Palladium-catalyzed carbenoid based N-H bond insertions: Application to the synthesis of chiral α-amino esters

Article abstract of DOI:10.1039/c3ob41331d

A highly efficient palladium-catalyzed carbenoid based N-H bond insertion has been developed. The α-amino esters were obtained in high isolated yields. Moreover, by choosing a suitable chiral auxiliary, stereoselective Pd-catalyzed N-H insertion has been realized. The chiral α-amino esters were obtained in high yields (up to 91%) and with excellent diastereoselectivities (d.r. > 19:1). The Royal Society of Chemistry.

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Palladium-Catalyzed Carbenoid Based N-H Bond Insertions:
Application to the Synthesis of Chiral α-Amino Esters
Gang Liu,a Jian Li,a Lin Qiu,a Li Liu,b Guangyang Xu,a Bing Maa and Jiangtao Suna,*
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
5
DOI: 10.1039/b000000x
40 palladium-catalyzed carbenoid based insertion into N-H bonds,
which delivers the insertion products in high yields. Moreover, by
A highly efficient palladium-catalyzed carbenoid based
N-H bond insertion has been developed. The α-amino
choosing a suitable chiral auxiliary, the chiral α-amino esters
esters were obtained in high isolated yields. Moreover,
were obtained in high yields and with excellent
diastereoselectivities.
by choosing suitable chiral auxiliary, the stereoselective
10 Pd-catalyzed N-H insertion has been realized. The
chiral α-amino esters were obtained in high yields (up
to 91%) and with excellent diastereoselectivities (d.r. >
19:1).
45
Initially, we examined the reaction of p-chloro-aniline with α-
phenyl diazoacetate in the presence of various palladium
resources at room temperature in dichloromethane. Within 12
hours, PdCl2 gave the insertion product in moderate yield (Table
1, entry 1). Pd(OAc)2, Pd(TFA)2 and Pd2(dba)3 exhibited similar
50 catalytic reactivity towards this reaction and gave the insertion
products in nearly 30% yield (Table 1, entries 2 to 4). However,
Pd(PPh3)4 and Pd(dppf)Cl2 did not work in this insertion at all,
which means the presence of phosphorus ligands thoroughly stop
the reaction (Table 1, entries 5 and 6). Solvent screen showed
55 1,2-dicholoroethane (DCE) is the best one (Table 1, entry 12).
Higher reaction temperature resulted in a decreased yield (Table 1,
entry 13). High reaction temperature resulted in lots of side
products (Table 1, entry 13). Finally, we found when the reaction
stirred at room temperature for 3 hours then at 40oC for 6 hours,
60 the insertion product was obtained cleanly in 85% isolated yield
(Table 1, entry 14). This phenomenon probably can be explained
with the fact that the first step is more selective at lower reaction
temperatures while one of the latter step requires higher reaction
temperatures. In addition, low catalyst loading resulted in a
65 decreased isolated yield (Table 1, entry 15).
The C-N bond formation has been recognized as one of the most
15 useful synthetic method in organic synthesis.1 Moreover, the
importance of aromatic C-N bond in pharmaceuticals and natural
products attracted lots of interests to develop efficient approaches
in this research area.2 In addition, palladium catalyzed coupling
reactions between amines and aryl iodides, bromides and triflates
20 have been widely accepted as one of the most efficient methods
to construct the C-N bond.3 Besides this, the metal-catalyzed
carbenoid insertion into N-H bond, is obviously a highly efficient
C-N bond transformation by using diazo compounds as the
precursors.4 As reviewed by Gillingham,4b in the carbenoid
25 insertions, a metal-carbenoid is typically generated in situ from a
diazo precursor and then reacted with N-H bond to afford the
insertion products. To date, the metal complex of Rh5 and Cu,6
have been broadly applied in the carbenoid based X-H (where X
is any heteroatom such as nitrogen, oxygen or sulfur etc. )
30 insertions. Other metal complex, such as Ru,7 Ag8, Fe9 and Au,10
also have been investigated in this reaction (Scheme 1).
Table 1 Pd-catalyzed carbenoid based N-H bond insertion:
Optimization of reaction conditionsa
Yield
(%)b
Entry
Palladium complex
PdCl2
Solvent
CH2Cl2
1
45
38
30
30
0
2
Pd(OAc)2
Pd(TFA)2
Pd2(dba)3
Pd(PPh3)4
Pd(dppf)Cl2
PdCl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
DCE
3
4
5
6
0
Scheme 1 Metal-catalyzed carbenoid based N-H insertion
35
7
61
27
42
38
40
8
PdCl2
THF
During the past decade, palladium based carbenoid has been
well studied in various transformations.11 However, to our
knowledge, the palladium based carbenoid has little or no use in
the X-H insertion. Herein, we wish to report the successful
9
PdCl2
DMF
10
11
PdCl2
DMSO
toluene
PdCl2
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DOI: 10.1039/C3OB41331D
for 6 hours. bIsolated yield.
