Iridium-catalyzed decarboxylative N-alkylation of α-amino acids with primary alcohols

Article abstract of DOI:10.1055/s-0033-1340474

A new decarboxylative N-alkylation reaction of α-amino acids has been developed. A variety of tertiary amines were obtained in good to excellent yields via the decarboxylative N-alkylation reaction of α-amino acids with primary alcohols catalyzed by a CpIr complex. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0033-1340474

LETTER
▌539
lIertteirdium-Catalyzed Decarboxylative N-Alkylation of α-Amino Acids with
Primary Alcohols
Decarboxylative N-Alkylation of α-Amino Acids with Alcohols
Jiashou Wu,*a,b Huajiang Jiang,a Dingben Chen,a Jianfen Shen,a Datong Zhao,*b Jing Xiang,c Qizhong Zhoua
a
School of Pharmaceutical and Chemical Engineering, Taizhou University, Taizhou 318000, Zhejiang, P. R. of China
Fax +86(576)85137169; E-mail: jsw79@tzc.edu.cn
b
Zhejiang Hisoar Pharmaceutical Co., LTD., Taizhou 318000, Zhejiang, P. R. of China
Fax +86(576)88828200; E-mail: zhaodt@hisoar.com
c
College of Chemistry and Environmental Engineering, Yangtze University, Jingzhou 434020, Hubei, P. R. of China
Received: 27.09.2013; Accepted after revision: 24.11.2013
R3
Abstract: A new decarboxylative N-alkylation reaction of α-amino
R2
acids has been developed. A variety of tertiary amines were ob-
tained in good to excellent yields via the decarboxylative N-alkyla-
tion reaction of α-amino acids with primary alcohols catalyzed by a
Cp*Ir complex.
OH
N
R1
R1
[M]
[M]
Key words: iridium, amine, decarboxylative N-alkylation, amino
acid, alcohol
H
H+
R3
R3
O
– H2O, – CO2
R3
R2
R1
–
R2
R1
+
N
+
Amines are highly important organic compounds. They
are widely used in pharmaceutical and agrochemical in-
dustry. A variety of methods have been developed for
their synthesis.1 Transition-metal-catalyzed dehydrative
coupling of amines with alcohols using the borrowing hy-
drogen strategy has aroused great interest in recent years
as an attractive alternative to the conventional synthetic
methods for amines in terms of the atom economy and en-
vironmental benignancy.2
N
R1
–
R2
N
COOH
H
Scheme 1 Proposed reaction pathway for amine synthesis
[Cp*IrCl2]2 is a highly active catalyst for transfer-hydro-
genation reactions.2 It was selected as the catalyst for the
decarboxylative N-alkylation reaction of benzyl alcohol
(1a) with proline (2a). To our delight, the reaction pro-
ceeded smoothly with KOH as base in toluene under ar-
gon at 110 °C to give the desired decarboxylative amine
product 3a in 73% yield upon isolation (Table 1, entry 1).
The reaction of 1a and 2a does not occur in the absence of
the Cp*Ir complex (Table 1, entry 2). The reaction effi-
ciency was affected by the ratio of α-amino acid and alco-
hol. We found that the reaction with a higher amount of
amino acid 2a than that of 1a (2a/1a = 1.3:1) provided the
α-Amino acids are readily available natural compounds.
Therefore, the use of α-amino acids as the nitrogen-con-
taining motifs in organic synthesis is very attractive. Re-
cently, several research groups have reported a series of
cascade decarboxylative reactions using α-amino acids as
azomethine ylide precursors.3 Azomethine ylides are re-
active intermediates widely used in organic synthesis.4 It
can be generated in situ by the decarboxylative reaction of
α-amino acid with aldehyde or ketone. Protonation of azo-
methine ylide results in the formation of iminium which amine product 3a in 84% isolated yield (Table 1, entry 4).
can be captured by suitable nucleophile to give the addi-
tion product.3a–e It is well known that carbonyl intermedi-
ates can be generated in situ using borrowing hydrogen
strategy from alcohols.2 Based on our previous work on
iminium reduction,5 we envisioned that it is possible to
transfer hydrogenation of the protonated azomethine ylide
intermediate with the metal hydride species previously
produced from the dehydrogenation reaction of alcohol to
give the amine product (Scheme 1). We report herein new
decarboxylative N-alkylation reactions of α-amino acids
with alcohols.
