Nucleophilic phosphine-catalyzed [3+2] cycloaddition of allenes with N-(thio)phosphoryl imines and acidic methanolysis of adducts N-(thio)phosphoryl 3-pyrrolines: a facile synthesis of free amine 3-pyrrolines

Article abstract of DOI:10.1016/j.tet.2008.07.075

In this report, the dipolarophile imines with easily removable activating group O,O-diethyl(thio)phosphoryl have been investigated in the nucleophilic phosphine-catalyzed [3+2] cycloaddition reaction of electron-deficient allenes. Under the catalysis of a tertiary phosphine, N-(thio)phosphorylimines readily undergo the [3+2] cycloaddition reaction with ethyl 2,3-butadienoate or ethyl 2,3-pentadienoate, affording the corresponding N-(thio)phosphoryl 3-pyrrolines in moderate to high yields with good diastereoselectivity. Removal of the (thio)phosphoryl group from the adducts has been successfully achieved via the acidic methanolysis of the P-N bond, giving the free amine 3-pyrrolines in fair to good yields without severe aromatization. Thus, a facile synthesis of N-unsubstituted 3-pyrrolines is established from the phosphine-catalyzed [3+2] cycloaddition reaction of allenes with imines.

Full text of DOI:10.1016/j.tet.2008.07.075

Tetrahedron 64 (2008) 9471–9479
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Nucleophilic phosphine-catalyzed [3þ2] cycloaddition of allenes
with N-(thio)phosphoryl imines and acidic methanolysis of adducts
N-(thio)phosphoryl 3-pyrrolines: a facile synthesis of free amine 3-pyrrolines
y
*
Bo Zhang, Zhengrong He , Silong Xu, Guiping Wu, Zhengjie He
The State Key Laboratory of Elemento-Organic Chemistry and Department of Chemistry, Nankai University, 94 Weijin Road, Tianjin 300071, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 12 May 2008
Received in revised form 11 July 2008
Accepted 18 July 2008
Available online 23 July 2008
In this report, the dipolarophile imines with easily removable activating group O,O-diethyl(thio)-
phosphoryl have been investigated in the nucleophilic phosphine-catalyzed [3þ2] cycloaddition reaction of
electron-deficient allenes. Under the catalysis of a tertiary phosphine, N-(thio)phosphorylimines readily
undergo the [3þ2] cycloaddition reaction with ethyl 2,3-butadienoate or ethyl 2,3-pentadienoate,
affording the corresponding N-(thio)phosphoryl 3-pyrrolines in moderate to high yields with good dia-
stereoselectivity. Removal of the (thio)phosphoryl group from the adducts has been successfully achieved
via the acidic methanolysis of the P–N bond, giving the free amine 3-pyrrolines in fair to good yields
without severe aromatization. Thus, a facile synthesis of N-unsubstituted 3-pyrrolines is established from
the phosphine-catalyzed [3þ2] cycloaddition reaction of allenes with imines.
Dedicated to Professor Chuchi Tang on the
occasion of his 70th birthday
Keywords:
Ó 2008 Elsevier Ltd. All rights reserved.
Cycloaddition reaction
Tertiary phosphine
Acidic methanolysis
3-Pyrroline
1. Introduction
of the pyrroline heterocycle, delivering the corresponding pyrrole
product even if much easier-removed sulfonyl groups like nosyl
In recent years, the nucleophilic catalysis by tertiary phosphines
has attracted much attention within the chemistry community.
