Pd-Catalyzed C(sp3)-H Carbonylation of Alkylamines: A Powerful Route to γ -Lactams and γ-Amino Acids

Article abstract of DOI:10.1021/acs.orglett.5b01658

A novel Pd-catalyzed direct C(sp³)-H carbonylation of alkylamines for the synthesis of-lactams and -amino acids has been developed, in which TEMPO was used as the crucial sole oxidant. The synthetic prospect was demonstrated by the concise total synthesis of rac-Pregbalin.

Full text of DOI:10.1021/acs.orglett.5b01658

Letter
pubs.acs.org/OrgLett
Pd-Catalyzed C(sp3)−H Carbonylation of Alkylamines: A Powerful
Route to γ‑Lactams and γ‑Amino Acids
Pei-Long Wang,† Yan Li,† Yun Wu,† Chao Li,† Quan Lan,† and Xi-Sheng Wang*,†,‡
†Department of Chemistry, University of Science and Technology of China, Hefei 230026, China
‡Key Laboratory of Synthetic and Self-Assembly Chemistry for Organic Functional Molecules, Chinese Academy of Sciences,
Shanghai Institute of Organic Chemistry, Shanghai, 200032, China
S
* Supporting Information
ABSTRACT: A novel Pd-catalyzed direct C(sp3)−H carbon-
ylation of alkylamines for the synthesis of γ-lactams and γ-
amino acids has been developed, in which TEMPO was used as
the crucial sole oxidant. The synthetic prospect was
demonstrated by the concise total synthesis of rac-Pregbalin.
Scheme 1. Pd-Catalyzed Directed C(sp3)−H Carbonylation
ransition-metal catalyzed carbonylation with carbon
with CO
Tmonoxide (CO), the most important and readily available
C1 feedstock, has attracted extensive attention in academic
research and industrial applications.1 While a variety of
transition-metal catalyzed insertions of CO into C(sp2)−H
bonds have been developed in recent decades,2 the direct
carbonylation of C(sp3)−H bonds has been less studied and
remains as a big challenge. Since the pioneering research work
of Fujiwara in 1989,3 palladium-catalyzed carbonylation via
nondirected alkyl and benzylic C(sp3)−H bond activation
under 10−50 atm of CO has been accomplished to introduce
the easily transformable carbonyl group to simple alkanes4 and
toluenes.5,6 Unfortunately, these methods are still hampered by
some limitations such as the requirement of a large excess of
alkanes or toluenes, high pressure of CO, and/or lack of
regioselectivity.
To address these issues in nondirected C(sp3)−H carbon-
ylation, a directing group strategy has been introduced to
transition-metal catalyzed C(sp3)−H bond activation in recent
years. The Yu group7 and the Chatani group8 described the Pd-
carbon monoxide (CO) in the presence of a catalytic amount of
and Ru-catalyzed β-carbonylation of aliphatic amides to afford
the succinimides independently (eq 1, Scheme 1). Recently, a
protocol for the synthesis β-lactams via Pd-catalyzed carbon-
ylation of secondary aliphatic amines was reported by Gaunt
and co-workers,9 in which a four-membered-ring cyclo-
palladium intermediate was proposed (eq 2, Scheme 1). With
the only examples mentioned above developed, the palladium-
catalyzed directed C(sp3)−H carbonylation is still at its first
stage and the substrate scope remains limited. Herein, we
report a novel Pd-catalyzed C(sp3)−H carbonylation of
alkylamines for the synthesis of γ-lactams and γ-amino acids,
with TEMPO used as the crucial sole oxidant, and the synthetic
utility was demonstrated by the concise total synthesis of rac-
Pregabalin.
Pd(OAc)2 (10 mol %) at 130 °C. While most of the commonly
used oxidants in both Pd(II)/Pd(0) and Pd(II)/Pd(IV)
catalytic cycles, such as Cu(II), Ag(I), PhI(OAc)2, DDQ,
NFSI, CAN, K2S2O8, etc., showed no reactivity in this
transformation, to our excitement, the desired carbonylation
product 2a was obtained when 2 equiv of TEMPO were used as
the sole oxidant, albeit in low yield (38%, entry 8, Table 1).
