Weak coordinated nitrogen functionality enabled regioselective C-H alkynylationviaPd(ii)/mono-N-protected amino acid catalysis

Article abstract of DOI:10.1039/d0cc04739b

The exploration of weak coordinated amine derivative enabled regioselective C-H functionalization remains challenging due to the elusive achievement of reactivity and selectivity simultaneously. Herein, regioselective C-H alkynylation of various readily transformable nitrogen functionalities was developed with great efficiency, with the assistance of the mono-N-protected amino acid (MPAA) ligandviaPd(ii) catalysis proceedingvia5, 6 and 7-membered palladacycle intermediates.

Full text of DOI:10.1039/d0cc04739b

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DOI: 10.1039/D0CC04739B
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Weak Coordinated Nitrogen Functionality Enabled Regioselective
C‒H Alkynylation via Pd(II)/Mono-N-Protected Amino Acid
Catalysis
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
Bifu Liu,a Wensen Ouyang,b Jianhong Nie,b Yang Gao,b Kejun Feng,a Yanping Huo,b Qian Chen,b
Xianwei
Li*b
The exploration of weak coordinated amine derivatives enabled emerged as a reliable platform enabled concise construction of
regioselective C‒H functionalization remained challenging due to functionalized amine libraries.3 In this context, to well balance
the elusive achievement of reactivity and selectivity the reactivity of the metal catalyst and regioselectivity of the
simultaneously. Herein, regioselective C‒H alkynylation of various amine substrates, great efforts have been devoted in the
readily transformable nitrogen functionality, was developed with catalytic system and ligand design, which led to fruitful
great efficiency, with the assistance of mono-N-protected amino accomplishment. However, strong directing strategy with rigid
acid (MPAA) ligand under Pd(II) catalysis proceed via 5, 6 and 7- and intrinsic functionality, et. al., quinolone or pyridine derived
membered palladacycle intermediates.
amides and sulfonamides, would be hard to remove or for the
further transformation (Scheme 2). To omit the tedious
procedure for the additional introduction and removal of
directing groups, the use of readily available and
transformable amine derivatives held great synthetic
practicality.
Amines serves as versatile building blocks and ubiquitous
structural skeletons in pharmaceuticals, material and life
science. For instance, besides amino acids, benzylamines,
phenylethylamines, benzedrines also act as vital precursors of
pharmaceuticals, such as ampicillin, sensipar, sertraline,
venlafaxine and cinacalcet, which exhibited great bioactivities
as drugs (Scheme 1).1 The great utility of amines has
stimulated continuous development of general strategies for
their efficient construction and rapid manipulation, e.g.,
reductive amination, cross-couplings and direct C‒H
amination.2
a) CH Functionalization with strong coordinated amides and sulfonamides:
CP
R1
H
R1
R2
Cat.
Y
Y
H
N
H
N
Ar
Ar
CPs
R2
X = C, S=O; CPs: coupling partners
X
X
O
O
b) MPAA accelerated CH arylation with NHTf via Pd(II) catalysis:
R1 Ar
R1
R2
H
Pd(II) cat.
NHCOR'
R1 Ar
(Yu)
FG
NHTf
NHTf
R
R2
R2
ligand
R3
FG = CHO, CN, N3...
R3
R3
CO2
H
c) This work: MPAA facilitated Pd(II)-catalyzed CH alkynylation:
N-FG
n
OH
N-FG
n
Pd(II) cat.
NH2
Si
Br
H
O
H
H
N
Me
Me
S
OH
N-Boc-D-Leu-OH ligand
H
TIPS
via 5, 6, 7-membered palladacycle
HN
NH
n = 1, 2, 3
N
OMe
O
O
N
S
OEt
NH
O
HO
HO
Me
N
R
nNHTf
R
O
Ar
N
H
neupro
ampicillin
(broad-spectrum penicillin)
Formoterol
asthma/COPD
Ar
R
muscular skeletal disorder
Me Me
Me
Me
TIPS
S
TIPS
TIPS
TIPS
H
N
Me
N
O
Scheme 2. C‒H Functionalization of amine derivatives.
