Asymmetric synthesis of β-lactam via palladium-catalyzed enantioselective intramolecular c(sp3)-h amidation

Article abstract of DOI:10.1021/acscatal.9b04768

β-Lactams are important scaffolds in drug design and frequently used as reactive intermediates in organic synthesis. Catalytic reactions featuring intramolecular C-H amidation of alkyl carboxamide substrates could provide a straightforward disconnection strategy for β-lactam synthesis. Herein, we report a streamlined method for asymmetric synthesis of β-aryl β-lactams from propanoic acid and aryl iodides via Pd-catalyzed sequential C(sp³)-H functionalization. The lactam-forming reaction provides an example of Pd^II-catalyzed enantioselective intramolecular C(sp³)-H amidation reaction and proceeds up to 94% ee. The use of a 2-methoxy-5-chlorophenyl iodide oxidant is critical to control the competing reductive elimination pathways of the Pd^IV intermediate to achieve the desired chemoselectivity. Mechanistic studies suggest that both steric and electronic effects of the unconventional aryl iodide oxidant are responsible for controlling the competing C-N versus C-C reductive elimination pathways of the Pd^IV intermediate.

Full text of DOI:10.1021/acscatal.9b04768

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Article
Asymmetric Synthesis of #-Lactam via Palladium-Catalyzed
Enantioselective Intramolecular C(sp3)–H Amidation
Hua-Rong Tong, Wenrui Zheng, Xiaoyan Lv, Gang He, Peng Liu, and Gong Chen
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.9b04768 • Publication Date (Web): 13 Nov 2019
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ACS Catalysis
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Asymmetric Synthesis of -Lactam via Palladium-Catalyzed
3
Enantioselective Intramolecular C(sp )–H Amidation
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1
Hua-Rong Tong, Wenrui Zheng, Xiaoyan Lv, Gang He, * Peng Liu, * and Gong Chen *
1State Key Laboratory and Institute of Elemento-Organic Chemistry, College of Chemistry, Nankai University,
Tianjin 300071, China
2Department of Chemistry, University of Pittsburgh, Pittsburgh, PA 15260, USA
ABSTRACT: β-Lactams are important scaffolds in drug design and frequently used as reactive intermediates in
organic synthesis. Catalytic reactions featuring intramolecular C–H amidation of alkyl carboxamide substrates
could provide a straightforward disconnection strategy for β-lactams synthesis. Herein, we report a streamlined
method for asymmetric synthesis of β-aryl β-lactams from propanoic acid and aryl iodides via Pd-catalyzed
3
II
sequential C(sp )-H functionalization. The lactam-forming reaction provides an example of Pd -catalyzed
3
enantioselective intramolecular C(sp )–H amidation reaction, and proceeds in up to 94% ee. The use of a 2-
IV
methoxy-5-chlorophenyl iodide oxidant is critical to control the competing reductive elimination pathways of Pd
intermediate to achieve the desired chemoselectivity. Mechanistic studies suggest that both steric and electronic
effects of the unconventional aryl iodide oxidant are responsible for controlling the competing C-N vs C-C
IV
reductive elimination pathways of Pd intermediate. Key words: Pd, C−H amidation, enantioselective, -lactams,
bidentate auxiliary
3
INTRODUCTION
mediated C(sp )–H functionalization chemistry, new
enantioselective reaction modes needs to be developed.
3
Palladium-catalyzed
functionalization has emerged as a powerful strategy
to construct various aliphatic frameworks. Among the
directing groups, amide-linked bidentate auxiliaries
have shown unique advantage of high reactivity and
versatility in forming new bonds. However, the
complexation mode of these bidentate auxiliaries also
caused inherent obstacles for enantiocontrol due to the
lack of suitable coordination sites on metal center.
Despite the challenge, recent endeavors showed such
enantio-induction is possible (Scheme 1A). Notably,
Duan reported that Pd -catalyzed aminoquinoline
directed
C(sp )–H
Recently, Wu demonstrated the reaction pathway of
Pd -catalyzed AQ-directed -C–H functionalization of
-alkyl and 3-aryl propanamide can be modulated to
give -lactam products in high yield and
chemoselectivity when excess amount of
pentafluorophenyl iodide was used as oxidant
(Scheme 1B). It was believed that the strong electron-
withdrawing property of C
suppressing the C-C reductive elimination (RE) of Pd
intermediate, promoting the intramolecular C-N RE.