Further increasing the amino acid loading did not improve
the yield (Table 1, entry 5). Among the bases screened,
NaHCO3 gave the best result with 86% yield within 24
hours in toluene (Table 1, entry 8). Decreasing the reac-
tion temperature led to a lower yield (Table 1, entry 9 vs.
entry 8). With other solvents such as DMF or DMSO, no
reaction occurred (Table 1, entries 10 and 11). Other cat-
alysts [Ir(cod)Cl]2, [Ru(p-cymene)Cl2]2, and [Cp*RhCl2]2
were inactive (Table 1, entries 12–14).
Under these optimized conditions (Table 1, entry 8), de-
carboxylative N-alkylation of proline with various prima-
ry alcohols was examined, and the results are summarized
in Table 2.6 A variety of benzylic alcohols bearing various
functional groups were employed in the reaction to give
the corresponding amine products with good to excellent
SYNLETT 2014, 25, 0539–0542
Advanced online publication: 08.01.2014
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0033-1340474; Art ID: ST-2013-W0920-L
© Georg Thieme Verlag Stuttgart · New York

540
J. Wu et al.
LETTER
Table 1 Optimization of the Reaction Conditionsa
3-methoxy-1-propanol (1ac) with proline gave 1-(3-me-
thoxypropyl)pyrrolidine in 69% yield (Table 2, entry 29).
OH
cat. (0.5 mol%)
+
Table 2 Decarboxylative N-Alkylation of Proline with Various Pri-
N
mary Alcoholsa
COOH
base, solvent
N
H
110 °C, 24 h
1a
2a
3a
OH
[Cp*IrCl2]2 (0.5 mol%)
+
COOH
N
N
NaHCO3, toluene
110 °C
R
Entry Cat.
2a (equiv) Base
Yield (%)b
H
R
1
2a
3
1
2
[Cp*IrCl2]2
none
1.0
1.0
1.1
1.3
1.5
1.3
1.3
1.3
1.3
1.3
1.3
1.3
KOH
73
0
Entry
Alcohol
Time (h) Yield (%)b
KOH
3
[Cp*IrCl2]2
[Cp*IrCl2]2
[Cp*IrCl2]2
[Cp*IrCl2]2
[Cp*IrCl2]2
[Cp*IrCl2]2
[Cp*IrCl2]2
[Cp*IrCl2]2
[Cp*IrCl2]2
[Ir(cod)Cl]2
KOH
78
84
83
73
72
86
70
trace
trace
trace
0
OH
1
24
86
4
KOH
1a
5
KOH
OH
OH
6
Na2CO3
K2CO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
2
3
24
24
97
95
Cl
7
1b
8
9c
10d
11e
12
13
14
Br
1c
Cl
OH
4
48
93
[Ru(p-cymene)Cl2]2 1.3
[Cp*RhCl2]2 1.3
0
1d
1e
a Reaction conditions: 1a (0.5 mmol), catalyst (0.5 mol%), base (10
OH
mol%), and 2a in solvent (3 mL) at 110 °C for 24 h.
5
6
24
24
89
91
b Isolated yield.
c At 90 °C.
d DMSO as solvent.
OH
e DMF as solvent.