H
N
HO
F3C
To this end, key challenges and limitations lied in the
acquisition of practical C‒H transformations mainly included:
1) with readily available substrates, and delivering to easily
decorative products,4 which would make the overall process in
a concise manner, enabling the practical delivery of complex
molecular libraries; 2) proximal directing strategy was often
used for the achievement of regioselectivity in the C‒H
functionalization, while the development of remote control
cyclometalation intermediates, would be synthetically useful
and highly desirable.5
Me
Me
urinary disorders
tolterodine,
duloxetine
cinacalcet,
hormonal disorders
, antidepressant
Scheme 1. Selective amines skeletons in pharmaceuticals.
Considering the atom and step-economy of the overall
process, direct C‒H functionalization of amine derivatives has
a. School of Chemistry and Material Engineering, Huizhou University, Huizhou,
516007, China.
b. School of Chemical Engineering and Light Industry, Guangdong University of
Technology, Guangzhou, 510006, China. Email: xwli@gdut.edu.cn.
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
Our continuous efforts toward the efficient construction of
functionalized alkynes,6 recently, we have developed weak
coordination functionalities, such as ketones, esters and primary
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sulfonamides facilitated ortho C‒H alkynylation via Ir(III) catalysis. product 3a (entries 9,10), while the use of Cu(I)VoierwCArutic(lIeI)Osnlainlet
Considering the synthetic utility of amines, and inspired by Yu’s instead of Ag(I) led to no desired produDctO(I:e1n0t.1r0y319/1D)0. CACd0d4i7t3io9nB
pioneer work on MPAA (mono-N-protected amino acids) of protonic acid such as PivOH led to poor yield of product 3a
accelerated C‒H bond functionalizations,7 we reported herein a (entry 12), solvent such as DMF or toluene gave inferior results
versatile Pd(II)/MPAA catalytic system enabled regioselective C‒H (entry 13). And lower the temperature to 60 oC gave
alkynylation of weak coordinated amine derivatives. Key feature of moderated yield of 3a (entry14).
this transformation included: 1) amines, imines and amides could
With the optimal conditions in hand, we next explored the
serve as readily accessible and transformable substrates, via synthetic generality of aryl ethylamines in this regioselective C‒H
possible 5, 6 and 7-membered palladacycle intermediates. 2) Amino alkynylation under MPAA/Pd(II) catalysis (Scheme 3). Halides such
acid could also enable regioselective C‒H alkynylation of aryl as chloro at para or ortho position of arenes (3b, 3d), were
aldehydes via transient directing strategy, the overall compatible, which could be further modified via metal-catalyzed
transformation served as reliable platform, leading to rapid cross-couplings. Aryl ethylamines with readily transformable
construction of alkyne libraries.
Table 1. Optimization of reaction conditions. a
groups, e.g., nitro, on the arenes, also showed great efficiency (3c).
Notably, this transformation was sensitive to steric hindrance, when
exposure meta-substituted phenyl ethylamines to the standard
reaction conditions (3e, 3f), this C‒H alkynylation took place
exclusively at less hindered position. Heterocycles were also
suitable substrates in this reaction, when with 2-ethylamine
substituted thiophene under Pd(II)/MPAA catalysis, directing ability
of weak coordinated NHTf transcended the innate chemoselectivity,
and C‒H alkynylation proceeded at C3 position without the
observation of C5‒H alkynylation product (3g). Amino acid
derivatives, e.g., L-Tyrosine, (3i), could well participate in this C‒H
alkynylation.
Pd(OAc)2 (5 mol%)
NHTf
TIPS
N-Boc-L-Leu-OH (30 mol%)
NHTf
TIPS
Br
NaOAc (30 mol%)
AgOAc (1.0 equiv.)
DCE, 100 oC, 12 h
1a
Entry
2a
3a
Yield (%)b
83
Variation of standard condition
Standard condition
1
2
PdCl2 as the catalyst
79
NiCl2 as the catalyst
3
n.r.
n.r.
n.r.
n.r.
55
[Ru(p-cymene)Cl2]2 as the catalyst
[RhCp*Cl2]2 as the catalyst
with N,N-Dimethylglycine as the ligand
with Ac-Phe-OH as the ligand
with Ac-Gly-OH as the ligand
without Pd(OAc)2
4
5
Pd(OAc)2 (5 mol%)
N-Boc-L-Leu-OH (30 mol%)
NHTf
NHTf
O
HO
O
6
Ar
2a
Ar
NaOAc (30 mol%)
AgOAc (1.0 equiv.)