II
1
3
2
-4
9
6
F
5
group is responsible for
IV
1
0
5
-8
II
Herein, we report
asymmetric synthesis of -aryl
a
streamlined method for
(
AQ)-directed benzylic -C–H arylation of 3-
arylpropanamides with aryl iodides can proceed in
moderate to good enantioselectivity using BINOL-
5a
based chiral phosphoric acid or amide ligands. Shi
II
reported Pd -catalyzed pyridinylisopropylamine
3
(
PIP)-directed
enantioselective
-C(sp )-H
alkynylation of 3-alkyllpropanamides with alkynyl
bromide can proceed in good to excellent ee using a
6
b
fluoro-substituted 3,3’-di-F-BINOL ligand. To further
expand the synthetic utility of bidentate auxiliary-
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3
A) Enantioselective C(sp )-H functionalization using bidentate DG
3
Scheme 1. Pd-catalyzed enantioselective C(sp )–H
functionalization directed by N,N-bidentate auxiliary
groups.
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
O
O
Duan
P
N
OH
NH2)
O
(AQ)
(
AQ
O
Ar' HN
*
H
H HN
+
Ar'-I
Ar
Ar
O
PdCl2(CH3CN)2 (cat)
Cs2CO3, p-xylene, 140 o
C
up to 82% ee
F
OH
R'
(PIP)
Shi
OH 3,3'-di-F-
N
R'
X
BINOL
PIP
HN
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
H
H HN
+
F
R
*
O
R
O
PdI2 (cat)
up to 96% ee
B) Synthesis of -lactam via intramolecular C-H amidation
O
N
PdIV
RE of PdIV
:
R
CC vs CN
N
Ar
F
F
F
F
I
Wu
[
Ox]
F
R'
N
Pd(OAc)2 (cat), AgOAc
(Q)
N
R'
MW, 150 o
C
N
racemic
H
H HN
Ar
O
O
Ar
O
OMe
*
[Ox]
CH
arylation
Ar-I
Q
Cl
I
- Q
3,3'-di-F-BINOL (ligand)
PdCl2(PhCN)2 (cat)
sol, Cs2CO3, 100 o
HN
this
work
H
N
O
C
Ar
propanamide
up to 94% ee
excellent chemoselectivity
*
3
Table 1. Pd-catalyzed quinoline-directed enantioselective intramolecular C(sp )-H amidation of 1 using chiral phosphate
ligand.
ArI (4 equiv)
Ligand (20 mol%)
Cs2CO3 (1.5 equiv), Ar, 100 oC, 48 h
(
AQ)
N
N
N
+
H
H HN
standard conditions A:
Ar HN
N
PdCl2(CH3CN)2 (10 mol%)
I-2 & L-4, + dba (30 mol%), neat
Ph
O
O
*
O
*
1
2
3
Entry
Change from the standard conditions [A]
equiv)
Conditions [A]: I-2 & L-4
Yield of 2 /3 (%)a,b
recovered 1
ee of 2
(%)
85
0
4
69
72
82
73
60
86
(
(%)
25
20
47
28
22
5
c
1
2
3
4
5
6
7
8
9
59 (54 ) / 15
[A’]: Cs
[A’]: Cs
[A’]: PdCl
2
CO
CO
3
 Ag
 K
CN)
2
CO
3
54 / 17
44 / 8
46 / 18
54 / 18
77 / 16
59 / 18
31 / 8
2
3
2
CO
3
2
(CH
3
2
 Pd(OAc)
2
[A’]: Neat  m-xylene
[A’]: Neat  1,3-di-CF
[A’]: No dba
[A’]: I-2 (4  2 equiv)
[A’]: AQ (Q-1)  Q-2
3
Ph
21
54
d
d
d
87 / 11
0
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Selected results under modified conditions [A']: one of the three factors (ligand, ArI or Q) in standard conditions A is modified as specified
1
2
3
4
5
6
7
8
9
Ligand:
Ar': 3',5'-di-CF3-C6H3-
Ar'
Q analogs:
F
O
O
O
O
O
O
O
O
O
O
O
O
N
P
P
P
N
2
OMe
P
OH
NH2
OH
OH
H2N
H N
F
Ar'
L-1
/3 (%): 38/7
L-2
L-3
Q-1 (AQ)
Q-2 (MQ)
L-4
2/3 (%): 87/11d
2
2/3 (%): 20 / 6
ee% of 2: 56
2/3 (%): 52/11
ee% of 2: 52
2/3 (%): 59/15
ee% of 2: 85
2/3 (%): 59/15
ee% of 2: 85
ee% of 2: 11
ee% of 2: 86
ArI:
F
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
F3C
CF3
MeO
Cl
F
F
F
Cl
CF3
F
F
F
MeO
MeO
I
MeO
MeO
OMe
I
I
I
I
I
I
I
I
I
I
I
I-1
I-2
I-3
I-5
I-6
I-7
I-8
I-9
I-10
I-11
I-12
I-4
2
/3 (%): 35/3 2/3 (%): 59/15 2/3 (%): 32/0 2/3 (%): 13/64 2/3 (%): 19/33 2/3 (%): 43/11
2/3 (%): 55/6
ee% of 2: 60
2/3 (%): 58/0
ee% of 2: 55
2/3 (%): 26/34 2/3 (%): 15/0 2/3 (%): 0/0 2/3 (%): 9/40
ee% of 2: 63 ee% of 2: 57
ee% of 2: 79
ee% of 2: 8
ee% of 2: 85 ee% of 2: 58 ee% of 2: 54
ee% of 2: 46 ee% of 2: 60
1
(
a) Yields are based on H-NMR analysis of reaction mixture on a 0.1 mmol scale. (b) ee was determined by HPLC using a chiral
column. (c) Isolated yield. (d) Product bearing the corresponding modified Q group. See SI for additional screening conditions
and ArI oxidants.