Gratifyingly, the yield was improved to 80% when the amount
of TEMPO was increased to 4 equiv (entry 9, Table 1), and a
slight reduction of the temperature to 120 °C had almost no
effect to the transformation. To improve the yield further, a
careful survey of solvents was then performed, which revealed
both p-xylene (85% yield) and anisole (84% yield) were the
optimal choice (entries 11−17). Lastly, as a control experiment,
we confirmed that the result showed none of the desired
We commenced our study by examining the C(sp3)−H
activation/CO insertion of N-isobutylpicolinamide (1a), in
which picolinamide developed by Daugulis was used as a
bidentate directing group,10 the pilot substrate under 1 atm of
Received: June 7, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b01658
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a b h
, ,
Table 1. Pd-Catalyzed C(sp3)−H Carbonylation of N-
Scheme 2. Scope of N-Alkylpicolinamides
a b
,
Alkylpicolinamides: Optimization of Conditions
entry
oxidant
solvent
yield (%)
1
PhI(OAc)2
Cu(OAc)2
AgOAc
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
THF
0
2
3
4
5
6
7
8
9
0
0
DDQ
0
NFSI
0
CAN
0
K2S2O8
0
TEMPO
TEMPO
TEMPO
TEMPO
TEMPO
TEMPO
TEMPO
TEMPO
TEMPO
TEMPO
TEMPO
38
80
81
trace
0
c
cd
,
10
11
12
13
14
15
16
17
18
cd
,
cd
,
DCE
cd
,
o-xylene
m-xylene
p-xylene
mesitylene
anisole
p-xylene
74
74
85
72
84
0
cd
,
cd
,
cd
,
cd
,
cde
, ,
a
Unless otherwise noted, the reaction conditions were as follows: 1a
(0.2 mmol, 1.0 equiv), Pd(OAc)2 (10 mol %), oxidant (0.4 mmol, 2.0
b
equiv), CO (1 atm), solvent (1.0 mL), 130 °C, 24 h. Isolated yield.
c
d
e
4.0 equiv of TEMPO were used. 120 °C. No Pd(OAc)2.
product could be found in the absence of palladium acetate
(entry 18).
With the optimized conditions in hand, we next moved on to
examine the scope of N-alkylpicolinamide 1. The carbonylation
of 2-pyridyl-protected alkylamines with a quaternary β-carbon
atom proceeded smoothly to afford the corresponding
pyrrolidones in good to excellent yields (2b−c, Scheme 2).
While substrates containing a hydrogen atom at the carbon
atom adjacent to the reaction site showed lower reactivity in the
reported methods,7,8 protected alkylamines bearing only one
(2d−f) or even no β-alkyl group (2g−i) were well tolerated in
our catalytic system without any decline of catalytic activity.
Notably, n-propylamine derivative 1j was also well tolerated to
give pyrrolidone 2j in good yield (82%). To our best
knowledge, this is the first example of Pd-catalyzed directed
C−H carbonylation of nonsubstituted linear functionalized
alkanes so far. Additionally, a cyclopropyl C(sp3)−H bond was
also well compatible with this transformation to give an
excellent yield (2k, 89%).
a
Unless otherwise noted, the reaction conditions were as follows: 1
(0.2 mmol, 1.0 equiv), Pd(OAc)2 (10 mol %), TEMPO (4.0 equiv), p-
b
c
xylene (1 mL), CO (1 atm), 130 °C, 24 h. Isolated yield. 120 °C.
d
e
f
g
Anisole was used as solvent. 48 h. Pd(OAc)2 (20 mol %). 140 °C.
h
1
The diastereoisomeric ratio was determined by H NMR.
To demonstrate the synthetic utility of this novel method, N-
pyridyl protected pyrrolidone 2a was converted to a γ-amino
acid or γ-lactam with high selectivity, by subjection to simple
acidic or basic conditions, respectively (Scheme 3). Upon
Scheme 3. Synthetic Derivatization of Picolinoylpyrrolidone
As the most commercially available chiral sources, the α-
amino acids and amino alcohols have been widely used in
organic synthesis. Establishing streamlined synthetic ap-
proaches for the preparation of unnatural chiral derivatives
via C−H activation of these readily available chiral compounds
is an important research focus and has drawn much interest
from different groups recently. A range of commercial α-amino
acids and amino alcohols were converted to the corresponding
picolinamides and subjected to the catalytic system. To our
great pleasure, a number of such chiral substrates were
compatible with our newly developed protocol, affording the
corresponding γ-lactams in good yields (2l−p). Interestingly,
the β-amino acid derivative was also the suitable substrate in
this transformation (83%, 2r).