H3CO
yields (Table 2, entries 1–17). Fluoro, chloro, bromo,
methyl, methoxy, benzyloxy, and dimethylamino substit-
uents were tolerated in the present reaction system. The
reaction using more sterically hindered alcohol substrates
such as 2-methoxybenzyl alcohol and 2-benzyloxybenzyl
alcohol yielded the desired amine products in 89% and
88% yields (Table 2, entries 15 and 16). With elevated
catalyst loading, heteroaromatic alcohols can also react
smoothly (Table 2, entries 18–21). Thus, the reaction of 2-
furanmethanol with proline gave 3r in moderate yield,
55% (Table 2, entry 18). High yields were obtained when
2- or 3-pyridyl methanol was used as substrate (Table 2,
entries 20 and 21). Alkyl alcohols were also good sub-
strates (Table 2, entries 22–29). For alkyl alcohol 1v, the
desired 1-phenethylpyrrolidine was obtained in 80% yield
(Table 2, entry 22). When alcohols with cyclohexyl sub-
stituent were performed (Table 2, entries 25 and 26), the
expected amine products 3y and 3z were isolated in good
yields (91% and 88%, respectively). The reaction of
1f
Cl
OH
OH
7
24
80
Cl
1g
Br
8
9
24
96
93
83
1h
1i
OH
Br
OH
10
96
90
1j
Synlett 2014, 25, 539–542
© Georg Thieme Verlag Stuttgart · New York

LETTER
Decarboxylative N-Alkylation of α-Amino Acids with Alcohols
541
Table 2 Decarboxylative N-Alkylation of Proline with Various Pri-
Table 2 Decarboxylative N-Alkylation of Proline with Various Pri-
mary Alcoholsa (continued)
mary Alcoholsa (continued)
OH
OH
[Cp*IrCl2]2 (0.5 mol%)
[Cp*IrCl2]2 (0.5 mol%)
+
+
COOH
COOH
N
N
N
N
NaHCO3, toluene
110 °C
NaHCO3, toluene
110 °C
R
R
H
H
R
R
1
2a
3
1
2a
3
Entry
11
Alcohol
Time (h) Yield (%)b
Entry
Alcohol
Time (h) Yield (%)b
F
OH
22
23
72
72
80
84
OH
72
93
1v
1k
OH
OH
Cl
12
13
14
96
96
96
78
85
90
Me2N
1w
1l
OH
OH
24
72
72
87
91
BnO
1x
1y
1m
OH
BnO
25g
OH
BnO
OH
OH
1n
OBn
26
72
88
OH
OH
1z
15
96
89
27g
28g
29g
72
72
72
72
78
69
1aa
1o
OMe
OH
16
17
96
96
88
84
1ab
MeO
1ac
OH
1p
MeO
OH
a Reaction conditions: 1 (0.5 mmol), [Cp*IrCl2]2 (0.5 mol%),
NaHCO3 (10 mol%), and 2a (0.65 mmol) in toluene (3 mL) at 110 °C
for 24 h.
MeO
1q
b Isolated yield.
c With 2.5 mol% of [Cp*IrCl2]2 at 90 °C.
d With 2.5 mol% of [Cp*IrCl2]2 at 90 °C.
e With 2.5 mol% of [Cp*IrCl2]2.
OH
OH
18c
19d
96
96
55
76
O
f With 1.5 mol% of [Cp*IrCl2]2.
1r
g With 0.5 mmol 2a and 1.0 mmol 1 due to evaporation of alcohol.
S
Other α-amino acids were also investigated (Scheme 2).
The reaction of pipecolic acid with 1c gave 3cb in 65%
yield. The decarboxylative N-alkylation reaction occurred
smoothly when primary α-amino acid glycine was used as
substrate. Notably, KOH was used in order to obtain high
yields.
1s
OH
OH
20e
21f
96
48
85
92
N
1t
In summary, we present a new method for the preparation
of tertiary amines via iridium-catalyzed decarboxylative
N-alkylation of α-amino acids with primary alcohols. Fur-
ther investigation, including the scope and mechanism of
this reaction, is in progress in our laboratory.
N
1u
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 539–542

542
J. Wu et al.
LETTER
Zhang, S.; Guo, F.; Zhang, B.; Hu, P.; Wang, Z. J. Org.
Chem. 2012, 77, 11161.
OH
+
(4) (a) Coldham, I.; Hufton, R. Chem. Rev. 2005, 105, 2765.
(b) Pandey, G.; Banerjee, P.; Gadre, S. R. Chem. Rev. 2006,
106, 4484.
(5) Wu, J.; Wang, F.; Ma, Y.; Cui, X.; Cun, L.; Zhu, J.; Deng, J.;
Yu, B. Chem. Commun. 2006, 1766.
N
[Cp*IrCl2]2 (0.5 mol%)
N
H
2b
COOH
NaHCO3, toluene
110 °C
Br
Br
1c
3cb, 65%
(6) General Procedure for the Preparation of 3
To a solution of [Cp*IrCl2]2 (0.0025 mmol), amino acid 2
(0.65 mmol), and NaHCO3 (0.05 mmol) in toluene (3 mL)
under an atmosphere of argon was added alcohol 1 (0.5
mmol). The resulting mixture was stirred at 110 °C for a
certain period of time. The reaction mixture was cooled to
r.t., and H2O (5 mL) was then added. The resulting solution
was extracted with EtOAc. Purification on silicon gel
afforded the desired products 3.