II

-lactams via Pd -catalyzed quinoline-directed
enantioselective intramolecular C(sp )-H amidation of
enantioselective, a proper combination of chiral ligand
and oxidant need to be exploited.
3
3
-arylpropylamines using 3,3’-di-F-BINOL chiral
II
During our recent re-investigation of Pd -catalyzed
AQ-directed enantioselective C(sp )-H arylation of 3-
phenylpropanamide 1 with aryl iodides, we noticed
that -lactam 2 was formed as a side product in varied
yield and enantioselectivity using chiral phosphate
ligands (Table 1). While pentafluoro phenyl iodide I-
oxidant gave the best reactivity and chemo-
selectivity (lactam vs C-H arylation) in Wu’s racemic
6
b,11,12
ligand
and 2-methoxy-5-chlorophenyl iodide as oxidant.
3
RESULTS AND DISCUSSION
-Lactams are important scaffolds in drug design
and frequently used as reactive intermediates in
organic synthesis.
via metal-catalyzed intramolecular C-H carbene
insertion has long been employed for synthesis of -
lactams. In recent years, Pd-catalyzed intramolecular
C(sp )-H functionalization reactions including C-H

5c
1
3,14
C-H functionalization strategy
1
-
system (Pd(OAc)
2
as catalyst and AgOAc as I
scavenger at 150 C), it gave poor reactivity under the
15
o
9a
3
conditions of PdCl
2
(CH
3
CN)
2
catalyst, Cs
2
CO
3
base
1
6
17
alkylation,
carbonylative
amination ,
and chiral phosphate ligand at lower temperature (100
carbamoylation process via Pd or PdII/0 catalytic
cycles have offered new ways to construct -lactams.
1
8
0/II
o
C),
which
are
critical
to
achieve
high
5
enantioselectivity in this AQ-directed system. In
comparison, 3,5-di-CF -phenyl iodide (I-2) stood out
among the electron-deficient ArI oxidants tested,
offering the best balance of chemo- and
enantioselectivity. A 59% yield of 2 with 85% ee along
with 15% yield of C-H arylation product 3 were
obtained using 4 equiv of I-2, 20 mol% of 3,3’-di-aryl
Among
these
reactions,
enantioselective
3
1
6
transformations based on C-H alkylation and
carbamoylation have also been demonstrated using
18
chiral phosphonite and phosphoramidites ligand
respectively. In comparison, catalytic reactions
featuring C-H amidation of alkyl carboxamide
substrates could provide a more straightforward
disconnection strategy. Racemic versions of this type
of transformation have been achieved via promoting
C-N RE from high valent metal intermediates under
oxidative conditions.
Table 2. Pd-catalyzed quinoline-directed enantioselective intramolecular C(sp )-H amidation of 1 using chiral BINOL
(3,5-di-CF
3
-C
6
H
3
)
substituted
BINOL-derived
6a
phosphate ligand L4
and 30 mol% of
o
dibenzylideneacetone (dba) additive at 100 C without
any solvent
19, 20
To make this transformation
3
ligand.