Many new phosphine-catalyzed reactions with highly synthetic
potentials have been discovered.1 The nucleophilic phosphine-
catalyzed cycloaddition reactions of allenes with imines are the
typical and important examples in this realm, which conveniently
construct five- or six-membered N-heterocycles (Scheme 1). Due to
the importance of such N-heterocyclic substructures in the
biologically active substances, particularly pharmaceuticals,2 those
reactions have been extensively studied with regard to their
synthetic potentials.3 In those reactions, aryl substituted N-tosyl
imines are most often used for their better reactivity, giving N-tosyl
heterocycle products generally in high yields. Since tosyl group is
not easy to be removed under mild conditions, in most cases
products have been reported as N-tosylated ones.3 Particularly,
direct deprotection of the sulfonyl group from a fragile [3þ2] cy-
cloaddition adduct 3-pyrroline usually results in an aromatization
and 2-trimethylsilylethanesulfonyl are used.3b,c This situation
intrigued us exploring some effective and easy-deprotected
activating groups for the substrate imine so that the synthetic
values of the phosphine-catalyzed cycloaddition reactions of
allenes with imines could be extended to those N-unsubstituted
heterocycles.
Ts
N
R1
R2
R1 = H, alkyl, aryl
R2 = H
R1
Ar
CO2R
CO2R
tert. PR'3
cycloaddn.
+
Ts
Ar
N
N
Ts
R
1 = H, R2 = CH3
Ar
CO2R
Scheme 1. N-Heterocycles from tertiary phosphine-catalyzed cycloadditions of allenes
with imines.
* Corresponding author. Fax: þ86 22 2350 2458.
E-mail address: zhengjiehe@nankai.edu.cn (Z. He).
Present address: Department of Chemistry, Xiaogan University, Xiaogan, Hubei
y
As part of our ongoing research efforts on nucleophilic phos-
phine-catalyzed carbon–carbon bond forming reactions,4 we
432000, PR China.
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.07.075

9472
B. Zhang et al. / Tetrahedron 64 (2008) 9471–9479
Table 1
herein report the results on the [3þ2] cycloaddition reaction of
allenes with N-(thio)phosphoryl imines. The cycloaddition re-
action, catalyzed by either Ph3P or air-stable and highly nucleo-
philic PTA (1,3,5-triaza-7-phosphaadmantane), readily afforded
the [3þ2] cycloaddition products N-(thio)phosphoryl 3-pyrrolines
1 in fair to good yields. Also, the N-(thio)phosphoryl 3-pyrrolines 1
were successfully deprotected through a HCl-mediated acidic
methanolysis, affording the corresponding free amine 3-pyrrolines
2 in moderate isolated yields. Thus, a facile synthesis for free
amine 3-pyrrolines is established via the phosphine-catalyzed
[3þ2] cycloaddition reaction of allenes with N-(thio)phosphoryl
imines.
Phosphine-catalyzed [3þ2] cycloaddition reaction of allenes with N-thiophosphoryl
iminesa
R
S
S
P(OEt)2
N
P(OEt)2
N
CO2Et
R
R
Ar
Cat. (20 mol%)
CH2Cl2, r.t.
Ar
+
+
S
Ar
CO2Et
CO2Et
N
P(OEt)2
cis-1
trans-1
Entry Ar
R
Reaction time (h) Yield of 1b (%) Ratio of cis-1/trans-1c
1
2
C6H5
p-CH3C6H4
H
H
H
H
H
H
20
24
40
7
8
6
1a, 49
1b, 60
1c, 62
1d, 68
1e, 41
1f, 76
1g, 77
1h, 53
1i, 76
1j, 70
1k, 99
3
4
5
6
p-CH3OC6H4
p-ClC6H4
o-ClC6H4
p-NO2C6H4
C6H5
2. Results and discussion
Most recently, O,O-diethylthiophosphoryl has been successfully
used as an activating group for the imine substrate in the phos-
phine-catalyzed aza-Morita–Baylis–Hillman reaction in our labo-
ratories.5 Due to its better stability on storage than its oxo-analogue
N-phosphoryl imine, N-thiophosphoryl imine was first chosen as
the substrate in the phosphine-promoted [3þ2] cycloaddition with
activated allenes, although N-phosphoryl analogue has a similar
reactivity in this reaction (vide infra).
