Copper/DIPEA-catalyzed, aldehyde-induced tandem decarboxylation-coupling of natural α-amino acids and phosphites or secondary phosphine oxides

Article abstract of DOI:10.1021/jo200981h

A copper/DIPEA-catalyzed, aldehyde-induced intermolecular decarboxylative coupling reaction of natural α-amino acids and phosphites or secondary phosphine oxides was developed. In this process, a series of potentially useful ligands for organic synthesis

Full text of DOI:10.1021/jo200981h

NOTE
pubs.acs.org/joc
Copper/DIPEA-Catalyzed, Aldehyde-Induced Tandem
DecarboxylationꢀCoupling of Natural r-Amino Acids
and Phosphites or Secondary Phosphine Oxides
Dongxu Yang,† Depeng Zhao,† Lijuan Mao,† Linqing Wang,† and Rui Wang,†,‡
†Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Medicine, State Key Laboratory
of Applied Organic Chemistry, and Institute of Biochemistry and Molecular Biology, Lanzhou University, Lanzhou 730000, P. R. China
‡State Key Laboratory for Oxo Synthesis and Selective Oxidation, Lanzhou Institute of Chemical Physics, Chinese Academy of Sciences,
Lanzhou 730000, China
S Supporting Information
b
ABSTRACT: A copper/DIPEA-catalyzed, aldehyde-induced intermo-
lecular decarboxylative coupling reaction of natural R-amino acids and
phosphites or secondary phosphine oxides was developed. In this pro-
cess, a series of potentially useful ligands for organic synthesis and
biologically important unnatural amino acid derivatives (tertiary amino
phosphorus compounds) were obtained.
Scheme 1. Proposed Mechanism for the Decarboxylative
Three-Component Coupling Reaction
hosphorusꢀcontaining compounds have received intense
P
interest in recent years because of their wide applications
as ligands for metal-catalyzed CꢀC bond formation1 and their
potential biological activities.2 In particular, R-amino phospho-
nates have been widely used owing to their extensive role as
antibacterial agents,3 antiviral agents,4 and enzyme inhibitors5
and their catalytic antibody activities.6 The addition of phos-
phorus nucleophiles to imine catalyzed by Lewis acid is one of the
most convenient and traditional methods to provide such
compounds.7 Recently, a copper-catalyzed aerobic phosphona-
tion of N-protected tetrahydroisoquinoline based on cross-
dehydrogenative coupling (CDC) reactions was reported.8 This
method provides a new route to synthesize R-amino phospho-
nates but is limited to a narrow range of substrates. Very recently,
Li’s research group reported a CꢀC bond-forming reaction
based on a copper- or iron-catalyzed oxidative decarboxylative
coupling of sp3-hybridized carbons with N-benzylproline.9 Most
rencently, Yang’s and Liang’s group reported the first example of
copper-catalyzed decarboxylative coupling of N-benzylproline
with Ph2P(O)H compounds to construct CꢀP bonds.10 This
new reaction expands the scope and synthetic utility of the
catalytic decarboxylative coupling reactions previously devel-
oped. However, this method still suffers from a fundamental
drawback as Li’s work:9 these methods need other oxidants9 or
transition metals10 besides copper to facilitate the reaction. In
2010, Seidel and Li’s group successfully improved the method
involving a new reaction pathway, respectively, and they both
reported an interesting aldehyde-induced intermolecular tandem
decarboxylationꢀcoupling of secondary R-amino acids with
alkynes to afford propargylic amino derivatives, releasing H2O
and CO2 as the only byproducts.11,12 In these methods, the
carboxylic acids provide the possibility for site-specific functio-
nalization of the R-amino acids skeletons, using decarboxylative
coupling reactions to generate amine derivatives. On this basis,
and considering our interest in building phosphorus-containing
compounds,13 we decided to try to develop a new way of synthesis
of R-amino phosphonates. We propose a model for the dec-
arboxylative three components coupling reaction which is out-
lined in Scheme 1.
Previous research indicated the condensation of proline with
an aldehyde resulted in the formation of azomethine ylide A,10,11
and the phosphite can be activated by employing an appropriate
base since the equilibrium between B and C could shift toward
the reactive phosphinous acid C. Then protonation of the dipole
by the pronucleophile phosphinous acid C results in the forma-
tion of ion pairs which then convert into products 3. Further-
more, in order that this work has a wider range of applications, we
also tried to use other phosphorus nucleophiles, such as diaryl
phosphine oxides and even the less reactive dialkyl phosphine
oxides, to synthesize R-amino phosphine oxides.