DCE, 100 oC, 12 h
N
O
1
H
N-Boc-L-Leu-OH
7
TIPS
3
8
64
Cl
NHTf
TIPS
NHTf
F
NHTf
NHTf
9
n.r.
26
Cl
O2N
without AgOAc
10
11
12
13
TIPS
TIPS
TIPS
NHTf
3b
3c
3d
3e
, 78%
, 84%
, 79%
NHTf
, 87%
Cu(OAc)2 instead of AgOAc
Addition of PivOH (0.5 equiv.)
Toluene or DMF as the solvent
< 10
22
MeO
NHTf
TIPS
NHTf
CO2Me
TIPS
S
TfO
TfO
< 10
58
TIPS
, 77%
TIPS
60 o
C
14
3f
3g
3h
3i
, 70%
, 74%
, 72%
O
O
Ligand:
O
OH tBu
O
O
O
Ph
OH
OH
N
N
HN
Scheme 3. Regioselective C‒H alkynylation of aryl ethylamines.
OH
H
O
N
O
H
N-Boc-L-Leu-OH
N,N-Dimethylglycine Ac-Phe-OH
Ac-Gly-OH
The above regioselective C‒H alkynylation of aryl
ethylamines, which might proceed via 6-membered iridacycle
intermediates, encouraged us to further investigate the
synthetic potential in C‒H alkynylation of benzyl amines via a
possible 5-membered organometallic intermediates. As
depicted in Scheme 4, halides such as fluoro (5c), chloro (5a,
5d), bromo (5f, 5g) could be compatible, affording to the
corresponding C‒H alkynylation products in high yields.
Electron-donating groups, e.g., methyl, methoxyl substituted
benzyl amines (5b, 5e, 5i) exhibited relatively higher yields to
that of electron-withdrawing groups. Notably, this
regioselective C‒H alkynylation showed no significant position
effect, for instance, with ortho, meta and para-methoxyl group
substituted benzyl amines (5h, 5i, 5j), proceeded smoothly.
Great efficiency was also observed in the regioselective C‒H
alkynylation with (R)-1-(naphthalen-1-yl)ethan-1-amine and
(R)-1-phenylethan-1-amine (5k, 5l).
a
Standard conditions: 1a (0.2 mmol), 2a (0.3 mmol), Pd(OAc)2 (5 mol%),
NaOAc (20 mol%), AgOAc (30 mol%), N-Boc-D-Leu-OH (10 mol%), DCE (1 mL),
air, 100 oC, 12 h.
To commence our study on amine directed ortho C‒H
alkynylation, we selected sulfonamide 1a as the model
substrate,8 and with bromoalkyne 2a as the alkynylation
reagent,9,10 under various metal catalysis. The results revealed
that Pd(II) exhibited great reactivity with the assistance of
mono-N-protected amino acid N-Boc-D-Leu-OH, and Pd(OAc)2
exhibited better performance than PdCl2 (entry 2). Notably,
the use of Ni(II), Rh(III), Ru(II) catalyst led to no desired alkyne
product 3a (entries 3-5). Notably, the addition of N-protected
amino acid derivatives significantly facilitate this
transformation (entries 6-8), and N-Boc-D-Leu-OH as ligand
gave the optimal yield of the ortho C‒H alkynylation product
3a. Control experiments showed that Pd(II) and AgOAc were
critical for the generation of the desired ortho alkynylation
Readily transformable imidate esters, which have been
demonstrated to serve as traceless directing groups in C‒H
2 | J. Name., 2012, 00, 1-3
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a) Remote control CH alkynylation of amines via 7-membered palladacycle intermediate:
activation,11 could also well participate in this regioselective
C‒H alkynylation (7a). The alcohol derived ketoxime 6b could
also furnish the desired C‒H alkynylation product 7b under this
versatile Pd(II)/MPAA catalytic system via a possible 6-
membered palladacycle intermediate. Notably, sterically
hindered alkyl substituted bromoalkyne was also suitable
alkynylation reagent, which enabled regioselective C‒H
alkynylation of primary amide, leading to alkyne product 7c.
Inspired by this amino acid ligand facilitated regioselective C‒H
alkynlation, amino alcohols and amino acids derived amides
could well undergo this reaction with great regioselectivity (7d,
7e). Notably, stereoselective construction of conjugated
enynes (7f, 7g, 7h), which serve as key skeletons in
pharmaceutical and advanced materials, were also realized.
