolated yield. It was worth mentioning that this reaction could
also be extended to cyclopentanone oxime esters to give 4j-l in
moderate yields under standard reaction conditions. However,
α-phenyl cyclohexanone oxime ester failed.
To further demonstrate the synthetic utility of the present
coupling method, structural modifications and functional
group inter-conversions of the resultant alkyl amines were
performed. As delineated in Scheme 2, the 3º alkyl amine 3i,
possessing both cyano group and aryl bromide, could be
coupled with an array of aryl boric acids via Suzuki-Miyaura
coupling to give 7-9 in good to excellent yields. The bromo
atom could also be transformed into the corresponding
organoboron, and compound 10 was obtained in 95% yield,
which maximized the likelihood to do further transformation.
For the cyano moiety of 3i, α-alkylation could be successfully
achieved to produce 11 in 65% yield. Reduction of the cyano
group followed by the protection of the newly formed primary
amine with Boc group would lead to 12 in 45% yield over two
steps. What’s more, nucleophilic attack of the cyano moiety
with methyl magnesium bromide would ultimately generate
ketone 13 in 72% yield.
Scheme 1. Synthesis of 1º Alkyl Amines
To elucidate the reaction mechanism, we performed
preliminary mechanistic studies (Scheme 3). Addition of 3.0
O
Ph
N
O
equivalent
tetramethylpiperidinooxy
of
radical
scavengers
or
2,2,6,6-
butylated
Cu(OTf)2 (15 mol%)
1,10-phen (15 mol%)
1a
N
CN
HCl
(TEMPO)
HCl·H2N
CN
+
toluene, 80 o
62%
C
hydroxytoluene (BHT) into the reaction mixture would totally
suppress the desired reaction, and the adducts 14 and 15 were
isolated. These experimental results suggested that this
reaction involved a radical process. In this context,9-12 we
proposed that the nitrogen nucleophiles firstly coordinated to
the Cu(I) salt. The formed complexes would undergo SET
process with the cycloketone oxime esters to release Cu(II)
species and initiate the homolytic ring-opening to generate the
alkyl radical intermediates. Then the Cu(II) species could
recombine with the alkyl radicals to form Cu(III)
intermediates,11,12 which ultimately delivered the desired alkyl
amines and regenerate Cu(I) salt through reductive
elimination22 (a scheme for the catalytic cycle, see SI).
Ph
Ph
5
92%
NH
Ph
6
1° alkyl amine
Ph
As direct routes to primary amines are highly warranted,20
we tested the possibility to access 1º alkyl amine under
current stage. 1a and benzophenone imine, which commonly
used as ammonia surrogate,21 were subjected to the standard
conditions. To our delight, the proposed alkyl radical coupled
with the imine to generate the elongated imine 5, which could
be facilely converted to 1º alkyl amine 6 upon acid hydrolysis
(Scheme 1).10,11a In this regard, the collective results illustrated
the broadly applicable features of the current approach in
performing C(sp3)–N coupling to obtain 1º, 2º and 3º alkyl
amines.
Scheme 3. Mechanistic Investigations
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
Please do not adjust margins

Please do not adjust margins
ChemComm
Page 4 of 5
COMMUNICATION
Journal Name
2017, 139, 12153; (e) J. M. Ahn, T. S. Ratani, K. I. Hannoun, G. C. Fu
CN
Cu(OTf)2 (15 mol%)
1,10-phen (15 mol%)
and J. C. Peters, J. Am. Chem. Soc., 2017, 139, 1V2i7ew16A;rti(cfl)e OCn.liDne.
O
Ph
N
H
DOI: 10.1039/C9CC02030F
N
O
+
3a
+
Ph Ph
Matier, J. Schwaben, J. C. Peters and G. C. Fu, J. Am. Chem. Soc.,
2017, 139, 17707; (g) J. M. Ahn, J. C. Peters and G. C. Fu, J. Am.
Chem. Soc., 2017, 139, 18101.
BHT (2.0 equiv)
tBu
tBu
toluene, 80 o
C
(0%)
1a
(2.0 equiv)
2a
O
(1.0 equiv)
14
1a
(57% based on
)
10. D. M. Peacock, C. B. Roos and J. F. Hartwig, ACS Cent. Sci., 2016, 2,
647.
11. (a) R. Mao, J. Balon and X. Hu, Angew. Chem., Int. Ed., 2018, 57,
9501; (b) R. Mao, A. Frey, J. Balon and X. Hu, Nat. Catal., 2018, 1,
120.