We began by establishing reaction conditions for a Cu (I)-
catalyzed decarboxylationꢀcoupling phosphonation. Initially,
the reaction of 1.0 equiv of diethyl phosphite 1a, 1.5 equiv of
proline 2a, 1.4 equiv of p-cyanobenzaldehyde, and 30 mol % of
Received: May 18, 2011
Published: June 30, 2011
r
2011 American Chemical Society
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dx.doi.org/10.1021/jo200981h J. Org. Chem. 2011, 76, 6426–6431
|

The Journal of Organic Chemistry
NOTE
Table 1. Optimization of the Reaction Conditions
entrya
catalyst
additive
solvents
temp (°C)
time (h)
yieldb (%)
1
2
CuCl
CuBr
CuI
CuBr
CuI
CuBr
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
xylene
100
100
100
130
130
130
130
130
130
130
130
130
130
130
130
130
130
130
130
130
10
10
10
10
10
20
20
10
10
10
10
10
10
10
10
10
10
20
24
24
33
42
3
37
4
43
5
57
6
66
7
68
8
DIPEA (30%)
TEA (30%)
72
9
60
10
11
12
13
14
15
16
17
18
19
20
DMA (30%)
60
TMEDA (30%)
DMAP (30%)
DIPEA (30%)
DIPEA (30%)
DIPEA (30%)
DIPEA (30%)
DIPEA (30%)
DIPEA (30%)
DIPEA (30%)
DIPEA (30%)
72
56
67
CF3ꢀC6H3
DMF
12
37
DMSO
toluene
toluene
toluene
toluene
N.R
71c
92 (83)d
91
77e
a Unless otherwise noted, reactions were carried out on a 0.3 mmol scale in 2.5 mL of toluene under air with 1.0 equiv of 1a (0.3 mmol), 1.5 equiv of 2a
(0.45 mmol), 1.4 equiv of p-cyanobenzaldehyde (0.42 mmol), and 0.3 equiv of catalyst . b Reported yields were based on 1a and determined by 31P NMR
with use of an internal standard. c The reaction was carried out under argon protection. d The yield was given in the parentheses. e The reaction was
carried out by using 0.15 equiv of CuI.
CuCl as the catalyst stirred in toluene at 100 °C for 10 h under
air. The desired product 3a was obtained in 33% yield (Table 1,
entry 1). When other Cu (I) salts were used as catalysts, the
yields were not significantly improved (entries 2 and 3). To
further improve the yield, the reaction was performed at 130 °C
for 10 h, and a moderate yield was obtained using CuI as catalyst
(entry 5). When the reaction time was extended to 20 h, the yield
increased to 68%. To our great delight, when N,N-diisopropylethy-
lamine (DIPEA) or tetramethylethylenediamine (TMEDA) was
added to the reaction, the conversion was significantly enhanced;
the desired product 3a was obtained in 72% yield when the
reaction was carried out for 10 h. Solvent screening indicated that
toluene was still the best solvent for this reaction, and when the
reaction time was extended to 20 h, the desired product was
obtained in 92% yield (entry 18). However, lowering the catalyst
loading of CuI to 15 mol % resulted in a decrease in yield (entry 20).
We also found that when the reaction was carried out under nitrogen
atmosphere, the result was not improved indeed (entry 17).
The diphenyl phosphite even offered an almost quantitative yield
by the NMR test (entry 4).
At the same time, we also constructed of PꢀC bonds employ-
ing phosphine oxides using this new decarboxylationꢀcoupling
method and also achieved excellent results. Diethyl-, diallyl-, and
diphenylphosphine oxides performed smoothly reactions and
got almost quantitative yields (entries 5ꢀ7). After expanding the
scope of phosphorus nucleophiles, we then developed several
different amino acids substrates. When cyclic amino acid pipe-
colic acid 2b was used, the corresponding product 3h was
obtained in a moderate yield (entry 8). We suspect that perhaps
the substrate’s conformation of six-membered ring is not con-
ducive to the transformation. For catenarian amino acid N-
benzylvaline 2c, the corresponding product 3i was formed in
excellent yield (entry 9). The isopropyl did not prevent the site-
specific functionalization of the R-amino acids skeletons. Simi-
larly, N-benzylleuine 2d was also applicable to the current
transformation and provides the corresponding product 3j in
good yield (entry 10).
With the optimal conditions established above, we then exam-
ined the scope of the decarboxylationꢀcoupling reaction of the
substrates 1 and 2, and the results are summarized in Table 2.
Diethyl phosphite offered excellent yield by NMR, and dimethyl
and dipropyl phosphites were also employed with high efficiency
under the same reaction conditions (Table 2, entries 1ꢀ3).
Subsequently, our investigations were focused on the use of
various aldehydes. As illustrated in Table 3, the use of benzalde-
hydes bearing electron-withdrawing groups gave the correspond-
ing products 3l, 3m, and 3n in good yields, respectively (entries
2ꢀ4). Fortunately, benzaldehydes bearing electron-donating
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NOTE
Table 2. Substrate Scope of the Phosphorus Nucleophiles (1) and Amino Acids (2)a
* Reported yields were based on 1 and determined by 31P NMR with use of an internal standard. Yields are given in parentheses. b The reaction was
performed for 48 h under the same conditions. a Reactions were performed on a 0.3 mmol scale in 2.5 mL of toluene with 1.0 equiv of phosphorus
nucleophiles 1, 1.5 equiv of amino acids 2, 1.4 equiv of p-cyanobenzaldehyde, and 0.3 equiv of catalyst in a 130 °C oil bath for 20 h.
groups had no ill effect on the yields of the products (entries 6, 8,
and 9). However, benzaldehydes with ortho-substituted phenyl
were less reactive (entries 5 and 7). When the ortho-substituent
was nitro, the reaction did not even proceed due to the hard steric
hindrance (entry 7).
