Nickel-catalyzed carbodifunctionalization of: N -vinylamides enables access to γ-amino acids

Article abstract of DOI:10.1039/c9cc09866f

A nickel-catalyzed tandem reaction of N-vinylamides with arylboronic acids and bromodifluoroacetate has been developed. The use of amide carbonyl as a chelating group efficiently furnishes a series of protected α,α-difluoro-γ-amino acid esters. The reaction can also extend to bromoacetate and 2-bromomalonate. The advantages of this protocol are high functional group tolerance and a broad substrate scope, including a variety of N-vinylamides. In particular, the use of removable amide carbonyl groups provides potential opportunities for applications in peptide chemistry and protein engineering.

Full text of DOI:10.1039/c9cc09866f

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DOI: 10.1039/C9CC09866F
Journal Name
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Nickel-Catalyzed Carbodifunctionalization of N-Vinylamides
Enables Access to -Amino Acids
a
b
,a
, b
Received 00th January 20xx,
Accepted 00th January 20xx
Zhi-Fang Yang , Chang Xu , Xing Zheng* , Xingang Zhang*
DOI: 10.1039/x0xx00000x
www.rsc.org/
A
nickel-catalyzed tandem reaction of N-vinylamides with amino acids is difficult because of the difficulty in the cleavage
4
arylboronic acids and bromodifluoroacetate has been developed. of amide bond from 2-pyrrolidinone. We envisioned that the
The use of amide carbonyl as a chelating group efficiently furnishes rigid skeleton 2-pyrrolidinone bearing a chelating carbonyl
a series of protected ,-difluoro--amino acid esters. The reaction group may be unnecessary to promote the reaction and the use
can also extend to bromoacetate and 2-bromomalonate. The of simple enamides that bearing a removable amide carbonyl
advantages of this protocol are high functional group tolerance and moiety would lead to a variety of ,-difluoro--amino acids
broad substrate scope, including a variety of N-vinylamides. In (Scheme 1B). To the best of our knowledge, only limited
particular, the use of removable amide carbonyl groups provides methods to access this kind of structural motif have been
7
potential opportunities for applications in peptide chemistry and reported thus far, in which the requirement of multiple-step
protein engineering.
procedure restricts their widespread synthetic applications.
Herein, we report a nickel-catalyzed carbodifunctionalization of
N-vinylamides with a removable chelating group (Scheme 1B).
This reaction assembles simple enamides, arylboronic acids and
bromodifluoroacetate together, providing an efficient access to
diversified protected ,-difluoro--amino acids. The reaction
can also extend to bromoacetate and 2-bromomalonate. To
demonstrate the utility of this approach, transformations of the
resulting fluorinated -amino acids were performed to provide
the dipeptide and lactam efficiently, thus offering potential
opportunities for applications in the synthesis of peptide-based
Fluorinated amino acids have received increasing attention due
to their important applications in medicinal chemistry and
1
chemical biology. The incorporation of fluorinated amino acids
into peptides can improve the bioavailability, enzymatic
stability and therapeutic profile of peptides. Due to the unique
properties of fluorine atom(s), the fluorinated groups have
prominent effect on the primary and secondary structure of
peptides and proteins. Therefore, it is of great interest to
develop new and efficient methods to prepare fluorinated
amino acids.
Recently, we have developed a chelating group assisted (CGA)
strategy to prepare gem-difluoroalkylated 2-pyrrolidinone
derivatives through nickel catalyzed tandem reaction of N-vinyl
2
3
1
,2
bioactive molecules.
A. Previous Work
ArB(OH)2
cat. [Ni]
N
N
N
O
CF2R
NiII(L )X
and
+
O
O
CF2R
n
Ar
2
-pyrrolidinone with arylboronic acids and difluoroalkyl
BrCF R
2
Ar
4
via
bromides (Scheme 1A). This reaction uses carbonyl as a
chelating group, representing the first example of CGA, nickel-
catalyzed three-component difunctionalization of alkenes.
Difficult to Remove
5
,6
B. This Work
ArB(OH)2
Structure
Diversification
O
However, application of this reaction to the synthesis of -
H
cat. [Ni]
N
and
+
NH
O
CF2CO2Et
Ar
BrCF2CO2Et
a. Hunan Province Cooperative Innovation Center for Molecular Target New Drug
Removable
Study, Hunan Provincial Key Laboratory of tumor microenvironment responsive
drug research, Institute of Pharmacy and Pharmacology, University of South China,
Hengyang, Hunan, 421001, China. E-mail: zhengxing9166@sohu.com
Scheme
1 Chelating group assisted Ni-catalyzed tandem reaction of enamides
b.