7
CH3 48
25:1
46:1
11:1
7:1
8
p-CH3C6H4 CH3 48
9
10
11
p-ClC6H4
o-ClC6H4
p-NO2C6H4 CH3 48
CH3 48
CH3 48
6:1
a
For entries 1–6, the catalyst is PPh3; for entries 7–11, PTA is used as the catalyst.
Isolated yield based on the substrate imine.
b
c
Determined by 31P NMR.
To date, nucleophilic phosphines are only found to be effective
catalysts for the [3þ2] cycloaddition of electron-deficient allenes
with imines; nitrogen nucleophiles are ineffective in this reac-
tion.1a,b The efficiency of the cycloaddition highly depends on the
nucleophilicity of the employed catalyst phosphine and the re-
activity of the allene; for a more reactive allene, e.g., 2,3-buta-
phosphines (Ph3P, Ph2PMe, PhPMe2, PTA, and Bu3P) were screened
in the model reaction with N-thiophosphoryl phenylimine under
the same conditions (see Section 4, general procedure for ethyl 2,3-
pentadienoate), and the result is shown as follows: isolated yield of
the normal adduct/ratio of cis- and trans-isomers/catalyst: 0/Ph3P;
57%/18:1/Ph2PMe; 42%/11:1/PhPMe2; 77%/25:1/PTA; 27%/5:1/PBu3.
This result clearly showed that the catalyst PTA was the best in
terms of the product yield and diastereoselectivity. However, the
catalysis of PBu3 with the strongest nucleophilicity only produced
the normal adduct in a low yield (27%) due to the complexity of the
reaction. In our previous reports,4,5 the air-stable phosphine PTA
was found to be a convenient and versatile organocatalyst, with its
nucleophilicity comparable to those of pure trialkylphosphines, in
the phosphine-catalyzed Morita–Baylis–Hillman reaction and the
[3þ2] cycloaddition reaction of allenes with N-tosyl imines. Thus,
in this study PTA was preferably chosen as a stronger nucleophilic
phosphine catalyst. The experimental results (Table 1, entries 7–11)
revealed that the annulation of ethyl 2,3-pentadienoate with
N-thiophosphoryl imines smoothly proceeded under the catalysis
dienoate,
mediate its cycloaddition with various imines, giving the adducts
3-pyrrolines in high yields;3b for a less reactive
-substituted
a relatively weaker nucleophile Ph3P can readily
g
allenoate, a stronger nucleophilic catalyst like tributylphosphine is
then required to secure the efficiency of its cycloaddition with
imines.3c
In this study, two activated allenes, e.g., ethyl 2,3-butadienoate
and ethyl 2,3-pentadienoate (g-methyl allenoate), were selected to
investigate their annulation with N-thiophosphoryl imines [Eqs. 1
and 2]. The initial survey of optimal reaction conditions was
conducted on the [3þ2] cycloadditions of N-(O,O-diethyl)th-
iophosphoryl phenylimine with both the allenes. It was found that
methylene chloride delivered better product yields than other
solvents (THF, ether, acetonitrile, benzene, toluene, and DMSO). The
tertiary phosphine catalyst loading (20 mol %, compared to the
substrate imine) was chosen because reduced loadings (5 mol % or
10 mol %) resulted in either substantially prolonged reaction time
or much lower product yield.
Screening of the phosphine catalysts revealed that the nucleo-
philicity of the catalyst significantly affected its efficiency in the
[3þ2] cycloaddition of the allenes with N-thiophosphoryl imine.
For the reactive ethyl 2,3-butadienoate, Ph3P (20 mol %) delivered
better results in the reaction of this allene with N-thiophosphoryl
imine; in contrast, more nucleophilic phosphines such as Bu3P,
PTA, and PhPMe2 caused severe side reactions, giving the normal
cycloaddition product in lower yields. Thus, Ph3P was chosen as
the preferred catalyst for the allene ethyl 2,3-butadienoate. Under
the catalysis of Ph3P (20 mol %), various aromatic N-thio-
phosphoryl imines readily afforded the normal [3þ2] cycloaddition
adducts 1 in fair to good isolated yields (Table 1, entries 1–6). The
substrate imines, bearing either electron-donating or electron-
withdrawing groups in the benzene ring, both worked well in the
cycloaddition.