In summary, a copper/DIPEA-catalyzed, aldehyde-induced
tandem decarboxylationꢀcoupling of natural R-amino acids and
phosphites or secondary phosphine oxides has been developed.
In this process, a broad range of potential ligands for organic
synthesis and biologically important non-natural amino acid
derivatives (tertiary amino phosphorus compounds) can be
readily accessible. The use of natural R-amino acids as materials,
cheap copper salt as the catalyst, and the site-specific functionaliza-
tion are some of the numerous advantages of this new method.
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NOTE
Table 3. Substrate Scope and Limits of the Aldehyde (3)*
* Reactions were performed on a 0.3 mmol scale in 2.5 mL of toluene with 1.0 equiv of 1a, 1.5 equiv of 2a, 1.4 equiv of aldehydes, and 0.3 equiv of catalyst
in a 130 °C oil bath for 20 h. a The product 3q was not isolated.
’ EXPERIMENTAL SECTION
4.29ꢀ4.01 (m, 4H), 3.44 (d, J = 13.8 Hz, 1H), 2.96 (t, J = 6.9 Hz, 1H),
2.92ꢀ2.78 (m, 1H), 2.23ꢀ2.00 (m, 3H), 1.87ꢀ1.71 (m, 2H), 1.41ꢀ1.25
(m, 6H); 13C NMR (75 MHz, CDCl3) δ 145.4, 132.0, 129.1, 119.0, 110.6,
62.8 (d, J=6.8Hz),61.6(d,J= 7.4 Hz), 60.8, 59.9, 58.5, 54.5 (d, J=15.1Hz),
26.9, 24.5 (d, J = 6.0 Hz), 16.6 (dd, J = 9.1, 5.6 Hz); 31P NMR (121 MHz,
CDCl3) δ 26.60; IR (neat) 3451, 2979, 2227, 1228, 1026, 963,
794 cmꢀ1; HRMS (ESI) C16H23N2O3P [M + Na]+ calcd 345.1339,
found 345.1328.
[1-(4-Cyanobenzyl)pyrrolidin-2-yl]phosphonic acid di-
methyl ester (3b): yellow oil, the product was isolated using the
same procedure as 3a and obtained in 83% yield; 1H NMR (300 MHz,
CDCl3) δ 7.60 (d, J = 8.1 Hz, 2H), 7.48 (d, J = 8.0 Hz, 2H), 4.48 (d, J =
13.7 Hz, 1H), 3.86 (d, 10.3 Hz, 3H), 3.78 (d, 10.3 Hz, 3H), 3.46 (d, J =
13.7 Hz, 1H), 3.02 (t, J = 7.8 Hz, 1H), 2.97ꢀ2.83 (m, 1H), 2.25ꢀ1.99
(m, 3H), 1.85ꢀ1.76 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 145.1,
132.1, 129.2, 119.0, 110.7, 60.2 (d, J = 51.8 Hz), 58.3, 54.5 (d, J =
14.9 Hz), 53.8, 52.5 (d, J = 7.4 Hz), 26.9, 24.0 (d, J = 6.1 Hz); 31P NMR
(121 MHz, CDCl3) δ 28.71; IR (neat) 3405, 2955, 2228, 1228, 1684,
1232, 1033, 824 cmꢀ1; HRMS (ESI) C14H19N2O3P [M + H]+ calcd
295.1206, found 295.1208.
1H NMR (300 MHz), 13C NMR (75 MHz), and 31P NMR (121 MHz)
spectra were obtained in CDCl3. The chemical shifts are reported in
ppm relative to internal standard TMS (1H NMR), to residual signals of
the solvents (CHCl3, 7.26 ppm for H NMR and 77.0 ppm for 13C
1
NMR), and to external standard 85% H3PO4 (31P NMR). IR spectra
were recorded on FT-IR, and only major peaks are reported.
General Procedure (Table 2, Entry 1). CuI (0.09 mmol, 17.0 mg)
was added to a solution of proline (2a, 0.45 mmol, 52.0 mg) in toluene
(2.5 mL). The mixture was stirred for 10 min at room temperature, and then
N,N-diisopropylethylamine (0.09 mmol, 11.6 mg, 15.7 uL), 4-cyanoben-
zaldehyde (0.42 mmol, 55.0 mg), and diethyl phosphite (1a, 0.3 mmol,
38.4 μL) were added to the reaction mixture. The reaction was then put in a
130 °C oil bath as soon as possible, stirred for 20 h, and then cooled to room
temperature. The resulting suspension was diluted with CH2Cl2, and then it
was washed with water, extracted with CH2Cl2, and dried over Na2SO4.