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CO2Me
Pd(OAc)2 (5 mol%)
N-Boc-L-Leu-OH (30 mol%)
H
CO2Me
NHTf
DOI: 10.1039/D0CC04739B
NHTf
2a
NaOAc (30 mol%), K2CO3 (1.0 equiv.)
AgOAc (1.0 equiv.), DCE, 100 oC, 12 h
H
TIPS
8
9
b) Amino acids enabled transient direct strategy for ortho CH alkynylation of aryl aldehyde:
Pd(OAc)2 (5 mol%)
N-Boc-L-Leu-OH (30 mol%)
Me
Me
O
O
2-aminoisobutyric acid (50 mol%)
O
OH
2a
NH2
NaOAc (30 mol%)
AgOAc (1.0 equiv.)
DCE, 100 oC, 12 h
H
2-aminoisobutyric acid
TIPS
10, 32%
c) Sequential directed C3H alkynylation and C5H alkynylation of thiophene:
Pd(OAc)2 (5 mol%)
N-Boc-L-Leu-OH (30 mol%)
TIPS Pd(OAc)2 (5 mol%)
1-AdCO2H (30 mol%)
TIPS
NaOAc (30 mol%)
NaOAc (30 mol%)
H
S
NHTf
AgOAc (1.0 equiv.)
DCE, 100 oC, 12 h
2a
S
NHTf AgOAc (1.0 equiv.)
DCE, 100 oC, 12 h
2a
TIPS
S
NHTf
3g
, 75%
3g-2, 62%
d) Gram scale synthesis of ortho alkyne anilines:
Pd(OAc)2 (5 mol%)
N-Boc-L-Leu-OH (30 mol%)
Cl
Cl
NHTf
NHTf
2a
NaOAc (30 mol%)
AgOAc (1.0 equiv.)
DCE, 100 oC, 12 h
TIPS
5a, 86%, 1.16 g
Pd(OAc)2 (5 mol%)
NHTf
Ar
4a, 3 mmol
N-Boc-L-Leu-OH (30 mol%)
NHTf
2a
e) Further transformation of imidate ester substituted alkyne products:
Ar
NaOAc (30 mol%)
AgOAc (1.0 equiv.)
Me
OEt
OEt
O
Cu((OAc)2 (30 mol%)
DCE, 80 oC, 12 h;
TIPS
4
HBr (4 equiv.)
DCE, 100 oC, 12 h
O
NH
5
HOAc (0.5 mL)
60 oC, 12 h
Cl
MeMgBr (1.5 equiv.)
THF, reflux, 16 h
NHTf
NHTf
NHTf
TIPS
TIPS
TIPS
NHTf
11, 53%
7a
12, 81%
F
Cl
TIPS
5b, 93%
TIPS
5c, 92%
TIPS
TIPS
5a, 96%
5e, 94%
5i, 93%
5d, 88%
OMe
Br
Scheme 6. Synthetic transformations.
NHTf
NHTf
NHTf
NHTf
Me
Br
TIPS
TIPS
5f, 85%
TIPS
5g, 86%
TIPS
5h, 92%
According to the literature and experimental observations, it
was proposed that ligand exchange of Pd(II) catalyst to the
amine substrates initiated this transformation (Scheme 7).
Notably, with the assistance of MPAA, deprotonation took
place with lower activation barrier, delivering to the
corresponding 5, 6 and 7-membered palladacycle intermediate
B. Further oxidation of the palladacycle intermediate with
bromoalkyne might procced to give PdIV species C, which
underwent subsequent reductive elimination14 to afford the
desired alkynes. Alternatively, alkyne migratory insertion into
the palladacycle B led to the palladacycle species C’, which
followed by trans β elimination to release the desired
alkynes.8, 15-17
MeO
NHTf
NHTf
NHTf
NHTf
MeO
TIPS
TIPS
TIPS
TIPS
5j, 82%
5k, 76%
5l, 79%
Scheme 4. Regioselective C-H alkynylation of benzyl amines.
Pd(OAc)2 (5 mol%)
N-Boc-L-Leu-OH (30 mol%)
N-FG
N-FG
Si
Br
NaOAc (30 mol%)
AgOAc (1.0 equiv.)