For the relatively less reactive allene ethyl 2,3-pentadienoate,
a more nucleophilic phosphine catalyst was expectedly needed in
its cycloaddition with N-thiophosphoryl imine. Five selected
Figure 1. The crystal structure of 2k picrate (for clarity, the picrate anion is omitted).

B. Zhang et al. / Tetrahedron 64 (2008) 9471–9479
9473
of PTA (20 mol %), giving the normal adducts 1 in good to excellent
yields with high diastereoselectivities. In the reported phosphine-
catalyzed [3þ2] cycloaddition of -substituted allenoates or
R
O
P(OEt)2
N
CO2Et
g
Cat. (20 mol%)
CH2Cl2, r.t.
R
Ph
+
alkynoates with N-tosyl imines, the cis-adduct (the substituents at
2- and 5-positions locating on the same side of the pyrroline ring) is
always predominant over the trans in the products.1a,b,3c In the case
of N-thiophosphoryl imine, the diastereoselectivity in its PTA-me-
diated [3þ2] cycloaddition with ethyl 2,3-pentadienoate is similar
with the cis-isomer being major in 1. The ratio of cis-1 and trans-1
was conveniently determined by integrating their respective 31P
NMR signals, which provided a good resolution of about 4 ppm
chemical shift separation (see Supplementary data). The cis-
configuration assignment of 1 was also secured by the X-ray
crystallography (CCDC 684846) of the free amine 3-pyrroline 2k
conjugate with picric acid (Fig. 1).6
O
Ph
CO2Et
dr.
P(OEt)2
N
ð3Þ
R
H
Cat.
PPh3
PTA
Adduct
1a'
Yield
40%
54%
9/1
1g'
Me
reactivity to its thio-analogue in the [3þ2] cycloaddition with
activated allenes.
The ease extent of the P–N bond cleavage is highly dependent
on the specific structure of the substrate phosphorus amide,7
although the P–N bond is generally considered to be pretty sus-
ceptible to the acidic alcoholysis or hydrolysis, and has already
found its value in organic synthesis, for instance, in the synthesis of
some polyamines.8 The P–N bond cleavages via the HCl-mediated
methanolysis in both O,S-dialkyl thiophosphoramidate9 and
diphenylthiophosphinic amide10 were achieved under mild con-
ditions by Tang and Haake et al. Following the Tang’s procedure,
deprotection of thiophosphoryl group from 1 was first attempted.
Under mild conditions (room temperature to gentle reflux in 3.5 M
HCl methanol solution), adducts 1 readily decomposed, giving the
corresponding free amine 3-pyrroline-3-carboxylic methyl esters 2
in fair to good isolated yields (Table 2). Obviously, the trans-
esterification with the methanol solvent occurred at the carboxyl-
ate group in 1 under above conditions. Thus, a facile synthesis of
free amine 3-pyrrolines is realized from the phosphine-catalyzed
[3þ2] cycloaddition of activated allenes with N-thiophosphoryl
imines.
In the cases of 1a–f, a small amount (less than 5% of the
theoretical yield) of the aromatization by-product N-thio-
phosphoryl pyrrole 3 was detected from the crude product [Eq. 4].
In the case of 1d, pure 3d (Ar¼p-chlorophenyl) was isolated in 5%
yield and identified by their NMR data (see Supplementary data).
In all methanolysis cases of 1, no deprotected free amine pyrroles
from the corresponding 3 were observed. Apparently, the aro-
matization by-product 3 possesses a better stability against the
S
P(OEt)2
CO2Et
PPh3 (20 mol%)
N
+
Ar
CH2Cl2, r.t.