12. Y. Liang, X. Zhang and D. W. C. MacMillan, Nature, 2018, 559, 83.
13. A. Kaga and S. Chiba, ACS Catal., 2017, 7, 4697.
Cu(OTf)2 (15 mol%)
1,10-phen (15 mol%)
O
Ph
N
H
N
N
O
O
+
3a
+
Ph Ph
CN
TEMPO (2.0 equiv)
toluene, 80 o
C
(0%)
1a
(2.0 equiv)
2a
15
1a
(60% based on
)
(1.0 equiv)
In summary, we have developed a copper-catalyzed direct
C(sp3)–N coupling of cycloketone oxime esters and nitrogen
nucleophiles. This reaction protocol is featured with wide
functional-group compatibility and broad substrate scope. All
of the N-aryl/alkylanilines, anilines and benzophenone imine
could be employed as the nitrogen nucleophiles to react with
cyclobutanone or cyclopentanone oxime esters for the
efficient assembly of a variety of 1º, 2º and 3º alkyl amines.
These resultant cyano-containing alkyl amines were further
shown to be versatile building blocks in a variety of chemical
transformations. Further applications and mechanistic studies
are in progress in our laboratory.
14. For a selected review, see: W. Yin and X. Wang, New J. Chem.,
2019, 43, 3254. For selected examples with transition metal
catalysts, see: (a) H.-B. Yang and N. Selander, Chem. Eur. J., 2017,
23, 1779; (b) B. Zhao and Z. Shi, Angew. Chem., Int. Ed., 2017, 56,
12727; (c) Y.-R. Gu, X.-H. Duan, L. Yang and L.-N. Guo, Org. Lett.,
2017, 19, 5908; (d) L. Yang, P. Gao, X.-H. Duan, Y.-R. Gu and L.-N.
Guo, Org. Lett., 2018, 20, 1034; (e) J.-F. Zhao, X.-H. Duan, Y.-R. Gu,
P. Gao and L.-N. Guo, Org. Lett., 2018, 20, 4614; (f) J.-F. Zhao, P.
Gao, X.-H. Duan and L.-N. Guo, Adv. Synth. Catal., 2018, 360, 1775;
(g) J. Wu, J.-Y. Zhang, P. Gao, S.-L. Xu, and L.-N. Guo, J. Org. Chem.,
2018, 83, 1046; (h) J.-Y. Zhang, X.-H. Duan, J.-C. Yang and L.-N. Guo,
J. Org. Chem., 2018, 83, 4239; (i) D. Ding and C. Wang, ACS Catal.,
2018, 8, 11324. (j) Y.-R. Gu, X.-H. Duan, L. Chen, Z.-Y. Ma, P. Gao
and L.-N. Guo, Org. Lett., 2019, 21, 917.
15. For selected examples with photoredox catalysis, see: (a) L. Li, H.
Chen, M. Mei and L. Zhou, Chem. Commun., 2017, 53, 11544; (b)
X.-Y. Yu, J.-R. Chen, P.-Z. Wang, M.-N. Yang, D. Liang and W.-J. Xiao,
Angew. Chem., Int. Ed., 2018, 57, 738; (c) X.-Y. Yu, Q.-Q. Zhao, J.
Chen, J.-R. Chen and W.-J. Xiao, Angew. Chem., Int. Ed., 2018, 57,
15505; (d) Z.-Y. Ma, L.-N. Guo, Y.-R. Gu, L. Chen and X.-H. Duan,
Adv. Synth. Catal., 2018, 360, 4341; (e) P.-Z. Wang, X.-Y. Yu, C.-Y. Li,
B.-Q. He, J.-R. Chen and W.-J. Xiao, Chem. Commun., 2018, 54,
9925; (f) B.-Q. He, X.-Y. Yu, P.-Z. Wang, J.-R. Chen and W.-J. Xiao,
Chem. Commun., 2018, 54, 12262; (g) X. Shen, J.-J. Zhao and S. Yu,
Org. Lett., 2018, 20, 5523.
We thank the financial support from the NSFC (21702027,
21602016), Fundamental Research Funds for the Central
Universities (2412017QD010, 2412019FZ017), Scientific
Research Foundation of Education Department of Jilin
Province (JJKH20180013KJ) and Young Scientific Research
Foundation of Jilin Province (20180520228JH).
Conflicts of interest
The authors declare no competing financial interest.
16. For C–O and C–N3 bonds formation, see: (a) W. Ai, Y. Liu, Q. Wang,
Z. Lu and Q. Liu, Org. Lett., 2018, 20, 409; (b) M. M. Jackman, S. Im,
S. R. Bohman, C. C. L. Lo, A. L. Garrity and S. L. Castle, Chem. Eur. J.,
2018, 24, 594; (c) B. Zhao, H. Tan, C. Chen, N. Jiao and Z. Shi, Chin.
