Asymmetric construction of quaternary α-nitro amides by palladium-catalyzed C(sp3)-H arylation

Article abstract of DOI:10.1039/c9cc07854a

Pd-Catalyzed enantioselective C(sp³)-H arylation of N-(o-Br-aryl) anilides has been disclosed, and quaternary α-nitro amides were constructed with up to 98% ee. The presence of the nitro group on the substrate enables the progress of the reaction and the ready transformation of the product to optically active quaternary amino acid derivatives.

Full text of DOI:10.1039/c9cc07854a

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DOI: 10.1039/C9CC07854A
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Asymmetric Construction of Quaternary α-Nitro Amides by Palla-
dium-Catalyzed C(sp3)–H Arylation
Wei-Xin Konga, Shi-Jing Xiea, Chen-Yao-Zi Caoa, Chao-Wei Zhanga, Chuanyong Wanga and Wei-
Received 00th January 20xx,
Accepted 00th January 20xx
Liang Duan*a,b
DOI: 10.1039/x0xx00000x
Pd-catalyzed enantioselective C(sp3)-H arylation of N-(o-Br-aryl) C(sp2)-H arylation of alkenyl triflates,10 and this catalytic system
anilides has been disclosed, and quaternary α-nitro amides were has been extended to construct a wide variety of compounds
constructed with up to 98% ee. The presence of the nitro group on with carbon-11 and phosphorous-centered chirality,12 planar
the substrate enables the progress of the reaction and the ready chirality,13 and axial chirality14. With respect to palladium-
transformation of the product to optically active quaternary amino catalyzed intramolecular asymmetric C(sp3)-H activation, only a
acid derivatives.
few successful examples15-18 were disclosed and the reactions
were usually carried out at high temperature (>135 °C) to break
the strong C(sp3)-H bond and complete the entire reaction
process via a concerted metalation deprotonation19 (CMD)
mechanism (Scheme 1). In this regard, Kündig has first disclosed
a palladium/chiral N-heterocyclic carbene catalyst for the
enantioselective construction of indolines with excellent
enantioselectivities.15 Soon after that, Kagan,16 and Cramer17
also reported their protocols for the same reaction
independently by using different chiral phosphine ligands. We
wondered that asymmetric C(sp3)-H reaction could happen at
relatively mild conditions by introducing a strong electron-
withdrawing group into the substrate, which may reduce the
required activation energy for the C(sp3)-H bond cleavage
according to CMD mechanism.20 On the basis of this hypothesis,
to continue our interest in the enantioselective C-H activation
reaction,12a,21 we reported an intramolecular arylation for the
construction of optically active quaternary α-nitro amides with
excellent enantioselectivities, which are suitable precursors for
the preparation of quaternary amino acid derivatives.
Quaternary α,α-disubstituted α-amino acids are important
and valuable chemicals that have been widely utilized as
enzyme inhibitors, ligands in catalysis, and key units for the
preparation of modified peptides and proteins not found in
nature.1 Compared to natural peptides, peptides made from
quaternary α-amino acids often show enhanced stability against
chemical and enzymatic degradation.2 Consequently synthetic
methodologies for quaternary α-amino acids have been
explored for decades.3 The main reported methods include the
alkylation or addition of a glycine ester and its equivalents to
electrophiles under phase transfer catalysis,4 the asymmetric
addition of cyanides to ketonimines,5 and the allylic alkylation
of glycine esters under transition-metal catalysis.6 Despite this
expressive progress, considering the wide utility of quaternary
amino acid derivatives, the development of new synthetic
methodologies is still a high necessity.