R
Me
N
OH
COOH
[Cp*IrCl2]2 (1.5 mol%)
2
+
KOH, toluene
110 °C
NH2
2c
R
1a R = H
1b R = Cl
1g R = OMe
R
4a R = H, 87%
4b R = Cl, 90%
4g R = OMe, 80%
General Procedure for the Preparation of 4
To a solution of [Cp*IrCl2]2 (0.0075 mmol), glycine (2c, 0.5
mmol), and KOH (0.15 mmol) in toluene (3 mL) under an
atmosphere of argon was added alcohol 1 (1.0 mmol). The
resulting mixture was stirred at 110 °C for a certain period of
time. The reaction mixture was cooled to r.t., and H2O (5
mL) was then added. The resulting solution was extracted
with EtOAc. Purification on silicon gel afforded the desired
products 4.
Scheme 2 Decarboxylative N-alkylation reactions of α-amino acids
with alcohols
Acknowledgment
We are gratefully to the Postdoctoral Research Foundation of Zhe-
jiang Province (No. BSH1302072), the Science & Technology
Foundation of Taizhou (No. 111ZD02 and No. 121ZD04), and the
Natural Science Foundation of China (No. 21172166).
Data of Unknown Compounds
Compound 3n: yellow oil. IR: 3063, 3032, 2961, 2784,
1606, 1589, 1510, 1455, 1378, 1265, 1227, 1163, 1136,
1023, 853, 809, 736 cm–1. 1H NMR (400 MHz, CDCl3): δ =
7.49–7.40 (m, 4 H), 7.39–7.32 (m, 4 H), 7.32–7.27 (m, 2 H),
7.00 (d, J = 1.8 Hz, 1 H), 6.87 (d, J = 8.1 Hz, 1 H), 6.82 (dd,
J = 8.2, 1.9 Hz, 1 H), 5.17 (s, 2 H), 5.14 (s, 2 H), 3.58 (s, 2
H), 2.58–2.46 (m, 4 H), 1.84–1.72 (m, 4 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 148.7, 148.3, 137.4, 137.3, 131.3,
128.5, 128.4, 127.8, 127.7, 127.4, 127.3, 122.2, 116.2,
114.8, 71.4, 71.2, 59.7, 53.6, 23.3 ppm. ESI-HRMS: m/z
calcd for C25H27NO2 [M + H]: 374.2115; found: 374.2117.
Compound 3o: yellow oil. IR: 3064, 3034, 2961, 2789, 1602,
1588, 1495, 1453, 1376, 1348, 1241, 1123, 1050, 1024, 880,
858, 754, 697 cm–1. 1H NMR (400 MHz, CDCl3): δ = 7.46–
7.42 (m, 3 H), 7.41–7.37 (m, 2 H), 7.36–7.31 (m, 1 H), 7.24
(dt, J = 8.2, 2.1 Hz, 1 H), 6.93–6.99 (m, 2 H), 5.09 (s, 2 H),
3.91 (s, 2 H), 2.74–2.78 (m, 4 H), 1.85–1.80 (m, 4 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 156.8, 137.1, 131.5, 128.9,
128.6, 127.9, 127.3, 125.1, 120.9, 111.9, 53.2, 52.5, 23.3
ppm. ESI-HRMS: m/z calcd for C18H21NO [M + H]:
268.1696; found: 268.1695.
References and Notes
(1) (a) Salvatore, R. N.; Yoon, C. H.; Jung, K. W. Tetrahedron
2001, 57, 7785; and references cited therein. (b) Chiappe,
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cited therein.
(2) For reviews, see: (a) Suzuki, T. Chem. Rev. 2011, 111, 1825.
(b) Guillena, G.; Ramón, D. J.; Yus, M. Chem. Rev. 2010,
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2010, 110, 681. (d) Nixon, T. D.; Whittlesey, M. K.;
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(3) (a) Zheng, L.; Yang, F.; Dang, Q.; Bai, X. Org. Lett. 2008,
10, 889. (b) Bi, H.-P.; Teng, Q.; Guan, M.; Chen, W.-W.;
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Synlett 2014, 25, 539–542
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