ð1Þ
S
N
P(OEt)2
CO2Et
in 41-76% yields
Ar
1a-f
Me
Ar
S
P(OEt)2
N
CO2Et
Me
PTA (20 mol%)
Ar
+
+
in 53-99% yields
dr. 6/1- 46/1
S
CO2Et
N
P(OEt)2
cis-1g-k, major
ð2Þ
S
P
P(OEt)2
N
N
N
Me
Ar
N
PTA
CO2Et
trans-1g-k, minor
The structural assignments of 1 are in good agreement with
their NMR data (1H, 13C, and 31P) and elemental analyses. The
presence of the phosphorus atom in 1 provides extra help in the
assignment of NMR signals. It is also noteworthy that the existence
of the chiral center at 2-position of the pyrroline ring in 1 results in
the differentiation of two ethoxy groups at phosphorus in the NMR
(1H and 13C) spectra (see Supplementary data).
Table 2
The free amine 3-pyrrolines 2 prepared via the acidic methanolysis of the adducts 1a
S
H
N
P(OEt)2
N
R
Ar
R
3.5 M HCl
Ar
CH3OH, r.t. - reflux
CO2Me
CO2Et
1
2
On the basis of data in Table 1 and those reported in the liter-
atures,3b,c,4b however, the N-thiophosphoryl imine is generally less
reactive than the corresponding N-tosyl imine in terms of the cat-
alyst loading and the product yield, in the phosphine-catalyzed
[3þ2] cycloaddition with activated allenes, although its overall
efficiency in this reaction is still acceptable.
For the purpose of comparison, a representative N-phospho-
ryl imine analogue was also investigated in the above cycload-
dition with the allenes. Thus, it was found that, under the
similar conditions with the N-thiophosphoryl imine, N-(O,O-
diethylphosphoryl) phenylimine readily gave normal cycloaddi-
tion products (1a0 and 1g0) in moderate isolated yields with
ethyl 2,3-butadienoate and ethyl 2,3-pentadienoate, respectively
Entry
Ar
R
Yield of 2b (%)
1
2
3
4
5
6
7
8
C6H5
H
H
H
H
H
H
CH3
CH3
CH3
CH3
CH3
2a, 69
2b, 76
2c, 64
2d, 86
2e, 63
2f, 71
cis-2g, 71
cis-2h, 38
cis-2i, 49
cis-2j, 55
cis-2k, 79
p-CH3C6H4
p-CH3OC6H4
p-ClC6H4
o-ClC6H4
p-NO2C6H4
C6H5
p-CH3C6H4
p-ClC6H4
o-ClC6H4
p-NO2C6H4
9
10
11
a
Reaction time: at room temperature (12 h) and under reflux (24 h).
Isolated yield based on 1.
b
[Eq. 3]. Apparently, the N-phosphoryl imine has
a
similar

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B. Zhang et al. / Tetrahedron 64 (2008) 9471–9479
P–N bond cleavage than its parent 1 under the conditions in this
study.
Sol
O(S)
P
O(S)
O(S)
H+
+
P
H2N
P
N
Sol
N
S
S
H
H
N
P(OEt)2
N
P(OEt)2
N
(Sol: solvent)
Ar
3.5 M HCl
CH3OH
Ar
Ar
+
Scheme 2. The acidic solvolysis of P–N bond: SN2(P) mechanism.
ð4Þ
CO2Me
CO2Me
CO2Et
In this work, the acidic methanolysis of 1 is believed to follow
the general rule mentioned above with regard to its mechanism,
although little mechanistic work has yet been intentionally done.