ArI (4 equiv)
(
AQ)
N
Ligand (20 mol%)
N
Cs2CO3 (1.5 equiv), Ar, 100 oC, 48 h
N
+
H
H HN
standard conditions B:
Ar HN
*
N
Ph
O
O
PdCl (PhCN)2 (10 mol%)
O
2
*
I-6 & L-9, 1,3-di-CF3Ph/t-AmOH (3/2)
1
2
3-(1-12)
Entry
Change from the standard conditions [B]
Yield of 2 {ee%}/3 a,b
recovered 1
ee of 2
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(
equiv)
Conditions [B]: I-6 & L-9
[B’]: Cs CO  Ag CO
 Pd(OAc)
 PdCl (CH
(%)
~1
76
23
~1
10
12
0
(%)
89
55
74
82
46
81
87
94
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
c
1
2
3
4
5
6
7
8
90 (84 ) / 6
2
3
2
3
13 / 2
59 / 13
88 / 5
[B’]: PdCl
[B’]: PdCl
[B’]: 1,3-di-CF
[B’]: I-6 (4  2 equiv)
[B’]: AQ (Q-1) Q-2
[B’]: AQ (Q-1) Q-9
2
2
(PhCN)
(PhCN)
2
2
2
2
3
CN)
2
3
Ph/tAmOH  m-xylene
65 / 20
72 / 14
c
d
92 (88 ) / 5
c
d
92 (89 ) / 6
0
Selected results under conditions [B']: one of the three factors (ligand, ArI, or Q) in conditions B is modified as specified
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Ligand:
Ar': 3',5'-di-CF3-C6H3-
Cl
Ph
F
Ar'
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
Cl
Ph
F
Ar'
L-5
L-6
L-7
L-8
L-9
2/3 (%): 31/11
ee% of 2: 53
2/3 (%): 75/15
ee% of 2: 73
2/3 (%): 82/14
ee% of 2: 62
2/3 (%): 74/16
ee% of 2: 69
2/3 (%): 90/6
ee% of 2: 89
ArI:
F
F3C
CF3
MeO
F
Cl
F
F
F
F
Cl
CF3
F
MeO
I
MeO
MeO
MeO
OMe
I
I
I
I
I
I
I
I
I
I
I
I-1
I-2
I-3
I-4
I-5
I-6
I-7
I-8
I-9
I-10
I-11
I-12
2
/3 (%): 55/0 2/3 (%): 80/12 2/3 (%): 95/0 2/3 (%): 12/87 2/3 (%): 42/53
ee% of 2: 80 ee% of 2: 83
2/3 (%): 90/6
ee% of 2: 89
2/3 (%): 91/4
ee% of 2: 87
2/3 (%): 90/3
ee% of 2: 77
2/3 (%): 36/57 2/3 (%): 26/0 2/3 (%): 0/0 2/3 (%): 8/88
ee% of 2: 83 ee% of 2: 49
ee% of 2: 84 ee% of 2: 87 ee% of 2: 84
ee% of 2: 81
Q analogs:
Ar'':
Ar''
CF3
MeO
N
N
2
OMe
N
2
NO2
N
Cl
N
2
I
OMe
N
H2N
H N
H N
H2N
H N
CF3
H2N
OMe
OMe
Q-10
Q-1 (AQ)
Q-2 (MQ)
Q-3
2/3 (%): 0/0
Q-4
Q-5
Q-6
Q-7
Q-8
Q-9 (PQ)
2/3 (%): 90/6
ee% of 2: 89
2/3 (%): 92/5
ee% of 2: 87
2/3 (%): 84/9
ee% of 2: 85
2/3 (%): 81/10
ee% of 2: 79
2/3 (%): 95/4
ee% of 2: 82
2/3 (%): 88/7
ee% of 2: 82
2/3 (%): 93/6
ee% of 2: 72
2/3 (%): 92/6
ee% of 2: 94
2/3 (%): 95/4
ee% of 2: 87
1
(
a) Yields are based on H-NMR analysis of reaction mixture on a 0.1 mmol scale. (b) ee was determined by HPLC using a chiral
column. (c) Isolated yield . (d) Product bearing the corresponding modified Q group. See Supporting Information for additional
screening conditions and ArI oxidants.
(
entry 1, standard conditions A). The structure of
quinoline auxiliary also had an impact on reactivity
and ee. Q-2 (MQ) , a C5-methoxy analog of AQ, gave
lactam product in significantly improved yield and ee
the best results. Reaction of 1 with 4 equiv of I-6, 10
mol% of PdCl
2
(PhCN)
2
catalyst, 20 mol% of L-9 in the
2
1
o
mixed solvent of 1,3-di-CF
3
-Ph and tAmOH at 100 C
gave 2 in 90% yield with 89% ee along with 6% of
arylation byproduct (entry 1, standard conditions B).
The use of MQ gave comparable results to AQ under
conditions B’ (entry 1 vs 7). Q-9 (PQ) with an ortho-
methoxyphenyl group on the C5 of AQ gave lactam
product with the highest ee of 94% (entry 8). It is also
(
entry 9). Beside electron-deficient ArIs, we found
electron-rich ArIs bearing various ortho substituents
can also promote the formation of 2 to varied extent.
For example, I-10 bearing an ortho-methyl group
exclusively gave cyclization product but low reactivity.
I-8 bearing two ortho-MeO groups gave 2 in 58% yield
and with moderate ee.
worth noting that 1) Use of Cs
2
CO
obtaining high ee. 2) Addition of Ag additives e.g.