After concentration of the solvents, the residue was purified on a silica gel
column (PE/EA, 4:1 to 1:1) to afford the corresponding product 3a in 83%
yield upon isolation as a yellowish oil: 1H NMR (300 MHz, CDCl3) δ 7.58
(d, J = 8.1 Hz, 2H), 7.47 (d, J = 8.1 Hz, 2H), 4.50 (d, J = 13.8 Hz, 1H),
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NOTE
[1-(4-Cyanobenzyl)pyrrolidin-2-yl]phosphonic acid dipro-
pyl ester (3c): yellow oil; 81% yield. 1H NMR (300 MHz, CDCl3) δ
7.60 (d, J = 8.2 Hz, 2H), 7.48 (d, J = 8.1 Hz, 2H), 4.53 (d, J = 13.8Hz, 1H),
4.08 (dq, J = 20.6, 6.7 Hz, 4H), 3.45 (d, J = 13.9 Hz, 1H), 3.01 (dd, J = 9.0,
6.6 Hz, 1H), 2.91 (ddd, J = 9.1, 6.0, 3.3 Hz, 1H), 2.26 ꢀ 1.99
(m, 3H), 1.86 ꢀ 1.75 (m, 2H), 1.72 ꢀ1.51 (m, 4H), 0.95 (td, J = 7.4,
4.7 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ 145.4, 131.9, 129.1, 119.0,
110.5, 68.3 (d, J = 7.2 Hz), 67.1 (d, J = 7.5 Hz), 60.7, 59.8, 58.4, 54.4 (d,
J = 15.2 Hz), 26.8 (d, J = 2.4 Hz), 24.4 (d, J = 6.0 Hz), 24.0 (d, J = 8.1 Hz),
10.0; 31P NMR (121 MHz, CDCl3) δ 26.47 ppm. IR (neat): 3453, 2968,
2227, 1229, 998, 851 cmꢀ1; HRMS (ESI) C18H27N2O3P [M + H]+ calcd
351.1832, found 351.1830.
[1-(4-Cyanobenzyl)pyrrolidin-2-yl]phosphonic Acid Diphen-
yl Ester (3d). The product 3d was isolated on a silica gel column (PE:
EA, 15:1 to 4:1) to get the corresponding yellow oil: 79% yield; 1H NMR
(300 MHz, CDCl3) δ 7.51 (d, J = 8.2 Hz, 2H), 7.38ꢀ7.21
(m, 8H), 7.21ꢀ7.09 (m, 4H), 4.56 (d, J = 13.6 Hz, 1H), 3.52 (d, J =
13.6 Hz, 1H), 3.46ꢀ3.28 (m, 1H), 3.05ꢀ2.90 (m, 1H), 2.54ꢀ2.18 (m,
3H), 2.15ꢀ1.58 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 144.9, 132.0,
129.7 (d, J = 13.3 Hz), 129.3, 125.1 (d, J = 13.3 Hz), 120.6 (d, J = 4.2 Hz),
120.7 (d, J = 4.2 Hz), 119.1, 110.6, 61.2, 60.0, 58.9, 54.5 (d, J = 15.4 Hz),
27.3, 24.7 (d, J = 5.6 Hz), 24.1; 31P NMR (121 MHz, CDCl3) δ 18.89;
IR (neat) 2969, 2227, 1489, 1192, 933, 766 cmꢀ1; HRMS (ESI)
C24H23N2O3P [M + H]+ calcd 419.1524, found 419.1519.
[1-(4-Cyanobenzyl)piperidin-2-yl]phosphonic acid dieth-
yl ester (3h): yellow oil; 32% yield; 1H NMR (300 MHz, CDCl3) δ
7.60 (d, J = 8.2 Hz, 2H), 7.49 (d, J = 8.2 Hz, 2H), 4.30 (d, J = 14.7 Hz,
1H), 4.23ꢀ4.05 (m, 4H), 3.77 (d, J = 14.8 Hz, 1H), 3.16ꢀ2.85 (m, 2H),
2.27 (dd, J = 12.1, 5.8 Hz, 1H), 2.03ꢀ1.62 (m, 3H), 1.60ꢀ1.46 (m, 3H),
1.34 (t, J = 7.1 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ 145.8, 132.0,
129.0, 123.0, 110.5, 61.6 (d, J = 30.7 Hz) 59.3, 57.3, 50.5, 25.9, 24.4, 22.3,
16.6, 13.9; 31P NMR (121 MHz, CDCl3) δ 27.81; IR (neat) 3453, 2979,
2227, 1218, 1025, 953, 790 cmꢀ1; HRMS (ESI) C17H25N2O3P [M +
Na]+ calcd 359.1495, found 359.1499.