The departure of the (thio)phosphoryl group from 1 is initiated
with the protonation of the pyrroline ring N atom, and completed
by the following nucleophilic attack of the solvent methanol at the
(thio)phosphoryl center of the protonated 1. It is known that the
protonation on nitrogen is a potent labilizing force in the nucleo-
philic cleavage of the P–N bond.10 The basicity of the N atom in the
(thio)phosphoramidates certainly determines its effective pro-
tonation, and in turn affects the reactivity of the (thio)phosphor-
amidates in the acidic methanolysis. In terms of the basicity of the
N atom, the inertness of the aromatization by-product 3 in the
acidic methanolysis may be accordingly interpreted: compared to
that of its precursor 1, the basicity of the N atom in 3 is weakened
due to the delocalization of its lone pair electrons to the whole
pyrrole ring; this weakened basicity subsequently results in the
deficiency or loss of activation (catalysis) via protonation.
r.t. - reflux
1a-f
2a-f (63-86%)
3a-f (< 5%)
S
H
N
P(OEt)2
N
Me
Ar
CO2Me
Me
3.5 M HCl
Ar
+
CH3OH
CO2Et
r.t. - reflux
1g-k
cis-2g-k (38-79%)
ð5Þ
S
P(OEt)2
N
Me
Ar
CO2Me
trans-4g-k (<11%)
Besides its activation for the P–N bond in the acidic meth-
anolysis, the protonation on nitrogen is also believed to play
a critical role in inhibiting the 3-pyrroline cycle from aromatization
into the pyrrole ring; protonation prevents the lone pair electrons
of the N atom from making any contribution to aromatization via
delocalization. This assertion may get some helpful support from
recent reports3b,c,12 on the deprotection of N-(2-trimethylsilyl-
ethanesulfonyl) 3-pyrrolines by fluoride: under the mediation of
n-Bu4NF and in a neutral media, the given 3-pyrrolines only gave
the corresponding deprotected aromatization products pyrroles in
moderate yields;3b,c,12a in sharp contrast, upon the treatment of
excessive HF, the corresponding free amine pyrrolines were
obtained in excellent yields.12b
O
H
N
P(OEt)2
N
Me
Ph
Me
3.5 M HCl
CH3OH, r.t. - reflux
in 56% overall yield
Ph
+
CO2Me
CO2Et
1g' (dr.9/1)
cis-2g
ð6Þ
H
N
Me
Ph
For cis- and trans-isomers of 1g–k, the remarkable difference in
their reactivity on the acidic methanolysis most likely results from
the different steric hindrance, imposed by the substituted pyrroline
moiety on the SN2(P) step. The difference in the basicity of the N
atoms for cis- and trans-1 should be negligibly small; compared to
that in cis-1, the trans-substituted pyrroline moiety in trans-1
apparently imposes more steric hindrance for the approach of the
nucleophile methanol molecule to the thiophosphoryl center from
the direction opposite to that of the P–N bond in the protonated 1. It
is known that the SN2(P) step is the rate-determining step in the
acidic fission of the phosphinic(oric) amides.10,11 On the other hand,
the ease of the P–N bond cleavage for both cis- and trans-isomers of
the N-phosphoryl adduct 1g0 is attributable to the better reactivity
than their thio-analogues in the acidic methanolysis, for the
phosphoryl group is more electrophilic in comparison with its
thio-analogue in the bimolecular nucleophilic substitution at the
phosphoryl center.
CO2Me
trans-2g
For the substrates 1g–k, to our surprise, their P–N bond meth-
anolysis had a distinct preference over the substrate’s configura-
tion: the dominant component in the substrate 1, cis-1, was readily
deprotected to its corresponding free amine cis-2; the minor
component trans-1 in the substrate stood inert except that its car-
boxylate group was changed by the transesterification, as observed
by 31P and 1H NMR measures [Eq. 5]. In the case of 1k, which
contained relatively more trans-isomer, a pure transesterification
product trans-4k (Ar¼p-nitrophenyl), supposedly derived from
trans-1k, was successfully isolated in 11% yield from the acidic
methanolysis crude product by the column chromatography, and
was identified by its NMR data. However, for the N-phosphoryl
adduct 1g0, its methanolysis under similar conditions gave the
corresponding free amine 3-pyrrolines 2g0 from both cis- and trans-
isomers [Eq. 6].