Key Laboratory of Organofluorine Chemistry, Center for Excellence in Molecular
Synthesis, Shanghai Institute of Organic Chemistry, University of Chinese
Academy of Sciences, Chinese Academy of Sciences, 345 Lingling Lu, Shanghai
We began our initial studies by choosing commercially
available N-vinylacetamide 1a, arylboronic acid 2a, and
bromodifluoroacetate 3a as model substrates (Table 1). A 44%
2
00032, China. E-mail: xgzhang@mail.sioc.ac.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
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yield of the desired α, α-difluoro-γ-amino acid ester 4 was
obtained when the reaction was carried out with 1a (1.0 equiv),
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With the viable reaction conditions in
D
h
O
a
I
n
:
d
10
,
.1
a
03
w
9
i
/
d
C
e
9C
r
C
an09
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e of
66
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arylboronic acids were examined (Table 2). Generally, both
electron-rich and electron-deficient arylboronic acids
underwent the current tandem reaction smoothly, providing
the corresponding products with moderate to high yields (5-15).
The reaction exhibited good functional group tolerance. A
variety of important functional groups, including ester,
enolizable ketone, formyl, nitrile, silyl, thioether and
dibenzo[b,d]furan moiety were compatible to the reaction (11-
2
a (2.0 equiv) and 3a (1.5 equiv) in the presence of NiCl
2
DME
(
5 mol %), bipyridine (bpy, L1, 5 mol %), and K CO (3.0 equiv) in
2
3
o
dioxane at 80 C (entry 1). Screening 4,4'-disubstituted bpy
revealed that the electronic nature of the substituents
influenced the reaction efficiency (entries 2-6). Electron-
donating groups decreased the yield of 4 (entries 2 and 3), but
3
the use of electron-deficient ligand 5,5'-diCF -bpy could
improve the yield of 4 to 60% (entry 6). This finding implies that 17, 20). Importantly, aryl bromide- and phenol-containing
a slightly electron-deficient bpy ligand may benefit the reaction arylboronic acids were also competent coupling partners (18,
efficiency through chelation of active nickel complex with amide 19), thus providing good platforms for downstream
transformations. It is also possible to scale up the reaction as
demonstrated by the gram-scale synthesis of compound 4.
carbonyl to form the key intermediate, thus facilitating the
catalytic cycle. 1,10-Phenanthroline (phen, L7) was also
examined, but less reactivity was observed (entry 7). A survey
Table 2 Ni-catalyzed difluoroacetylation-arylation of N-vinylacetamide 1aa
of the nickel catalysts revealed that Ni(OTf)
choice, providing 4 in 79% yield upon isolation (entry 10). Other
nickel catalysts, such as NiBr DME and NiBr diglyme, showed
comparable reactivity (entries 8 and 9). While, NiCl led to no
product (entry 11). A variety of bases were tested, K CO
remained the best base (for details, see the Supporting
Information). No product was obtained without nickel catalyst
or ligand (entries 12 and 13), thus demonstrating that the Ni/L6
plays an essential role in promotion of the reaction.