Ag CO gave significantly decreased ee (entry 2). 3)
Use of Pd(OAc) catalyst gave lower ee (entry 3). 4) 4
3
is critical for
2
3
2
3
As outlined in Table 2, we were pleased to find that
use of chiral BINOL ligands also gave moderate to
good enantioselectivity with both electron rich and
poor ArI oxidants.
group gave more 2 than I-4 bearing a meta-MeO and I-
2 (PhI). As seen in I-6 and I-7, installation of electron-
withdrawing group on C5 position of I-5 further
improved the chemo-selectivity. Due to the low cost, I-
6 was chosen for further reaction optimization. The
combination of di-F-BINOL ligand L-9 and L-6 gave
2
equiv of ArI is needed to achieve high yield (entry 6).
6b, 11, 12
I-5 bearing an ortho-MeO
Substrate scope. The reaction scope using AQ, MQ
and PQ auxiliary groups under the optimized reaction
conditions B were summarized in Scheme 2. The 3-
arylpropanamide starting materials can be readily
prepared via Pd-catalyzed mono-selective β C−H
arylation of the corresponding auxiliary-coupled
propanamide precursors with aryl iodides (see SI for
1
2
2
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details).5c, 19a The performance of auxiliaries slightly
amination gave compound 2c. Interestingly, the PQ
1
2
3
4
5
6
7
8
9
fluctuates depending on the β-aryl groups. In general,
substituents on the meta and para positions of aryl
groups were well tolerated (see 4, 8). Ortho-substituted
or electron-deficient aryl groups gave significantly
lower yield and ee (14, 11, 15). As exemplified by 13,
group can also be removed by the treatment of CAN to
2
7
give 17 in moderate yield and with 94% ee. The ee
value of 17 was increased to 99% after one
recrystallization in hexanes and ethyl acetate. Amide
activation of 17 by Boc and cleavage with LiOH gave
phenyl substituted β-amino acid 20 in good yield and
3
intramolecular amination of the unactivated C(sp )-H
28
bond gave very low yield and moderate ee under the
99% ee. Hartwig-Buchwald coupling of 17 with aryl
24
standard conditions.
iodide gave 21 in 90% yield.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
R''
A)
1
) PhI (1.5 equiv), Pd(OAc)2 (10 mol%),
CuF2 (1.5 equiv), DMA, 100 oC, 76%
mono-selective  C-H arylation
(mono:di = 10:1)
I-6 (4 equiv)
L-9 (20 mol%)
PdCl2(PhCN)2 (10 mol%)
Cs2CO3 (1.5 equiv)
(MQ)
OMe
N
R''
N
H
N
N
(Q')
O
H
HHN
N
Ph
O
Ar
H
HN
2) Cyclization, 88%, 87% ee
1,3-di-CF3Ph/t-AmOH (3/2)
Ar, 100 oC, 48 h
standard conditions B
*
Ar
O
*
3) Removal of MQ: CAN (3 equiv)
AQ (R" = H)
MQ (R" = OMe)
O
CH3CN/H2O = 4:1, 0 oC, 3 h
16
17
75%, 87% ee
PQ (R" = 2'-OMe-Ph)
CAN (5 equiv),
CH3CN/H2O = 4:1
0 oC, 12 h,
30%, 94% ee
(~ 35% of 2c recovered)
R = H
84% (89% ee) [AQ]
4
2,
Q'
Q'
2b, 88% (87% ee) [MQ]
N
O
1) Cu(OAc)2 (15 mol%)
NaI (2.0 equiv)
N
2c, 89% (94% ee) [PQ]
R
O
*
*
PhI(OAc)2 (2.0 equiv)
PivOH (30 mol%)
R = CH3
8a, 84% (73% ee) [AQ]
b, 92% (94% ee) [MQ]
c, 81% (91% ee) [PQ]
4a, 93% (89% ee) [AQ]
1
) mono-
selective
C-H arylation
78%
8
8
1,4-dioxane, 50 o
air, 6 h, 93%
iodination
4b, 91% (74% ee) [MQ]
C
N
OMe
4c, 94% (92% ee) [PQ]
PQ
HN
R = OCH3
5a, 86% (86% ee) [AQ]
b, 94% (64% ee) [MQ]
HN
Q'
O
2) Pd(PPh ) Cl (5 mol%)
3
2
2
2) Cyclization
89%, 94% ee
N
(PQ)
O
N
O
19
O
5
ArB(OH)2 (1.5 equiv)
Na2CO3 (2.0 equiv)
18
N
X-ray of 2c
5c, 78% (73% ee) [PQ]
*
Ph
*
R = Br
dioxane/H2O = 1:1
90 oC, Ar, 12 h, 90%
2
c
6
a, 61% (63% ee) [AQ]
9a, 83% (94% ee) [AQ]
9b, 92% (77% ee) [MQ]
9c, 91% (88% ee) [PQ]
6b, 75% (83% ee) [MQ]
6c, 56% (83% ee) [PQ]
B)
R = F
1) Boc O (2.5 equiv), DMAP
(1.1 equiv), THF, rt, 2 h
NHBoc
CO2H
2
7a, 57% (88% ee) [AQ]
b, 62% (83% ee) [MQ]
c, 41% (88% ee) [PQ]
7
7
Ph
*
.