3. Conclusions
Extensive work by Haake et al.10,11 on the acidic solvolytic
cleavage of the P–N bond in (thio)phosphoramidates has disclosed
that the amide substrate, after initial activation via the N-pro-
tonation, undergoes a bimolecular SN2(P) displacement by solvent
molecule (Scheme 2); in a given solvent, the basicity of the amide N
atom and the electrophilicity of the (thio)phosphoryl center are
therefore two important structural factors that significantly affect
the acidic solvolysis of (thio)phosphoramidates.
In conclusion, N-(thio)phosphoryl imines have proven to be
effective dipolarophiles in the phosphine-catalyzed [3þ2] cyclo-
addition with activated allenes, despite they are, in general, inferior
to N-tosyl imines with regard to their efficiencies in the reaction.
The ease with the deprotection of (thio)phosphoryl groups from the
cycloaddition products 1 via the acidic methanolysis, and the pro-
tonation of the N atom in 1 lead to a facile synthesis of free amine
3-pyrrolines through the phosphine-mediated [3þ2] cycloaddition

B. Zhang et al. / Tetrahedron 64 (2008) 9471–9479
9475
of allenes with imines. Most recently, an enantioselective version of
the [3þ2] cycloaddition of ethyl 2,3-butadienoate with N-diphe-
nylphosphinoyl imines is already realized under the catalysis of
chiral phosphinothiourea.13 Diphenylphosphinoyl has also been
used as an activating group for the imine substrate in the aza-
Baylis–Hillman reaction.14 Our results in this report indicate that
both phosphoryl and thiophosphoryl are convenient, cost-saving,
and easily removable activating groups for the imine dipolarophile.
It is therefore anticipated that N-(thio)phosphoryl imines could be
the right dipolarophiles for the phosphine-catalyzed enantiose-
lective [3þ2] cycloaddition with activated allenes, which could
further lead to an effective synthesis of enantiomer-enriched free
amine 3-pyrrolines and their hydrogenation products pyrrolidines.
These projected conversions are currently being explored in our
laboratory.
JAB¼17.2 Hz, JP–N–C–H¼6.0 Hz, 2H), 4.10–3.78 (m, 5H), 3.37 (m, 1H),
2.30 (s, 3H), 1.23 (t, J¼7.0 Hz, 3H), 1.14 (t, J¼7.2 Hz, 3H), 0.94 (t,
J¼7.0 Hz, 3H); 13C NMR (CDCl3, 100 MHz, TMS)
d 162.3, 139.1, 137.1,
136.8 (d, J¼9.0 Hz), 136.3 (d, J¼8.7 Hz), 128.6, 127.5, 67.8 (d,
J¼4.5 Hz), 62.6 (d, J¼4.8 Hz, P–O–CH2), 62.6 (d, J¼4.7 Hz, P–O–CH2),
60.5, 56.1 (d, J¼7.4 Hz), 21.1, 15.8 (d, J¼8.2 Hz), 15.3 (d, J¼8.9 Hz),
13.9; 31P NMR (CDCl3, 160 MHz, 85% H3PO4)
d 71.0 ppm. Anal. Calcd
for C18H26NO4PS: C, 56.38; H, 6.83; N, 3.65. Found: C, 56.21; H, 6.90;
N, 3.53.
4.2.3. Ethyl 1-(O,O-diethylthiophosphoryl)-2-(p-methoxyphenyl)-
3-pyrroline-3-carboxylate (1c)
The cycloaddition with N-thiophosphoryl p-anisylimine was
completed after stirred for 40 h. The title compound (250 mg, yield
62%) was obtained as colorless viscous oil after work-up and pu-
rification as described in the above general procedure. 1H NMR
4. Experimental section
4.1. General remarks
(CDCl3, 400 MHz, TMS)
d
7.21 (d, J¼8.0 Hz, 2H), 6.83 (s, 1H), 6.80 (d,
J¼8.0 Hz, 2H), 5.57 (pseudo t, JP–N–C–H¼5.6 Hz, 1H), 4.42 (dq,
JAB¼17.2 Hz, JP–N–C–H¼6.2 Hz, 2H), 4.10–3.78 (m, 5H), 3.76 (s, 3H),
3.39 (m, 1H), 1.21 (t, J¼7.2 Hz, 3H), 1.13 (t, J¼7.2 Hz, 3H), 0.96 (t,
Unless otherwise noted, all catalytic reactions were carried out
in an ambient atmosphere. Commercially available chemicals were
used as received. PTA was prepared from tetrahydroxy-
methylphosphonium sulfate according to a previous procedure.15
4-Substituted 2,3-butadienoates16 and N-(thio)phosphoryl im-
ines17 were also prepared as described in the literatures.