51
12
PdCl2
PdCl2
PdCl2
PdCl2
DCE
DCE
DCE
DCE
13c
14d
15e
20
85
The diastereoselective/enantioselective insertion of α-
diazocarbonyl compounds into N-H bond represents an attractive
approach to obtain optically pure α-amino acid derivatives.12
30 Zhou13, Fu14 and Feng15 reported copper-catalyzed highly
enantioselective N-H bonds insertions. However, as described by
Zhou and Feng, for α-aryl diazo substrates, low to moderate
enantioselectivities were observed. Also, Miyairi reported the
cinchona alkaloids catalyzed asymmetric N-H insertions in
35 moderate enantioselectivities.16
Based on the former results, we next investigated the use of
chiral α-aryl diazoesters as the substrates in the stereoselective N-
H insertions. As showed in table 3, solvent screen still showed
DCE is the best one. When 4b was selected as the chiral auxiliary
40 (Table 3, entry 5), low d.r. value was observed. The (-)-menthol
derived chiral diazoester gave 5:1 d.r. value (Table 3, entry 4). To
our delight, excellent diastereoselectivity of the insertion product
was obtained when (-)-phenyl-menthol17 was used (Table 3, entry
6).
52
aUnless otherwise noted, all reactions were carried out with p-
chloroaniline (1.1 mmol), α-phenyl-diazoacetate (1 mmol), Pd complex
(0.05 mmol) in 3 mL solvent at room temperature for 12 hours under
c
nitrogen; bIsolated yields based on α-phenyl-diazoacetate; The reaction
was performed at 40oC; dThe reaction was performed at room temperature
for 3 hours, then 40oC for 6 hours.; e2 mol% PdCl2 was used.
Upon the above results, we then investigated the substrate
scope under the optimized conditions (5 mol% PdCl2 in DCE at
r.t for 3 hours then 40oC for 6 hours). The results were
summarized in table 2. As observed, for the same diazo substrate,
the para-substituted anilines with electron-withdrawing groups
afforded the insertion products in higher yields (Table 2, entry 1
to entry 12) and p-nitroaniline gave the highest isolated yield
(Table 2, entry 3). The substituted anilines with electron-
10 withdrawing groups at the ortho or meta position, high yields
were also obtained. N-methyl aniline also gave the insertion
products in high yield (Table 2, entry 13). When α-benzyl
diazoacetate was used, high yield was observed when reacted
with 1a (Table 2, entry 16). However, alkyl amine did not work
15 in this case (Table 2, entries 17 and 18). As mentioned by Van
Vranken in the palladium-catalyzed three-component coupling
between α-diazoesters, vinyl-halides and amines, they did not
find any N-H insertion products.11c,11d Also, for the 2-
aminomethyl aniline, under this reaction conditions, the reaction
20 did not work too, which means the aniline N-H insertion was
inhibited in the presence of alkyl amine groups (Table 2, entry
19).
5
45
Table
3
PdCl2-catalyzed stereoselective N-H insertion:
Optimization of the reaction conditionsa, b
O
NH2
H
N2
N
PdCl2 (5 mol%)
OR*
OR*
+
DCE, rt to 40oC
Cl
O
Cl
1a
4
5a to 5c
Yield
(%)b
d.r.
(%)c
Entry
-OR*
Solvent
1
2
3
4
CH2Cl2
CH3CN
toluene
DCE
72
82
58
78
3:1
4:1
4:1
5:1
Table 2 Substrate scopea
4a
4b
25
5
6
DCE
DCE
93
89
1.2:1
Yield
(%)b
R1
R2
R3
Entry
1
p-Cl-Ph
H
H
H
H
H
H
H
H
H
H
H
H
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
85
82
93
90
84
74
78
84
78
87
85
82
86
88
84
82
-
>19:1
2
Ph
3
p-NO2-Ph
p-Br-Ph
p-MeO-Ph
p-Me-Ph
o-Br-Ph
o-I-Ph
4c
4
aAll reactions were carried out with p-chloroaniline (1.1 mmol), α-
phenyl-diazoacetate (1 mmol), PdCl2 (0.05 mmol), in DCE (3 mL). All
reactions were stirred at room temperature for 3 hours then 40oC for 6
hours; Isolated yield; D.r. values were determined by NMR analysis of
crude products.
5
6
b
c
7
8
9
o-Me-Ph
m-Cl-Ph
m-Br-Ph
m-Me-Ph
Ph
50
Under optimized reaction conditions, we next use chiral
diazoester 4c as the standard substrate for further investigation.