H
N
2) LiOH H2O (3 equiv)
20
THF:H2O = 2:1, rt, 2 h
75% over 2 steps, 99% eea
Q'
MeO2C
Q'
N
Ph
O
OCH3
Q'
N
N
O
*
O
*
17
O
*
4-MeO-PhI (2 equiv)
*
99% ee
after recrystallization)
(
10a, 64% (90% ee) [AQ]
11a, 60% (75% ee) [AQ]
11b, 53% (83% ee) [MQ]
11c, 27% (66% ee) [PQ]
12a, 85% (93% ee) [AQ]
12b, 95% (91% ee) [MQ]
12c, 93% (93% ee) [PQ]
CuI (5 mol%), DMEDA (10 mol%)
K3PO4 (2 equiv), dioxane, 110 o
N
10b, 89% (83% ee) [MQ]
0c, 87% (85% ee) [PQ]
Ph
O
C
1
*
24 h, Ar, 90%, 99% ee
21
Q'
OCH3 Q'
N
Q'
N
N
O
Scheme 3. Synthetic transformations. Isolated yield on a
0.2 mmol scale. a) ee of 20 was measured by HPLC analysis
of its benzyl ester (See SI).
O
O2N
O
*
*
*
1
1
1
3a, 0% [AQ]
3b, 3% (67% ee) [MQ]
3c, 4% (69% ee) [PQ]
14a, 57% (47% ee) [AQ]
14b, 45% (29% ee) [MQ]
14c, 47% (48% ee) [PQ]
15a, 0% [AQ]
15b, 0% [MQ]
15c, 0% [PQ]
3
Mechanistic
aminoquinoline-directed
study.
This
intramolecular
Pd-catalyzed
C-H
Scheme 2. Substrate scope of -C(sp )-H amidation.
1
Isolated yield of lactam products/ H-NMR yield of
arylation products on a 0.1 mmol scale under standard
conditions B.
amidation reaction is believed to follow the main
sequence of C-H palladation, oxidative addition (OA),
and reductive elimination (RE) (Scheme 4A). As in the
As shown in Scheme 3A, Pd-catalyzed mono-
selective β C-H arylation of MQ-coupled propenamide
II
3
previously
reported
Pd -catalyzed
C(sp )-H
5
,6
functionalization reactions, C-H palladation under
the asymmetric control of either BINOL-based
phosphate or di-F-BINOL ligand is likely the enantio-
determining step of this reaction, forming an
enantioenriched Pd -palladacycle (22). Following the
OA with ArI, Pd intermediate 23 can undergo either
1
6 with PhI and subsequent β C-H amination gave
compound 2b. Removal of the MQ group of 2b by the
treatment of cerium ammonium nitrate (CAN) in
acetonitrile and water gave the NH-free β-lactam
II
2
1,25
product 17 in 75% yield and with 87% ee.
As
IV
exemplified by 19, the Ar’’ group on the C5 position of
C-C or C-N RE to give the arylated or cyclized
AQ can be readily installed by Cu-mediated
products 24 and 25 respectively. Protodepalladation
26
regioselective iodination and Pd-catalyzed Suzuki
-
II
and dissociation of I ligand regenerates the active Pd
coupling with the corresponding aryl boronic acid. Pd-
catalyzed PQ-directed β C-H arylation and β C-H
catalyst. To understand the roles of the ArI oxidant on
the chemoselectivity, density functional theory (DFT)
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calculations were performed to study the C-C and C-N
RE transition states (TS) in reactions of model substrate
with various ArIs.29-32 Since previous computational
studies of the Pd-catalyzed directed C-H arylation
both 23 and 26 were considered computationally. As
shown in Scheme 4B, the calculated chemoselectivity
of C-C vs C-N RE of 26 agreed well with the
experimental product ratios. In comparison, the
calculated chemoselectivity of RE of the I -bound 23,
particularly with I-4, notably deviated from the
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
-
IV
-
with ArI suggested the I -bound Pd intermediate may
3
1c
undergo anionic ligand exchange prior to the RE, we
-
expect that 23 may react with HCO
3
generated in situ
observed ratios. Similar to the C F -I
6
5
IV
to form a new Pd intermediate 26. Therefore, RE from
A) Proposed reaction pathways
O
Ph
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
N
PdII
O
Ar O
Ar O
CC
CN
Ar
AQ
N
HN
Pd , Cs2CO3, chiral L Ph
II
N
PdIVN
-
Ph
PdIVN
HO2CO
Ar-I
OA
Ph
HCO3
27
PdII
RE
Ph
O
N
N
N
O
enantioselective
ligand
O
O
CH palladation
I
exchange
1
Ph
Ar
N
22
23
HO
26
RE
PdII
N
CN
CC
HO2CO
28
O
O
Ph