2
was the optimal
ArB(OH)2
Ni(OTf)2 (5 mol %)
L6 (5 mol %)
2
H
O
Ar
O
N
2
2
and
+
CF2CO2Et
K2CO3 (3.0 equiv)
1,4-dioxane, 80 oC, 8 h
N
H
BrCF2CO2Et
1a
2
3a
2
3
Ph
R
O
O
O
CF2CO2Et
CF2CO2Et
CF2CO2Et
N
N
N
H
H
H
R = Me, 5, 81%
R = tBu, 6, 62%
4
, 79%, 65%b
7, 92%
Table 1 Representative results for optimization of Ni-catalyzed difluoroacetylation-
arylation of N-vinylacetamide 1aa
R
CF3
CO2Et
B(OH)2
H
[
Ni] (5 mol%)
L (5 mol%)
O
N
O
O
O
Ph
H
CF2CO2Et
CF CO Et
2
2
CF CO Et
2
2
2
2
CF CO Et
O
N
2a
N
H
N
H
N
H
+
2 3
K CO (3.0 equiv)
1,4-dioxane, 80 oC, 8 h
R = PhO,
8, 67%
R = MeO, 9, 84%
and
1
0, 81%
11, 86%
1a
Ph
BrCF2CO2Et
3a
4
O
CHO
CO2Et
L1, R1 = H; L2, R1 = tBu
R1
R1
O
L3, R1 = OMe
O
O
F3C
CF3
CF2CO2Et
L4, R1 = F
N
H
CF2CO2Et
CF2CO2Et
N
N
N
H
N
N
N
H
N
N
L5, R1 = CO Me
2
L6
L7
1
2, 85%
13, 67%
14, 42%
b
Entry
[Ni]
L
Yield of 4 (%)
CN
TMS
SEt
1
2
3
4
5
6
7
8
9
NiCl
NiCl
NiCl
NiCl
NiCl
NiCl
NiCl
2
·DME
·DME
·DME
·DME
·DME
·DME
·DME
L1
L2
L3
L4
L5
L6
L7
L6
L6
L6
L6
L6
44
30
O
O
O
2
CF CO Et
2
2
CF CO Et
2
2
2
2
CF CO Et
N
H
N
H
N
H
2
2
2
2
2
22
1
5, 43%
16, 59%
17, 85%
32
Br
OH
36
O
O
O
O
60
CF2CO2Et
CF2CO2Et
CF2CO2Et
N
H
N
H
N
H
24
1
8, 68%
19, 58%
20, 36%
NiBr
NiBr ·diglyme
Ni(OTf)
NiCl
none
NiCl ·DME
2
·DME
76
a
Reaction conditions (unless otherwise specified): 1a (0.4 mmol, 1.0
equiv), 2 (0.8 mmol, 2.0 equiv), 3a (0.6 mmol, 1.5 equiv), K CO (3.0
synthesis.
2
3
2
76
b
equiv),
1,4-dioxane
(4
mL).
Gram-scale
1
1
1
1
0
1
2
3
2
80 (79)
nd
2
In addition to arylboronic acids, a series of N-vinylamides
were tested (Table 3). Substrates bearing removable N-
protecting groups, such as formyl and Boc, were applicable to
the reaction (21, 22). Even gram-scale synthesis of N-Boc ,-
difluoro--amino acid ester 22, moderate yield was still
obtained (22). Furthermore, N-vinylcarboxamides bearing
propionyl, butanoyl, or bulky isobutanoyl group, furnished the
corresponding products in good yields (23-25). N-
nd
2
none
nd
aReaction conditions (unless otherwise specified): 1a (0.4 mmol, 1.0
equiv), 2a (0.8 mmol, 2.0 equiv), 3a (0.6 mmol, 1.5 equiv), K CO (3.0
NMR using
2
3
b
19
equiv), 1,4-dioxane (4 mL). Determined by
F
fluorobenzene as an internal standard and number in parenthesis is the
isolated yield.
2
| J. Name., 2012, 00, 1-3
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Journal Name
vinylcyclobutanecarboxamide
carboxamide were also applicable to the reaction (26, 27),
offering good opportunities for the synthesis of diversified ,-
difluoro- γ -amino acid derivatives. Notably, non-fluorinated
bromoacetate and 2-bromomalonate (28-31) and internal
enamide (32) were also suitable substrates, thus demonstrating
the generality of this protocol.
COMMUNICATION
and
N-vinylthiophene-2- dipeptides. It is also possible to efficiently prepare fluorinated lactam
View Article Online
DOI: 10.1039/C9CC09 88 66F
3
5, a key intermediate for the synthesis of bioactive molecule, by
treatment of 22 with trifluoroacetic acid (Scheme 2C). Compared to
our previous report, the advantage of the current process is the
synthetic simplicity and diversity; in particular, the chelating group
amide carbonyl can be readily removed, providing an efficient route
for applications in the synthesis of peptide-based bioactive
molecules.