[1-[Benzyl(4-cyanobenzyl)amino]-2-methylpropyl]pho-
sphonic Acid Diethyl Ester (3i). The product 3i was isolated on a
silica gel column (PE:EA, 4:1 to 2:1) to obtain the corresponding yellow
oil: 81% yield; 1H NMR (300 MHz, CDCl3) δ 7.60 (d, J = 8.2 Hz, 2H),
7.47 (d, J = 8.2 Hz, 2H), 7.37ꢀ7.22 (m, 5H), 4.28ꢀ4.10 (m, 4H),
4.07ꢀ3.67 (m, 4H), 2.56 (dd, J = 15.8, 8.4 Hz, 1H), 2.16ꢀ1.99 (m, 1H),
1.35 (td, J = 7.0, 5.3 Hz, 6H), 1.02 (d, J = 6.7 Hz, 3H), 0.94 (d, J = 6.6 Hz,
3H); 13C NMR (75 MHz, CDCl3) δ 145.8, 139.0, 132.0, 129.7, 129.4,
128.3, 127.2, 119.0, 110.7, 63.1, 61.5, 61.0 (d, J = 22.1 Hz), 55.9, 55.4,
28.3 (d, J = 7.0 Hz), 28.0, 21.6 (d, J = 10.4 Hz), 21.0, 16.6; 31P NMR (121
MHz, CDCl3) δ 28.37; IR (neat) 3456, 2982, 2227, 1244, 1025,
957 cmꢀ1; HRMS (ESI) C23H31N2O3P [M + Na]+ calcd 437.1965,
found 437.1952.
[1-[Benzyl-(4-cyanobenzyl)amino]-3-methylbutyl]pho-
sphonic Acid Diethyl Ester (3j). The product 3j was isolated on a
silica gel column (PE:EA, 4:1 to 2:1) to obtain the corresponding yellow
oil: 69% yield; 1H NMR (300 MHz, CDCl3) δ 7.60 (d, J = 8.1 Hz, 2H),
7.47 (d, J = 8.1 Hz, 2H), 7.36ꢀ7.28 (m, 4H), 7.28ꢀ7.21 (m, 1H),
4.23ꢀ4.05 (m, 4H), 4.06ꢀ3.72 (m, 4H), 2.93 (ddd, J = 15.9, 10.1,
3.5 Hz, 1H), 1.91ꢀ1.78 (m, 1H), 1.78ꢀ 1.60 (m, 1H), 1.35 (td, J = 7.0,
2.9 Hz, 6H), 0.87 (d, J = 6.7 Hz, 3H), 0.42 (d, J = 6.5 Hz, 3H); 13C NMR
(75 MHz, CDCl3) δ 146.0, 139.1, 132.0, 129.7, 129.3, 128.3, 127.3,
119.0, 110.7, 61.5, 61.2 (d, J = 7.6 Hz), 55.2, 54.5 (d, J = 24.0 Hz), 52.5,
36.8, 24.2 (d, J = 11.2 Hz), 23.5, 20.9, 16.6, 11.9; 31P NMR (121 MHz,
4-[2-(Diethylphosphinoyl)pyrrolidin-1-ylmethyl]benzonitrile
(3e). The product 3e was isolated on a silica gel column (PE:EA, 2:1
1
to 0:1) to obtain the corresponding yellow oil: 94% yield; H NMR
(300 MHz, CDCl3) δ 7.60 (d, J = 8.2 Hz, 2H), 7.49 (d, J = 8.1 Hz, 2H),
4.57 (d, J = 14.2 Hz, 1H), 3.49 (d, J = 14.2 Hz, 1H), 3.09 (dd, J = 9.7,
6.2 Hz, 1H), 2.94 (ddd, J = 9.5, 6.5, 3.3 Hz, 1H), 2.26 ꢀ 2.07 (m, 2H),
1.99 ꢀ 1.68 (m, 7H), 1.25 (dt, J = 16.2, 8.1 Hz, 6H); 13C NMR (75
MHz, CDCl3) δ 145.1, 131.9, 128.8, 118.9, 110.3, 61.7, 60.6 (d, J =
10.7 Hz), 54.9 (d, J = 10.8 Hz), 26.2, 24.1 (d, J = 5.5 Hz), 19.4, 18.5, 17.1,
16.3, 5.6 (d, J = 18.9 Hz); 31P NMR (121 MHz, CDCl3) δ 53.30; IR
(neat) 3412, 2970, 2226, 1607, 1458, 1149, 764 cmꢀ1; HRMS (ESI)
C16H23N2OP [M + H]+ calcd 291.1621, found 291.1613.
CDCl3) δ 28.90; IR (neat) 3463, 2956, 2227, 1242, 1051, 956 cmꢀ1
;
HRMS (ESI) C24H33N2O3P [M + H]+ calcd 429.2302, found 429.2299.