DCE, 100 oC, 12 h
H
TIPS
6
2
7
O
OEt
O
Me
N
NH2
O
OH
NH
N
H
OTBS
MeO
TIPS
TIPS
TIPS
7d, 74%
7a, 63%
7b, 56%
7c, 31%
Me
O
Ph
O
O
Ph
O
OH
OMe
OMe
N
H
CO2Me
N
H
N
H
N
H
O
O
Ph
Ph
Ph
NHTf
PdIIX2
NHTf
TIPS
7e, 75%
TIPS
7g, 73%
TIPS
7h, 78%
n
TIPS
7f, 74%
n
1, 3, 8
MPAA assisted
deprotonation
reductive elimination
or trans  elimination
R
3, 5, 9
Scheme 5. Regio- and stereo-selective C‒H alkynylation.
NTf
PdII
X
X
n
n
O
n
or
O
Tf
N
PdII
N
Tf
Remote control of regioselectivity in the weak coordination
facilitated C‒H functionalization held great synthetic promise.5
Delightfully, this NHTf directed Pd(II)/MPAA catalysis could
also enable ortho C‒H alkynylation of L-Homophenylalanine
derivative, via possible 7-membered palladacycle intermediate
(Scheme 6-a). Notably, by using transient directing strategy,12
and with the assistance of 2-aminoisobutyric acid in this
Pd(II)/MPAA catalysis, ortho-selective C‒H alkynylation of
benzaldehyde was also achieved (Scheme 6-b). This
Pd(II)/MPAA catalysis also enabled sequential C3‒H and C5‒H
alkynylation of 2-(thiophen-2-yl)ethan-1-amine (Scheme 6-c).
Gram scale synthesis of alkyne product 5a was feasible
(Scheme 6-d). Significantly, the obtained imidate ester
directed C‒H alkynylation products could be readily
transformed to the corresponding ketone and ester 11 and 12
(Scheme 6-e), which serve as key precursors for the rapid
construction of complex skeletons via Diels-Alder reaction.13
PdIV
H
N
Br
iPr
OtBu
Br
R
C'
R
O
C
A
C-H activation
oxidation or
migratory insertion
n
B
N
Tf
PdII
Scheme 7. Proposed mechanism.
In summary, we have developed herein a versatile and
regioselective C‒H alkynylation of weak coordination nitrogen
functionality, enabled by Pd(II)/MPAA catalysis. Key features
included various benzylamines, arylethyl amines and
benzedrines could well serve as suitable substrates, via
possible 5, 6 and 7-membered palladacycle intermediates.
Moreover, readily transformable imines and amino
acid/alcohols derived amides could also enabled this
regioselective C‒H alkynylation. Further synthetic application
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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of this Pd(II)/MPAA catalysis in C‒H functionalization of weak
coordination is underway.
We are grateful for the financial supported by the National
Natural Science Foundation of China (21602032, 21502066),
the Natural Science Foundation of Guangdong Province (No.
2014a030310113), the Program for Innovative Research Team
of Huizhou University, the Open Fund of the Key Laboratory of
Functional Molecular Engineering of Guangdong Province
(No.2018kf02, South China University of Technology).
9
Conflicts of interest
There are no conflicts to declare.
10 For selected examples: a) Y. Ano, M. Tobisu, N. Chatani, J.
Am. Chem. Soc., 2011, 133, 12984; b) J. He, M. Wasa, K. S. L.
Chan, J.-Q. Yu, J. Am. Chem. Soc., 2013, 135, 3387; c) X. Ye, C.
Xu, L. Wojtas, N. G. Akhmedov, H. Chen, X. Shi, Org. Lett.,
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4 | J. Name., 2012, 00, 1-3
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ChemComm
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Journal Name
COMMUNICATION
View Article Online
DOI: 10.1039/D0CC04739B
Graphic abstract
MPAA facilitated Pd(II)-catalyzed C-H alkynylation:
N-FG
n
Pd(II) cat.
N-FG
n
TIPS
Br
N-Boc-L-Leu-OH ligand
H
TIPS
n = 1, 2, 3
via 5, 6, 7-membered palladacycle
O
OEt
NH
N
R
nNHTf
R
O
Ar
N
Ar
H
R
TIPS
TIPS
TIPS
TIPS
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