Ph
Ar
N
N
Ar
I
PdII
PdII
N
N
I
25
24
B) DFT calculations of RE barriers from 26 and 23
from 26
∆G‡ (kcal/mol)
from 23
∆G‡ (kcal/mol)
∆∆G‡
(CC)-
(CN) RE
∆∆G‡
TS
CC
RE
CC
CN
RE (CN) RE
(CC)-
CC
CN
RE
RE
F3C
CF3
OMe
Cl
ArI
RE
I-2
I-4
13.1
10.5
10.2
12.0
2.9
14.5
13.8
8.7
5.8
MeO
MeO
CN
RE
I-2
I
I-4
I
I-5
I
I-6
I
-1.5
-0.2
1.0
10.9
2.9
3.6
4.9
26
or 23
80/12
12/87
42/53
90/6
I-5
I-6
9.8
10.0
9.2
14.3
15.0
10.7
10.1
experimental ratio of (CN) / (CC) RE
products using different ArI
10.2
C) CC and CN RE transition states in the reaction with I-6
O
Cl
O
N
N
Ph
N
unfavorable
steric
repulsions
N
Cl
Pd
stabilizing
OMe-Pd
coordination
Pd
MeO
OMe
OCO2H
Ph
OCO2H
CN RE TS
(∆G‡
= 9.2 kcal/mol)
CC RE TS
∆G‡ = 10.2 kcal/mol)
(
Scheme 4. Mechanistic studies.
(I-1) oxidant used in Wu’s racemic system, reagent I-2
lactam with the use of ortho-methyl substituted I-10 is
due to similar steric effects that suppress the C-C RE.
However, reaction with I-10 suffers from low
reactivity, which is probably caused by the difficulty of
bearing two strongly electron-withdrawing CF
3
groups promotes the lactam formation by
IV
disfavouring C-C RE of Pd through electronic effects.
3
3
The enhanced selectivity for lactam products with
electron-rich ArIs bearing ortho-methoxyl groups (I-5
and I-6) is likely due to the steric repulsions between
the ortho-OMe group of ArI and the β-Ph that
destabilize the C-C RE transition state (Scheme 4C). A
weak o-OMe–Pd coordination in the C-N RE transition
state may further promote the C-N bond formation.
Addition of an electron-withdrawing Cl group at C5’
of I-5 fine-tuned the electronic property of I-6 and the
selectivity for C-N RE. The above computational
analysis suggests that the good chemoselectivity for
the initial OA to palladacycle.
Conclusion
II
In summary, we have developed the first Pd -
3
catalyzed enantioselective intramolecular C(sp )–H
amidation reaction with up to 94% ee. It offered a
streamlined method for the asymmetric synthesis of -
aryl -lactams from propanoic acid and aryl iodides
precursors. The identification of 2-methoxy-5-
chlorophenyl iodide oxidant is critical to achieve high
chemoselectivity. Mechanistic studies suggest that
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Chen, G. Syntheses and Transformations of α-Amino Acids
via Palladium-Catalyzed Auxiliary-Directed sp C-H
Functionalization. Acc. Chem. Res. 2016, 49, 635-645.
both steric and electronic effects of the unconventional
1
2
3
4
5
6
7
8
9
3
aryl iodide oxidant are responsible for controlling the
competing C-N vs C-C reductive elimination
3. a) Zaitsev, V. G.; Shabashov, D.; Daugulis, O. Highly
IV
pathways of Pd intermediate. The quinoline auxiliary
3
Regioselective Arylation of sp C-H Bonds Catalyzed by
group of the lactam products can be removed under
Palladium Acetate. J. Am. Chem. Soc. 2005, 127, 13154-13155.
mild conditions. Other Pd-catalyzed bidentate
b) Shabashov, D.; Daugulis, O. Auxiliary-Assisted
2
3
Palladium-Catalyzed Arylation and Alkylation of sp and
auxiliary-directed
enantioselective
C(sp )–H
3
sp Carbon-Hydrogen Bonds. J. Am. Chem. Soc. 2010, 132,
functionalization reactions are under current
investigation.
3
965-3972.
4
.
For selected examples of Pd-catalyzed bidentate DG-
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
mediated C(sp )−H functionalization: a) Nadres, E. T.;
AUTHOR INFORMATION
Corresponding Author
Daugulis, O. Heterocycle Synthesis via Direct C−H/N−H
Coupling. J. Am. Chem. Soc. 2012, 134, 7-10. b) Zhang, L.-S.;
Chen, G.; Wang, X.; Guo, Q.-Y.; Zhang, X.-S.; Pan, F.; Chen,
K.; Shi, Z.-J. Direct Borylation of Primary C-H Bonds in
Functionalized Molecules by Palladium Catalysis. Angew.