Cleavage and transformation of the C-H bond is a direct
pathway for the preparation of functionalized molecules, and
numerous methods have been developed recently with the use
of various metal catalysts.7 Asymmetric C-H activation has also
received much attention but with limited success.8,9 The
palladium-catalyzed asymmetric intramolecular arylation
reaction is a direct and efficient route for the generation of
fused carbocycles and heterocycles. Cramer et al. first reported
a seminal example on the enantioselective intramolecular
X
R
*
cat. Pd/ chiral ligand
N
N
EWG
EWG
X: Br or OTf
iPr
iPr
N
N
P
OiPr
P
P
I
iPrO
ref. 15a: Kündig
up to 95% ee
at 140 °C
ref. 16: Kagan
up to 93% ee
at 140 °C
ref. 17: Cramer
up to 96% ee at 135 °C
aCollege of Chemistry and Chemical Engineering, Yangzhou University, 180
Siwangting Road, Yangzhou 225002, China. E-mail: duanwl@yzu.edu.cn.
bSchool of Chemistry and Chemical Engineering, Shaanxi Normal University
Xi’an 710119, China
Scheme 1. Representative Examples on Asymmetric Pd-catalyzed Intramolecular
Arylation.
Electronic Supplementary Information (ESI) available: [details of any supplementary
information available should be included here]. See DOI: 10.1039/x0xx00000x
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Journal Name
This reaction was initiated with substrate 1a N-(o- temperature of 160 °C to achieve 60% yield with 5V2ie%w Aeretic.leTOhnelisnee
DOI: 10.1039/C9CC07854A
bromophenyl)-N-methyl-isobutyramide having a α-nitro group results imply that the current reaction also proceeds via a
in the presence of a palladium catalyst and phosphorus ligand concerted metalation deprotonation (CMD) mechanism.
(Table 1). First, screening achiral phosphine ligands indicated
To demonstrate the utility of the developed methods, the
that PCy3 is an effective ligand (Entry 1). As we expected, the nitro group of product 2b can be readily reduced to the amine
racemic reaction occurred with 81% yield at 100 °C, which is moiety (Scheme 4a), and the 4-PMB group on the nitrogen atom
much lower than the reported 160 °C for the C-H arylation of can also be removed under mild conditions to generate the
the amide having α-methyl moiety.22 Next, chiral phosphorus desired compound 2w in 90% yield (Scheme 4b).
ligands were further investigated, and neither the well-known
Table 1. Optimization of the Enantioselective C(sp3)-H Arylation of 1a.
BINAP L1 nor the BINOL skeleton-based phosphoramidite L2
gave the product (Entries 2 and 3), (S,S,S)-SKP ligand23 L3
O
R1
R1
O
N
10 mol% cat. 20 mol% ligand
N
developed by Ding et al. afforded the product with 50% ee
(Entry 4). The use of (S)-Methoxy-MOP24 generated 36% ee of
2a in 80% yield (Entry 5). Taddol-derived phosphoramidites (L5-
L9) have also been examined (Entries 6-15).25 The results
revealed that ligand L9 bearing a 3,5-(bis-tertbutyl)phenyl
substituent afforded product 2a with the highest
enantioselectivity (93% ee) with 32% yield (Entry 10). Switching
the palladium acetate to the Pd(Cp)allyl complex17a,26 and
increasing the amount of ligand to 25 mol% resulted in an
increase in the yield to 70% with the same level of enantiomeric
excess (Entry 11). Interestingly, by changing the methyl group
on the nitrogen atom to a 4-methoxyl benzyl (PMB) substituent,
the use of starting compound 1b led to the formation of desired
compound 2b with an improvement in both the
enantioselectivity and yield (Entry 12, 98% ee and 85% yield). In
contrast, the use of PCy3 as the ligand resulted in the formation
of N-Acyl-5,6-dihydrophenanthridine 2b' (43% yield) as the
major product along with 2b (35% yield), and NH substrate
without the PMB substituent on the nitrogen atom has no
reactivity under the same reaction conditions (Entry 12).27
These results suggest that ligand L9 plays an important role both
in the control of enantioselectivity of the C(sp3)-H product and
in the suppression of the formation of the byproduct via
relatively easy C(sp2)-H activation on the PMB aryl ring. Finally,
the screening of solvents did not further improve the yield and
enantiomeric excess of the product 2b (Entries 13 to 15).