As shown in table 4, all of the reactions proceeded smoothly and
furnished the chiral α-amino esters in moderate to high yields and
with moderate to excellent diastereoselectivities (up to 91% yield
55 and >19:1 d.r. value). The insertion products of electron-
withdrawing substituted anilines gave better diastereoselectivities
than the electron-donating substituted anilines. It is worth noting
that the N-methyl-aniline gave the inverse chiral center compared
with others (Table 4, 5g).18
10
11
12
13
14
15
16
17
18
19
Me
H
p-NO2-Ph
p-Cl-Ph
p-Me-Ph
p-NO2-Ph
benzyl
Ph
H
p-Cl-Ph
H
Benzyl
H
Piperidine
2-aminomethyl
H
Ph
-
60
H
Ph
-
aAll reactions were carried out with substituted anilines or amine (1.1
mmol), α-phenyl-diazoacetates (1 mmol), PdCl2 (0.05 mmol), in DCE (3
mL). All reactions were stirred at room temperature for 3 hours then 40oC
2
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Table 4 PdCl2-catalyzed stereoselective N-H insertion: Substrate
scopea, b, c
Cl
O
O
O
H
H
N
H
N
N
O
O
O
Cl
Ph
Ph
Ph
5e
5d
, 75%, 6:1
, 81%, >19:1
5c, 89%, >19:1
O
H
Me
O
Br
O
H
Cl
N
O
N
N
O
O
Ph
Ph
Ph
aAll reactions were carried out with aniline (1.1 mmol), α-diazoester (1
mmol), PdCl2 (0.05 mmol) in DCE (3 mL) at room temperature for 3
5h, 74%, >19:1
5f, 84%, >19:1
5g, 86%, >19:1
hours then 40oC for
determined by NMR analysis of crude products; The absolute
6
hours; bIsolated yields; cD.r. values were
O
H
O
O
H
H
N
O
N
N
O
O
configurations were determined by X-ray of 7h or by analogy.
Me
O2N
Br
Ph
Ph
Ph
The absolute and relative configurations of 5 and 7 were
unambiguously assigned by X-ray crystallographic analysis of the
optically pure compound 7h, which was obtained by
5i
5k, 86%, >19:1
, 82%, 9:1
5j, 91%, >19:1
aAll reactions were carried out with aniline (1.1 mmol), α-diazoester (1
mmol), PdCl2 (0.05 mmol) in DCE (3 mL) at room temperature for 3
20 recrystallization from
a mixture of dichloromethane. The
hours then 40oC for
determined by NMR analysis of crude products; The absolute
6
hours; bIsolated yields; cD.r. values were
structure enabled the (R) assignment of the newly formed
stereogenic center in 7h (Figure 1). The configurations of others
(5 and 7) were then assigned by analogy can compared with
literature.18
configurations were determined by X-ray of 7h or by analogy.
5
We then continue to investigate the substrate scope upon the
variation of the diazo substrates and the anilines at the same time.
For most cases, the chiral α-amino esters were obtained in high
yields and with excellent diasteroselectivities except 7f (Table 5,
7f). As observed the same phenomenon with the former reaction,
25
10 the N-methyl-aniline still gave the inverse chiral centers in (S)
configuration when reacted with different diazo esters (Table 5,
7e and 7g).18
Table 5 Substrate scopea, b, c
15
Fig 1 X-ray crystal structure of 7h.
For the possible reaction mechanism and stereoselectivity
30 (Figure 2), we concluded that the combination of PdCl2 with α-
phenyl diazoester gave the Pd-diazo intermediate a. Since higher
reaction temperature resulted in messy products, we thought low
temperature was essential for the carbene formation. Following
by loss of N2 delivers the Pd-carbenoid b. Nuclephilic attacked
35 by aniline rendering the intermediate c. The asymmetric
induction step was controlled by the steric factor of the chiral
auxiliary, in which the bulky ortho group made the addition of
aniline prone to attack from the less steric side. Then the
migration of hydrogen from nitrogen to carbon and the leaving of
40 palladium resulted in the formation of chiral α-amino ester.
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observed stereochemistry
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5
In conclusion, an efficient Pd-catalyzed carbenoid based N-H
insertion has been developed. Furthermore, using (-)-phenyl-
menthol as chiral auxiliary, the insertion products have been
obtained in high yields and with excellent diastereoselectivities
(>19:1). Currently, we are investigating other Pd-catalyzed
11 For reviews, see: (a) Y. Zhang, J. Wang, Eur. J. Org. Chem., 2011,
1015-1026; (b) Q. Xiao, Y. Zhang, J. Wang, Acc. Chem. Res., 2013,
65
70
75
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Van Vranken, Org. Lett., 2007, 9, 2047-2049; (d) R. Kudirka, S. K.
J. Devine, C. S. Adams, D. L. Van Vranken, Angew. Chem. Int. Ed.,
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10 carbenoid based X-H insertions and their further applications.
We gratefully acknowledge the National Natural Science
Foundation of China (21172023, 2102010) and A Project
Funded by the Priority Academic Program Development of
15 Jiangsu Higher Education Institutions (PAPD) for their
financial support.
12 For early studies of metal-catalyzed N-H insertions, see: (a) P. Yates,
J. Am. Chem. Soc., 1952, 74, 5376-5381; (b) S. Bachmann, D.
Fielenbach, K. A. Jørgensen, Org. Biomol. Chem., 2004, 2, 3044-
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Notes and references
a School of Pharmaceutical Engineering & Life Science, Changzhou
University, Changzhou 213164, P. R. China E-mail: jtsun08@gmail.com;
20 Fax: +86 519 86334598; Tel: +86 519 86334597
b School of Petroleum Engineering, Changzhou University, Changzhou
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18 The absolute configuration of 5g was assigned for (S), which was
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