J. Chem., 2018, 36, 995; (d) B. Zhao, C. Chen, J. Lv, Z. Li, Y. Yuan and
Z. Shi, Org. Chem. Front., 2018, 5, 2719.
17. For C–S, C–Se and C–Te bonds formation, see: (a) M. He, Z. Yan, F.
Zhu and S. Lin, J. Org. Chem., 2018, 83, 15438; (b) D. Anand, Y. He,
L. Li and L. Zhou, Org. Biomol. Chem., 2019, 17, 533; (c) M. Zheng,
G. Li and H. Lu, Org. Lett., 2019, 21, 1216;
Notes and references
1. (a) S. A. Lawrence, Amines: Synthesis Properties and Applications,
Cambridge University Press, Cambridge, 2004; (b) A. Ricci, Amino
Group Chemistry: From Synthesis to the Life Sciences, Wiley-VCH,
Weinheim, 2008; (c) S. Funayama and G. A. Cordell, Eds., Alkaloids:
A Treasure of Poisons and Medicines, Academic Press: Waltham,
MA, 2015.
2. R. N. Salvatore, C. H. Yoon and K. W. Jung, Tetrahedron, 2001, 57,
7785.
3. A. F. Abdel-Magid and S. J. Mehrman, Org. Process Res. Dev., 2016,
10, 971.
18. For C–B bonds formation, see: J.-J. Zhang, X.-H. Duan, Y. Wu, J.-C.
Yang and L.-N. Guo, Chem. Sci., 2019, 10, 161.
4. (a) R. T. Gephart and T. H. Warren, Organometallics, 2012, 31,
7728; (b) Y. Park, Y. Kim and S. Chang, Chem. Rev., 2017, 117,
9247; (c) D. Hazelard, P.-A. Nocquet and P. Compain, Org. Chem.
Front., 2017, 4, 2500.
19. (a) F. F. Fleming, Nat. Prod. Rep., 1999, 16, 597; (b) J. S. Miller and
J. L. Manson, Acc. Chem. Res., 2001, 34, 563; (c) F. F. Fleming, L.
Yao, P. C. Ravikumar, L. Funk, and B. C. Shook, J. Med. Chem., 2010,
53, 7902.
5. L. Huang, M. Arndt, K. Gooßen, H. Heydt and L. J. Gooßen, Chem.
Rev., 2015, 115, 2596.
6. G. C. Fu, ACS Cent. Sci., 2017, 3, 692.
20. L. Legnani, B. N. Bhawal, B. Morandi, Synthesis, 2017, 49, 776.
21. (a) G. Mann, J. F. Hartwig, M. S. Driver and C. Fernández-Rivas, J.
Am. Chem. Soc., 1998, 120, 827; (b) J. P. Wolfe, J. Åhman, J. P.
Sadighi, R. A. Singer and S. L. Buchwald, Tetrahedron Lett., 1997,
38, 6367; (c) S. Kramer, Org. Lett., 2019, 21, 65.
22. Alkyl-Cu(III) intermediate could also undergo syn-elimination
to generate an alkene, see: A. Faulkner, N. J. Race, J. S. Scott
and J. F. Bower, Chem. Sci., 2014, 5, 2416. In the current
reaction, we proposed that the coordination of nitrogen
nucleophiles made the Cu(III) intermediates crowded, which
could accelerate the reductive elimination process.
7. T.-Y. Luh, M.-k. Leung and K.-T. Wong, Chem. Rev., 2000, 100, 3187.
8. S. A. Macgregor, G. W. Neave and C. Smith, Faraday Discuss., 2003,
124, 111.
9. (a) A. C. Bissember, R. J. Lundgren, S. E. Creutz, J. C. Peters and G.
C. Fu, Angew. Chem., Int. Ed., 2013, 52, 5129; (b) H.-Q. Do, S.
Bachman, A. C. Bissember, J. C. Peters and G. C. Fu, J. Am. Chem.
Soc., 2014, 136, 2162; (c) Q. M. Kainz, C. D. Matier, A. Bartoszewicz,
S. L. Zultanski, J. C. Peters and G. C. Fu, Science, 2016, 351, 681; (d)
W. Zhao, R. P. Wurz, J. C. Peters and G. C. Fu, J. Am. Chem. Soc.,
4 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 5 of 5
ChemComm
View Article Online
DOI: 10.1039/C9CC02030F
Table of Contents Entry
Copper-catalyzed Ring-opening C(sp3)–N Coupling of Cycloketone
Oxime Esters: Access to 1º, 2º and 3º Alkyl Amines
Li Tian,a Shuangqiu, Gao,a Rui Wang,a Yang Li,a Chunlin Tang,a Lili Shi,*b and
Junkai Fu*a,b
aJilin Province Key Laboratory of Organic Functional Molecular Design & Synthesis, Department
of Chemistry, Northeast Normal University, Changchun 130024, China.
bKey Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Peking
University Shenzhen Graduate School, Shenzhen 518055, China.
Ph
Ph
NH
Ar/Alkyl
Ar
O
R
N
R1
NH2
N
R2
CN
O
n
Cu
+
Ar
n
N
H
R1, R2 = aryl, alkyl, H
n = 1, 2
nucleophiles
N
1°, 2° and 3° alkyl amines

earth-abundant copper salt

great functional-group compatibility

An access to 1º, 2º and 3º alkyl amines through copper-catalyzed C(sp3)–N coupling
of cycloketone oxime esters was realized.