O2N
Br
1-AdCOOH (30% mol),
K2CO3 (1.5 equiv.)
solvent, 100 °C, 24 h
O2N
1 = Me
2a,
R
1 = Me
1a,
R
1 = PMB
2b,
R
1 = PMB
1b,
R
PPh2
PPh2
O
OMe
PPh2
P
N
O
O
O
PPh2 Ph2P
L3
L1
L2
, Ar=phenyl, R=Et
L4
Ar
Ar
Ar
O
P
O
Ar
L5
O
O
L6,
L7,
L8,
L9,
Ar=phenyl, R=-(CH2)5-
Ar=phenyl, R=Me
NR2
Ar=3,5-dimethylphenyl, R=Me
Ar=3,5-di-tert-butylphenyl, R=Me
ligand
yield
ee
(%)c
entry
Pd. Salt
solvent
toluene
(mol%)
PCy3
(%)b
81
0
1
2
3
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
-
-
-
(R)-L1
(S)-L2
toluene
toluene
0
4
Pd(OAc)2
(S,S,S)-L3
toluene
6
50
5
6
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
(S)-L4
toluene
toluene
80
19
9
36
70
46
80
90
93
93
98
98
-
(R,R)-L5
(R,R)-L6
(R,R)-L7
(R,R)-L8
(R,R)-L9
(R,R)-L9
(R,R)-L9
(R,R)-L9
(R,R)-L9
(R,R)-L9
7
toluene
8
toluene
13
20
32
70
85
40
0
9
toluene
10
11d
12e
13e
14e
15e
toluene
Pd(Cp)(C3H5)
Pd(Cp)(C3H5)
Pd(Cp)(C3H5)
Pd(Cp)(C3H5)
Pd(Cp)(C3H5)
toluene
toluene
1,4-dioxane
DMF
t-amyl-OH
60
98
The substrate scope was examined under the optimized
conditions obtained (Table 2). Compound 1, which has diverse
electron-rich or -deficient moieties, such as methyl, methoxyl,
fluoro, chloro, trifluoromethyl, nitrile, and trifluoromethoxyl,
on the aryl ring at the 3-, 4-, 5-, and 6-positions were all
tolerated, and the corresponding products 2a-2q were
constructed in excellent enantioselectivity (88 to 98% ee). The
absolute configuration of product 2 was assigned to be S
according to X-ray crystal diffraction analysis of product 2k.28 In
addition, a double C-H arylation reaction was conducted by
employing substrate 1r, and the fused four-membered ring 2r
was isolated in 90% ee and 50% yield (Scheme 2). To further
elucidate the effect of the α-substituent group, the reaction was
conducted with compounds (1s-1u) containing trifluoromethyl,
ethyl ester, and ethyl moieties (Scheme 3). The progress of the
reaction was significantly affected by the electron density of the
α-substituent. The presence of an electron-deficient group
facilitated the progress of the reaction. The reaction of
substrate 2u, with an ethyl moiety under the current reaction
conditions, did not proceed at all at 120 °C and required a higher
aReaction conditions unless otherwise noted: 1a (0.10 mmol), catalyst (0.01 mmol),
ligand (0.02 mmol), K2CO3 (0.15 mmol), 1-AdCOOH (0.03 mmol), toluene (1 mL)
under a N2 atmosphere at 100 °C for 24 h. Isolated yields. Determined by chiral
HPLC. dWith Ligand (0.025 mmol), K2CO3 (0.20 mmol), 1-AdCOOH (0.05 mmol).
e1b (0.1 mmol), Catalyst (0.01 mmol), Ligand (0.025 mmol), K2CO3 (0.20 mmol),
1-AdCOOH (0.05 mmol), toluene (1 mL) under a N2 atmosphere at 100 °C for 24
h.
b
c
PdCp(C3H5) (20 mol%)
(50 mol%)
K2CO3 (4 equiv.)
L9
O
Br
O
N
N
1-AdCOOH (50 mol%)
toluene
O2
N
Br
100 °C 24 h
O2N
,
2r
50% yield, 90% ee
1r
Scheme 2. Enantioselective Double C-H Arylation of 1r.