(1-Benzylpyrrolidin-2-yl)phosphonic acid diethyl ester
(3k): colorless oil; 57% yield; 1H NMR (300 MHz, CDCl3) δ
7.38ꢀ7.29 (m, 4H), 7.26ꢀ7.22 (m, 1H), 4.44 (d, J = 13.0 Hz, 1H),
4.32ꢀ4.09 (m, 4H), 3.41 (d, J = 13.0 Hz, 1H), 2.99 (dd, J = 9.7, 6.1 Hz,
1H), 2.95ꢀ2.84 (m, 1H), 2.29ꢀ2.17 (m, 1H), 2.14ꢀ1.98 (m, 2H),
1.87ꢀ1.62 (m, 2H), 1.34 (td, J = 7.0, 3.5 Hz, 6H); 13C NMR (75 MHz,
CDCl3) δ 139.2, 128.8, 128.1, 126.7, 62.6 (d, J = 7.0 Hz), 61.7 (d, J = 7.1
Hz), 60.5, 60.1, 58.2, 54.2 (d, J = 15.1 Hz), 26.9, 24.3 (d, J = 6.0 Hz),
16.6; 31P NMR (121 MHz, CDCl3) δ 27.16; IR (neat) 3450, 2976, 1450,
1234, 1028, 961, 702 cmꢀ1; HRMS (ESI) C15H24NO3P [M + H]+ calcd
298.1567, found 298.1572.
4-[2-(Diallylphosphinoyl)pyrrolidin-1-ylmethyl]benzonitrile
(3f). The product 3f was isolated on a silica gel column (PE:EA, 2:1
1
to 1:3) to obtain the corresponding yellow oil; 96% yield. H NMR
(300 MHz, CDCl3) δ 7.61 (d, J = 8.1 Hz, 2H), 7.50 (d, J = 8.1 Hz, 2H),
6.06ꢀ5.81 (m, 2H), 5.38ꢀ5.12 (m, 4H), 4.53 (d, J = 14.2 Hz, 1H), 3.52
(d, J = 14.2 Hz, 1H), 3.16 (dd, J = 10.0, 6.1 Hz, 1H), 3.05ꢀ2.91 (m, 1H),
2.92ꢀ2.73 (m, 1H), 2.75ꢀ2.55 (m, 3H), 2.32ꢀ2.08 (m, 2H),
2.02ꢀ1.88 (m, 1H), 1.88ꢀ1.68 (m, 2H); 13C NMR (75 MHz, CDCl3)
δ 144.9, 131.9, 128.7, 127.6 (d, J = 21.9 Hz), 120.0 (d, J = 10.6 Hz),
118.8, 110.4, 61.8, 60.6 (d, J = 8.4 Hz), 54.7 (d, J = 10.7 Hz), 32.3 (d, J =
59.2 Hz), 30.4 (d, J = 61.5 Hz), 26.1, 24.1 (d, J = q5.1 Hz); 31P NMR
(121 MHz, CDCl3) δ 46.79; IR (neat) 3403, 2965, 2226, 1603, 1179,
911, 727 cmꢀ1; HRMS (ESI) C18H23N2OP [M + H]+ calcd 315.1621,
found 315.1612.
4-[2-(Diphenylphosphinoyl)pyrrolidin-1-ylmethyl]benzo-
nitrile (3g). The product 3g was isolated on a silica gel column (PE:EA,
4:1 to 1:2) to obtain the corresponding yellow oil: 87% yield; 1H NMR
(300 MHz, CDCl3) δ 8.08ꢀ7.92 (m, 2H), 7.92ꢀ7.77 (m, 2H),
7.57ꢀ7.40 (m, 8H), 7.27 (d, J = 8.1 Hz, 2H), 3.94 (d, J = 13.6 Hz,
1H), 3.77ꢀ3.58 (m, 1H), 3.39 (d, J = 13.6 Hz, 1H), 3.01ꢀ2.77 (m, 1H),
2.37ꢀ2.18 (m, 2H), 2.18ꢀ1.95 (m, 1H), 1.78ꢀ1.62 (m, 1H),
1.62ꢀ1.43 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 144.9, 132.359,
132.0ꢀ31.3 (m), 131.1, 130.3, 128.8, 128.2 (d, J = 11.0 Hz), 118.8,
110.3, 63.9, 62.6, 61.0, 54.7 (d, J = 9.1 Hz), 27.1, 24.4 (d, J = 3.4 Hz); 31P
NMR (121 MHz, CDCl3) δ 30.61; IR (neat) 3456, 2982, 2227, 1244,
1025, 957 cmꢀ1; HRMS (ESI) C24H23N2OP [M + H]+ calcd 387.1621,
found 387.1633.
[1-(4-Chlorobenzyl)pyrrolidin-2-yl]phosphonic acid dieth-
yl ester (3l): colorless oil; 62% yield; 1H NMR (300 MHz, CDCl3) δ
7.31ꢀ7.26 (m, 4H), 4.40 (d, J = 13.1 Hz, 1H), 4.29ꢀ4.08 (m, 4H), 3.37
(d, J = 13.1 Hz, 1H), 2.97 (dd, J = 9.5, 6.3 Hz, 1H), 2.93ꢀ2.84 (m, 1H),
2.25ꢀ1.99 (m, 3H), 1.87ꢀ1.65 (m, 2H), 1.33 (td, J = 7.1, 3.2 Hz, 6H);
13C NMR (75 MHz, CDCl3) δ 137.9, 132.4, 130.0, 128.2, 62.7 (d, J = 6.8
Hz), 61.6 (d, J = 7.3 Hz), 60.5, 59.5, 58.2, 54.3 (d, J = 15.3 Hz), 26.9, 24.4
(d, J = 6.0 Hz), 16.5; 31P NMR (121 MHz, CDCl3) δ 26.90; IR (neat)
3461, 2977, 1489, 1232, 1027, 961, 801 cmꢀ1; HRMS (ESI)
C15H23ClNO3P [M + H]+ calcd 332.1177, found 332.1172.