4
Table 3 Ni-catalyzed carbodifunctionalization of N-vinylamidesa
O
O
Ar
Ph
Ph
ArB(OH)2
A
B
C
R1
Ni(OTf)2 (5 mol %)
L6 (5 mol %)
CF2CO2Et
2
1) 6 N HCl
H
R
R
N
H
O
N
dioxane, 80 o
C
and
O
+
or
K2CO3 (3.0 equiv)
1,4-dioxane, 80 oC, 8 h
R
CF2CO2Et
2) (Boc) O, THF
CF CO H
1
N
2
2
2
BrCF2CO2Et
BocHN
Ar
H
or
4
33, 64%
1
2
CHR R
1
2
BrCHR R
N
H
3
Ph
1) (Boc)2O, DMAP, rt
Ph
) NaOH, 0 o
2
C
Ph
Ph
Ph
3) NH -Val-OMe
2
O
F
F
O
HOBT, EDC,Et2N/DMAP
CH3CN, rt
H
N
CF2CO2Et
H
N
BocHN
O
O
O
H
O
CF2CO2Et
CF2CO2Et
21
CF2CO2Et
H
N
Et
N
H
34, 80% (dr = 1:1)
BocHN
H
Ph
Ph
21, 46%
22, 63%, 46%b
23, 78%
CF3CO2H, DCM
Ph
Ph
Ph
CF2CO2Et
HN
BocHN
F
O
F
22
O
O
O
3
5, 50%
CF2CO2Et
CF2CO2Et
CF2CO2Et
nPr
N
iPr
N
N
Scheme 2 Transformations of N-protected ,-difluoro--amino acid esters
H
H
H
2
4, 70%
25, 88%
26, 86%
On the basis of previous reports,4, 9, 10 a plausible mechanism was
proposed (Scheme 3). The reaction was initiated by nickel(I) (A),
which was generated through the comproportionation of nickel(II)
Ph
OPh
2
CO Et
1
1
O
O
O
and in situ generated nickel(0) . Transmetallation of nickel(I) with
CF2CO2Et
CH CO Et
2 2
CH CO Et
S
2
2
I
N
H
N
N
H
arylboronic acid provided arylnickel(I) complex [Ar-Ni (L
n
)] (B).
H
Complex B reacted with bromodifluoroacetate via a single electron
27, 85%
28, 48%
29, 53%
II
transfer (SET) pathway to give arylnickel(II) complex [Ar-Ni (L
n
)Br] (C)
and difluoroacetyl radical. Subsequently, the difluoroacetyl radical
was trapped by N-vinylamide to generate a new alkyl radical. With
the aid of chelating amide carbonyl,4, 9 recombination of C with the
newly generated alkyl radical to produce the key intermediate
nickel(III) complex E. Finally, reductive elimination of E produced the
final product and released the nickel(I) simultaneously.
CO2Et
CO2Et
Ph
O
CO2Et
CO2Et
O
CO2Et
CO2Et
O
CF2CO2Et
Me
N
H
N
N
H
H
H
30, 58%
31, 58%
32, 58%, dr = 13:1
aReaction conditions (unless otherwise specified): 1 (0.4 mmol, 1.0
equiv), 2 (0.8 mmol, 2.0 equiv), 3 (0.6 mmol, 1.5 equiv), K
equiv), 1,4-dioxane (4 mL). Gram-scale synthesis.
2
CO
3
(3.0
In conclusion, we have developed a nickel catalyzed
carbodifunctionalization of enamides with arylboronic acids
and bromodifluoroacetate. The reaction can also extend to
bromoacetate and 2-bromomalonate. The use of removable
amide carbonyl as a chelating group provides an efficient
strategy to prepare a variety of ,-difluoro--amino acid
derivatives. The resulting fluorinated amino acids can serve as
useful building blocks for various transformations, including
efficient synthesis of peptide and lactam. Because of the high
functional group tolerance, broad substrate, and synthetic
b
To demonstrate the utility of this protocol, transformations of
different N-protected ,-difluoro--amino acid esters were
conducted (Scheme 2). Treatment of compound 4 with 6 N HCl in
dioxane afforded deprotected ,-difluoro--amino acid efficiently,
which subsequently was protected with Boc to provide N-Boc amino
acid 33 in 64% yield (Scheme 2A). Additionally, the N-protected ,-
difluoro--amino acid ester could be used for the synthesis of
dipeptide. As shown in Scheme 2B, protection of compound 21 with simplicity and efficiency of this protocol, it provides potential
Boc, followed by deprotection of formyl group under basic condition opportunities for applications in peptide chemistry and protein
afforded N-Boc amino acid, which was then condensed with valine engineering. Further studies to develop catalytic asymmetric
methyl ester (NH
:1 dr value. Notably, the resulting diastereoisomers could be easily
2
-Val-OMe) to give dipeptide 34 in 80% yield with synthesis are in progress in our lab, and will be reported in due
course.
1
separated by flash chromatography to afford two optically pure
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Journal Name
0
II
Ni (Ln) + Ni (Ln)X2
Soc., 2017, 139, 10653; (b) J. Derosa, V. T. Tran, M.VNiew. BAortiuclleoOunsl,inJe.