Chem. Int. Ed. 2014, 53, 3899-3903. c) Xu, J.-W.; Zhang, Z.-Z.;
Peng Liu: pengliu@pitt.edu,
Gang He: hegang@nankai.edu.cn,
Gong Chen: gongchen@nankai.edu.cn.
The authors declare no competing financial interest.
3
Rao, W.-H.; Shi, B.-F. Site-Selective Alkenylation of δ-C(sp )-
H Bonds with Alkynes via a Six-Membered Palladacycle. J.
Am. Chem. Soc. 2016, 138, 10750-10753. d) Kim, Y.; Kim, S.-T.;
Kang, D.; Sohn, T.-I.; Jang, E.; Baik, M.-H.; Hong, S.
Stereoselective Construction of Sterically Hindered
Oxaspirocycles via Chiral Bidentate Directing Group-
ASSOCIATED CONTENT
Detailed synthetic procedures, compound characterization,
NMR spectra, X-ray crystallographic data, and computational
details are provided. This material is available free of charge
via the Internet at http://pubs.acs.org.
3
Mediated C(sp )-O Bond Formation. Chem. Sci. 2018, 9, 1473-
1480.
ACKNOWLEDGMENT
5. a) Yan, S.-B.; Zhang, S.; Duan, W.-L. Palladium-Catalyzed
3
G.C. thanks NSFC-21672105, NSFC-21421062, NSFC-
91753124 and NSFC-21725204, the Ph.D. Candidate
Research Innovation Fund of the College of Chemistry Nankai
University and Laviana for financial support of the
experimental part of this work. P.L. thanks NSF CHE-1654122
for financial support. DFT calculations were performed at the
Center for Research Computing at the University of
Pittsburgh and the Extreme Science and Engineering
Discovery Environment (XSEDE) supported by NSF.
Asymmetric Arylation of C(sp )-H Bonds of Aliphatic
Amides: Controlling Enantioselectivity Using Chiral
Phosphoric Amides/Acids. Org. Lett. 2015, 17, 2458-2461. b)
Wang, H.; Tong, H.-R.; He, G.; Chen, G. An Enantioselective
Bidentate Auxiliary Directed Palladium-Catalyzed Benzylic
C-H Arylation of Amines Using a BINOL Phosphate Ligand.
Angew. Chem. Int. Ed. 2016, 55, 15387-15391. c) Tong, H.-R.;
Zheng, S.; Li, X.; Deng, Z.; Wang, H.; He, G.; Peng, Q.; Chen,
G.
Pd(0)-Catalyzed
Bidentate
C–H
Auxiliary
Arylation
Directed
of 3-
Enantioselective
Benzylic
Arylpropanamides Using the BINOL Phosphoramidite
Ligand. ACS Catal. 2018, 8, 11502-11512.
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0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
16. alkylation: Pedroni, J.; Boghi, M.; Saget, T.; Cramer, N.
Access to β-Lactams by Enantioselective Palladium(0)-
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and Ligand for Asymmetric C(sp )-H Functionalization.
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18. C(sp )-H CO: Cabrera-Pardo, J. R.; Trowbridge, A.; Nappi,
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Palladium(II)-Catalyzed
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3
Monoarylation/Amidation of C(sp )-H bonds. Angew. Chem.
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2
013, 135, 14206-14214. c) Grosheva, D.; Cramer, N. Ketene
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1
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Aminal Phosphates: Competent Substrates for
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ACS Catal. 2017, 7, 7417-7420.
3
Because the solvent parameters for 1,3-di-CF -Ph are not
24. Reaction of the corresponding β-ethenyl and acetylenyl
propanamide substrates gave a complex reaction mixture
under the standard conditions A or B. Reaction of the
corresponding β-methoxypropanamide substrate did not
give any desired β-arylated product under the standard
conditions.
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decomposition byproducts.
available, m-xylene was used as solvent in the calculations.
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2
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2
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2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
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9
0
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3
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9
0
1
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8
9
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4
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9
0
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9. DFT calculations were performed using Gaussian 16,
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3
Dissociative Ligand Ionization: Catalytic C(sp )-H
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3
J. Palladium-Catalyzed C(sp )–H Bond Functionalization of
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33. Our DFT calculations indicate that replacing the ortho-OMe
groups in I8 with Me groups significantly increases the
barrier of OA due to steric repulsions with the ortho-Me
groups. See SI for details.
R'
OMe
[Ox]
(Q) N
R'
Cl
I
N
N
H
HN
3,3'-di-F-BINOL (chiral ligand)
PdCl2(PhCN)2 (cat)
Ar
O
*
Ar
O
sol, Cs2CO3, 100 o
C
AQ (R" = H);
MQ (R" = OMe);
up to 94% ee
excellent chemoselectivity
PQ (R" = 2'-OMe-Ph)
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