[1-(4-Bromobenzyl)pyrrolidin-2-yl]phosphonic acid dieth-
yl ester (3m): colorless oil; 71% yield; 1H NMR (300 MHz, CDCl3) δ
7.42 (d, J = 8.3 Hz, 2H), 7.32ꢀ7.22 (m, 2H), 4.38 (d, J = 13.2 Hz, 1H),
4.28ꢀ4.12 (m, 4H), 3.36 (d, J = 13.2 Hz, 1H), 2.97 (dd, J = 9.5, 6.4 Hz,
1H), 2.92ꢀ2.83 (m, 1H), 2.24ꢀ2.04 (m, 3H), 1.84ꢀ1.63 (m, 2H), 1.33
(td, J = 7.1, 3.1 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ 138.5, 131.2,
130.4, 120.5, 62.7 (d, J = 7.0 Hz), 61.7 (d, J = 7.3 Hz), 60.6, 59.5, 58.3,
6430
dx.doi.org/10.1021/jo200981h |J. Org. Chem. 2011, 76, 6426–6431

The Journal of Organic Chemistry
NOTE
54.3 (d, J = 15.2 Hz), 26.9, 24.4 (d, J = 5.9 Hz), 16.5; 31P NMR
(121 MHz, CDCl3) δ 26.87; IR (neat) 3456, 2977, 1486, 1234, 1027,
963, 800 cmꢀ1; HRMS (ESI) C15H23BrNO3P [M + H]+ calcd
376.0672, found 376.0667.
’ ASSOCIATED CONTENT
S
Supporting Information. Detailed spectroscopic data for
b
the products. This material is available free of charge via the
Internet at http://pubs.acs.org.
[1-(4-Nitrobenzyl)pyrrolidin-2-yl]phosphonic acid diethyl
ester (3n): yellow oil; 85% yield. 1H NMR (300 MHz, CDCl3) δ 8.17
(d, J = 8.7 Hz, 2H), 7.55 (d, J = 8.6 Hz, 2H), 4.56 (d, J = 13.9 Hz, 1H),
4.33ꢀ4.04 (m, 4H), 3.52 (d, J = 14.0 Hz, 1H), 3.16ꢀ2.96 (m, 1H), 2.93
(ddd, J = 9.1, 5.9, 3.4 Hz, 1H), 2.31ꢀ2.02 (m, 3H), 1.87ꢀ1.74 (m, 2H),
1.34 (dt, J = 12.8, 6.4 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ 147.5,
146.9, 129.1, 123.4, 62.8 (d, J = 7.0 Hz), 61.6 (d, J = 7.3 Hz), 60.8,
59.6 (d, J = 2.1 Hz), 58.5, 54.5 (d, J = 15.1 Hz), 26.8 (d, J = 2.4 Hz),
24.5 (d, J = 6.0 Hz), 16.5 (d, J = 9.3 Hz); 31P NMR (121 MHz, CDCl3) δ
’ AUTHOR INFORMATION
Corresponding Author
wangrui@lzu.edu.cn
’ ACKNOWLEDGMENT
26.52; IR (neat) 3450, 2978, 1520, 1346, 1026, 961, 741 cmꢀ1
;
HRMS (ESI) C15H23N2O3P [M + H]+ calcd 343.1427, found 343.
1427.
We gratefully acknowledge financial support from NSFC
(20932003 and 90813012) and the National S&T Major Project
of China (2009ZX09503-017).
[1-(2-Methylbenzyl)pyrrolidin-2-yl]phosphonic acid di-
ethyl ester (3o): colorless oil; 69% yield; 1H NMR (300 MHz,
CDCl3) δ 7.39ꢀ7.28 (m, 1H), 7.19ꢀ7.05 (m, 3H), 4.44 (d, J =
13.0 Hz, 1H), 4.30ꢀ4.05 (m, 4H), 3.36 (d, J = 13.0 Hz, 1H),
3.01ꢀ2.91 (m, 1H), 2.92ꢀ2.83 (m, 1H), 2.40 (s, 3H), 2.26ꢀ2.03 (m,
3H), 1.80ꢀ1.69 (m, 2H), 1.32 (td, J = 7.1, 4.6 Hz, 6H); 13C NMR
(75 MHz, CDCl3) δ 137.5, 137.0, 130.0, 129.4, 126.7, 125.4, 62.5 (d, J =
6.9 Hz), 61.5 (d, J = 7.5 Hz), 61.2, 58.9, 58.6 (d, J = 2.7 Hz), 54.6 (d, J =
15.4 Hz), 26.9 (d, J = 2.2 Hz), 24.3 (d, J = 6.0 Hz), 19.3, 16.6; 31P NMR
(121 MHz, CDCl3) δ 27.21; IR (neat) 3464, 2977, 1233, 1027, 961,
790 cmꢀ1; HRMS (ESI) C16H26NO3P [M + H]+ calcd 312.1723, found
312.1729.