2 | J. Name., 2012, 00, 1-3
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In summary, we have disclosed a direct meVthiewodArtifcolerOntlhinee
construction of quaternary α-nitro amides with excellent
enantioselectivities. The involvement of the α-nitro group in the
substrate not only enables the success of the expected
transformation but also facilitates the product transformation
to quaternary amino acid derivatives.
O
PdCp(C3H5) (10 mol%)
L9
K2CO3 (2.0 equiv.)
(25 mol%)
R
DOI: 10.1039/C9CC07854A
O
N
N
Br
1-AdCOOH (50 mol%)
toluene
R
100 °C 24 h
,
1a
1t
, 1s
R = CF3
R = NO2
R = CO2Et
2a, 2s-2u
, 1u
R = Et
O
O
N
N
O
O
N
N
We thank Prof. Kuiling Ding at Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences for kindly donating
ligand L3. This work was financially supported by the NSFC
(21672183, and 21871168), the Priority Academic Program
Development of Jiangsu Higher Education Institutions, and Top-
notch Academic Programs Project of Jiangsu Higher Education
Institutions.
O2N
F3C
EtOOC
Et
120 °C: N.R.
2t
2u
2a
2s
no desired product
formed
70% yield, 93% ee 60% yield, 62% ee
160 °C: 60% yield, 52% ee
Scheme 3. Investigations on α-Substituent Effect of 1.
Table 2. Substrate Scopea,b,c
PdCp(C3H5) (10 mol%)
L9
K2CO3 (2 equiv.)
O
R2
(25 mol%)
R2
O
N
N
O2N
R1
Br
AdCOOH (50 mol%)
toluene
Conflicts of interest
There are no conflicts to declare”.
R1
O2N
100 °C 24 h
,
PMB
PMB
PMB
N
O
N
O
O
O
N
N
OMe
OMe
O2N
O2N
O2N
O2N
Notes and references
2a
2b
2c
2d
70% yield, 93% ee
85% yield, 98% ee
71% yield, 95% ee
77% yield, 97% ee
PMB
1
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Vol. 3 ed. A. B. Hughes, Wiley-VCH, Weinheim, 2010; (b)
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PMB
PMB
PMB
O
N
O
O
O
N
N
N
F
O2N
O2N
O2N
O2N
2e
2f
78% yield, 98% ee
2g
2h
70% yield, 95% ee
30% yield, 97% ee
81% yield, 98% ee
PMB
PMB
N
PMB
F
O
O
O
N
N
F
F
F
2
3
O2N
O2N
O2N
2i
2j
2k
74% yield, 98% ee
64% yield, 97% ee
83% yield, 97% ee
2k
ORTEP illustration of
PMB
PMB
PMB
PMB
O
N
O
O
O
N
N
N
Cl
CF3
Cl
CF3
O2N
O2N
O2N
O2N
2l
2m
2n
50% yield, 88% ee
2o
51% yield, 97% ee
71% yield, 95% ee
86% yield, 98% ee
PMB
PMB
O
N
O
N
CN
OCF3
O2N
O2N
2p
30% yield, 96% ee
2q
84% yield, 96% ee
4
aReaction conditions unless otherwise noted: 1 (0.10 mmol), [PdCp(C3H5)] (0.01
mmol), L9 (0.025 mmol), K2CO3 (0.20 mmol), 1-AdCOOH (0.05 mmol), in toluene
b
(1 mL) under a N2 atmosphere at 100 °C for 24 h. Yield of the isolated product.
cThe ee was determined by HPLC.
PMB
N
PMB
N
Zn (30 equiv.)
AcOH (40 equiv.)
O
O
(a)
(b)
i-PrOH, rt, 5 h
O2N
H2N
2v
2b
98% ee
78% yield, 98% ee
PMB
N
H
O
O
N
TFA [0.5 M]
anisole (4 equiv.)
rt, 24 h
5
O2N
O2N
2w
2b
98% ee
90% yield, 98% ee
Scheme 4. The Product Transformation.
Conclusions
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif
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