O
Ar
CF2CO2Et
S. Chen, K. M. Engle, J. Am. Chem. Soc., 20D17O,I:11309.1,013096/C579;C(Cc0)9W86. 6LiF,
J. K. Boon, Y. Zhao, Chem. Sci., 2018, 9, 600.
R
N
ArB(OH)2
H
I
Ni (Ln)X
6
For a nickel-catalyzed three-component conjunctive cross-coupling
of nonfluorinated substrates, see: (a) T. Qin, J. Cornella, C. Li, L. R.
Malins, J. T. Edwards, S. Kawamura, B. D. Maxwell, M. D. Eastgate,
P. S. Baran, Science, 2016, 352, 801; For nickel-catalyzed three-
component reductive couplings, see: (b) A. Garcia-Dominguez, Z.
Li, C. Nevado, J. Am. Chem. Soc., 2017, 139, 6835; (c) W. Shu, A.
Garcia-Dominguez, M. T. Quiros, R. Mondal, D. J. Cardenas, C.
Nevado, J. Am. Chem. Soc., 2019, 141, 13812.
A
H
N
CF2CO2Et
NiIII(Ln)X
I
R
Ar-Ni (Ln) B
O
Ar
E
EtCO2CF2Br
7
(a) T. Okano, N. Takakura, Y. Nakano, A. Okajima, S. Eguchi,
Tetrahedron, 1995, 51, 1903; (b) T. Tsukamoto, T. Kitazume, J. J.
McGuire, J. K. Coward, J. Med. Chem., 1996, 39, 66.
H
N
R
CF2R
EtCO2CF2
O
II
8 (a) T. Yajima, K. Yamaguchi, R. Hirokane, E. Nogami, J. Fluorine
Chem., 2013, 150, 1; (b) T. Sifferlen, A. Boller, A. Chardonneau, E.
Cottreel, J. Gatfield, A. Treiber, C. Roch, F. Jenck, H. Aissaoui,J. T.
Williams, C. Brotschi, B. Heidmann, R. Siegrist, C. Boss, Bioorg.
Med. Chem. Lett., 2015, 25, 1884; (c) H. Aissaoui, C. Boss, C.
Brotschi, B. Heidmann, T. Sifferlen, J. T. Williams, WO 2012063207
A1, 2012.
Ni (Ln)X
+
II
Ar
Ar-Ni (Ln)X
C
D
O
R
N
H
1
9 C. Xu, Z.-F. Yang, L. An, X. Zhang, ACS Catal., 2019, 9, 8224.
10 Q. Lin, T. Diao, J. Am. Chem. Soc., 2019, 141, 17937.
Scheme 3 Proposed mechanism
1
1 J. Cornella, E. Gomez-Bengoa, R. Martin, J. Am. Chem. Soc., 2013,
35, 1997.
1
This work was financially supported by the National Natural
Science Foundation of China (No. 21931013, 21672238, and
2
1421002), the Strategic Priority Research Program of the
Chinese Academy of Sciences (No. XDB20000000) and SIOC.
Conflicts of interest
There are no conflicts to declare.
Notes and references
1
(a) J. T. Welch, A. Gyenes, M. J. Jung, in General Features of
Biological Activity of Fluorinated Amino Acids: Design,
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R. Smits, B. Koksch, Curr. Top. Med. Chem., 2006, 6, 1483.
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For selected reviews, see: (a) E. N. G. Marsh, Acc. Chem. Res., 2014,
4
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S. Ye, B. Koksch, Chem. Soc. Rev., 2012, 41, 2135; (e) A. A. Berger,
J. Voller, N. Budisa, B. Koksch, Acc. Chem. Res., 2017, 50, 2093; (f)
V. Gouverneur, K. Seppelt, Chem. Rev., 2015, 115, 563; (g) S.
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(
h) J. Moschner, V. Stulberg, R. Fernandes, S. Huhmann, J. Leppkes,
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K. Müller, C. Faeh, F. Diederich, Science, 2007, 317, 1881; (b) W. K.
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5
J. W. Gu, Q. Q. Min, L. C. Yu, X. Zhang, Angew. Chem., Int. Ed., 2016,
5
5, 12270.
For applications of CGA strategy in the Ni-catalyzed
carbodifunctionalization of alkenes, see: (a) B. Shrestha, P. Basnet,
R. K. Dhungana, S. Kc, S. Thapa, J. M. Sears, R. Giri, J. Am. Chem.
4
| J. Name., 2012, 00, 1-3
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