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[1-(3-Methylbenzyl)pyrrolidin-2-yl]phosphonic acid di-
ethyl ester (3p): colorless oil; 69% yield; 1H NMR (300 MHz,
CDCl3) δ 7.25ꢀ7.08 (m, 3H), 7.05 (d, J = 6.8 Hz, 1H), 4.40 (d, J =
13.0 Hz, 1H), 4.29ꢀ4.12 (m, 4H), 3.37 (d, J = 13.0 Hz, 1H), 3.05ꢀ2.85
(m, 2H), 2.34 (s, 3H), 2.22 (td, J = 9.3, 6.8 Hz, 1H), 2.17ꢀ2.00 (m, 2H),
1.79ꢀ1.62 (m, 2H), 1.34 (td, J = 7.1, 3.3 Hz, 6H); 13C NMR (75 MHz,
CDCl3) δ 139.2, 137.6, 129.6, 127.9, 127.5, 125.9, 62.6 (d, J = 7.0 Hz),
61.7 (d, J = 7.5 Hz), 60.6, 60.2, 58.3, 54.3 (d, J = 15.2 Hz), 26.9, 24.3 (d,
J = 6.1 Hz), 21.4, 16.6 (d, J = 4.8 Hz); 31P NMR (121 MHz, CDCl3) δ
27.24; IR (neat) 3452, 2978, 2232, 1458, 1232, 1028, 962, 748 cmꢀ1
;
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HRMS (ESI) C16H26NO3P [M + H]+ calcd 312.1723, found 312.1733.
(1-Naphthalen-2-ylmethylpyrrolidin-2-yl)phosphonic acid
1
diethyl ester (3r): colorless oil; 76% yield; H NMR (300 MHz,
CDCl3) δ 7.87ꢀ7.76 (m, 3H), 7.74 (s, 1H), 7.55 (d, J = 8.4 Hz, 1H),
7.49ꢀ7.39 (m, 2H), 4.60 (d, J = 13.0 Hz, 1H), 4.33ꢀ4.14 (m, 4H), 3.56
(d, J = 13.0 Hz, 1H), 3.05 (dd, J = 9.6, 6.0 Hz, 1H), 3.00ꢀ2.85 (m, 1H),
2.28 (td, J = 9.3, 6.9 Hz, 1H), 2.19ꢀ1.99 (m, 2H), 1.85ꢀ1.67 (m, 2H),
1.35 (td, J = 7.0, 5.0 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ 137.0,
133.3, 132.6, 127.7, 127.6, 127.6, 127.3, 127.0, 125.8, 125.4, 62.7 (d, J =
6.7 Hz), 61.7 (d, J = 7.1 Hz), 60.7, 60.4, 58.4, 54.4 (d, J = 15.0 Hz), 27.0,
24.4 (d, J = 5.8 Hz), 16.6 (d, J = 5.8 Hz); 31P NMR (121 MHz, CDCl3) δ
27.16; IR (neat) 3461, 2977, 1231, 1027, 960, 755, 547 cmꢀ1; HRMS
(ESI) C19H26NO3P [M + H]+ calcd 348.1723, found 348.1712.
(1-Benzo[1,3]dioxol-5-ylmethylpyrrolidin-2-yl)phospho-
nic acid diethyl ester (3s): colorless oil; 80% yield; 1H NMR (300
MHz, CDCl3) δ 6.89 (s, 1H), 6.75 (q, J = 8.1 Hz, 2H), 5.93 (s, 2H), 4.33
(d, J = 12.9 Hz, 1H), 4.28ꢀ4.07 (m, 4H), 3.32 (d, J = 12.9 Hz, 1H),
2.98ꢀ2.84 (m, 2H), 2.29ꢀ2.16 (m, 1H), 2.15ꢀ1.97 (m, 2H),
1.85ꢀ1.68 (m, 2H), 1.33 (tt, J = 9.2, 4.5 Hz, 6H); 13C NMR (75
MHz, CDCl3) δ 147.5, 146.4, 133.3, 121.8, 109.3, 107.8, 100.8, 62.7 (d,
J = 6.9 Hz), 61.8, 60.4, 59.9, 58.1, 54.2 (d, J = 15.1 Hz), 26.9, 24.4, 16.6;
31P NMR (121 MHz, CDCl3) δ 27.13; IR (neat) 3428, 2978, 1489,
1443, 1240, 1033, 807 cmꢀ1; HRMS (ESI) C16H24NO5P [M + H]+
calcd 342.1465, found 342.1454.
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