treatment of 2a with 6 N HCl at 100 °C, both amide bonds
were hydrolyzed to give a γ-amino acid salt in 93% isolated
yield. Meanwhile, treatment of 2a with NaOH (10%) at 0 °C
afforded the 4-methylpyrrolidone 4 in 95% yield by removal of
the pyridyl protecting group only. The excellent control of
transformation to γ-amino acids or γ-lactams, both existing
expansively in biologically important natural and unnatural
B
DOI: 10.1021/acs.orglett.5b01658
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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To further exhibit the synthetic potential of this trans-
formation, we next attempted to carry out a concise total
synthesis of rac-Pregabalin, whose (S)-isomer was known as an
anticonvulsant drug and as an adjunct therapy for partial
seizures.11 Starting from the recemic alkylamine 5, protection
with 2-pyridyl chloride afforded the bidentated amide 6, which
underwent the Pd-catalyzed carbonylation of C(sp3)−H bond
to give the protected γ-lactam 7 in 80% yield. The rac-
Pregabalin was then obtained in 86% yield followed by
deprotection of 7 upon treatment with 6 N HCl and
neutralization (Scheme 4).
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In conclusion, we have developed a direct carbonylation of
alkylamines via Pd-catalyzed C(sp3)−H bond activation under
1 atm of CO for syntheses of γ -lactams and γ-amino acids, in
which TEMPO was found to be the crucial sole oxidant. The
synthetic potential was demonstrated by concise total synthesis
of rac-Pregbalin. Further research to apply this protocol to the
total synthesis of complex natural products is currently
underway in our laboratory.
(6) For nondirected C(sp3)−H carbonylation with CO catalyzed by
ASSOCIATED CONTENT
* Supporting Information
■
transition metals other than palladium, see: (a) Nizova, G. V.; Suss-
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Experimental procedure and characterization of all new
compounds. The Supporting Information is available free of
charge on the ACS Publications website at DOI: 10.1021/
acs.orglett.5b01658.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: xswang77@ustc.edu.cn.
(7) Yoo, E. J.; Wasa, M.; Yu, J.-Q. J. Am. Chem. Soc. 2010, 132, 17378.
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
(9) McNally, A.; Haffemayer, B.; Collins, B. S. L.; Gaunt, M. J. Nature
2014, 510, 129.
We gratefully acknowledge the National Basic Research
Program of China (973 Program 2015CB856600), the National
Science Foundation of China (21372209), the Chinese
Academy of Sciences, the Excellent Young Scientist Foundation
of Anhui Province (2013SQRL003ZD), China Postdoctoral
Science Foundation (2014M560513), and the Fundamental
Research Funds for the Central Universities (WK2060190046)
for financial support.
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(12) When this manuscript was in preparation for submission, an
oxalyl amide assisted Pd-catalyzed γ-C(sp3)−H carbonylation, with
AgOAc used as oxidant and m-CF3PhCO2H as additive, was reported
online; see: Wang, C.; Zhang, L.; Chen, C.; Han, J.; Yao, Y.; Zhao, Y.
Chem. Sci. 2015, DOI: 10.1039/c5sc00519a. Some comparisons
between this reported method and our protocol were listed as follows:
(a) While substrates containing a hydrogen atom at the carbon atom
adjacent to the reaction site showed lower reactivity in Yao and Zhao’s
method (23%−56% yields), protected alkylamines bearing only one
(2d−f) or even no β-alkyl group (2g−i) were well tolerated in our
catalytic system without any decline in catalytic activity (65%−90%
yields). (b) n-Propylamine derivative 1j was tolerated in our catalytic
system to give a good yield (82%), but was not compatible with Yao
and Zhao’s case (<5%). (c) TEMPO, the lower cost oxidant, was used
in our system instead of silver salts. (d) To demonstrate the synthetic
perspective, we converted the carbonylation product to the lactam and
γ-amino acid, and the novel method was also used for the total
synthesis of Pregabalin.
D
DOI: 10.1021/acs.orglett.5b01658
Org. Lett. XXXX, XXX, XXX−XXX