J¼7.2 Hz, 3H); 13C NMR (CDCl3, 100 MHz, TMS)
d 162.2, 158.9, 136.7
(d, J¼9.0 Hz), 136.1 (d, J¼8.8 Hz), 134.2, 128.7, 113.3, 67.4 (d,
J¼4.6 Hz), 62.5 (d, J¼4.8 Hz, P–O–CH2), 60.4, 55.9 (d, J¼7.1 Hz), 55.1,
15.7 (d, J¼7.8 Hz),15.3 (d, J¼8.5 Hz),13.9; 31P NMR (CDCl3, 160 MHz,
85% H3PO4)
d 71.0 ppm. Anal. Calcd for C18H26NO5PS: C, 54.12; H,
6.56; N, 3.51. Found: C, 54.35; H, 6.77; N, 3.45.
4.2. General procedure for the PPh3-catalyzed [3D2]
cycloaddition of ethyl 2,3-butadienoate with N-(O,O-
diethylthiophosphoryl) imines
4.2.4. Ethyl 1-(O,O-diethylthiophosphoryl)-2-(p-chlorophenyl)-3-
pyrroline-3-carboxylate (1d)
The cycloaddition with N-thiophosphoryl p-chlorophenylimine
was completed after stirred for 7 h. The title compound (274 mg,
yield 68%) was obtained as colorless viscous oil after work-up and
purification as described in the above general procedure. 1H NMR
To a solution of the substrate imine (1 mmol) and PPh3 (52 mg,
0.2 mmol) in anhydrous CH2Cl2 (5 mL), a solution of ethyl 2,3-
butadienoate (224 mg, 2 mmol) in CH2Cl2 (3 mL) was dropwise
added over 1 h with stirring at room temperature. The solution was
stirred till the imine was completely consumed (monitored by TLC).
The solvent and volatile components were removed on a rotary
evaporator, and the resulting residue was subjected to silica gel
column chromatography eluted with a mixture of petroleum ether–
ethyl acetate (35:1, v/v) to give the corresponding pure adduct 1.
(CDCl3, 400 MHz, TMS)
d 7.25 (m, 4H), 6.86 (s, 1H), 5.60 (pseudo t,
JP–N–C–H¼5.6 Hz, 1H), 4.42 (dq, JAB¼17.2 Hz, JP–N–C–H¼5.6 Hz, 2H),
4.10–3.78 (m, 5H), 3.46 (m, 1H), 1.21 (t, J¼7.2 Hz, 3H), 1.15 (t,
J¼7.0 Hz, 3H),1.00 (t, J¼7.0 Hz, 3H); 13C NMR (CDCl3,100 MHz, TMS)
d
162.1, 140.8, 136.8 (d, J¼8.4 Hz), 136.3 (d, J¼7.7 Hz), 133.2, 129.1,
128.1, 67.5 (d, J¼4.8 Hz), 62.8 (d, J¼4.7 Hz, P–O–CH2), 60.7, 56.0 (d,
J¼6.6 Hz), 15.7 (d, J¼8.2 Hz), 15.4 (d, J¼8.7 Hz), 13.9; 31P NMR
(CDCl3, 160 MHz, 85% H3PO4)
d 70.9 ppm. Anal. Calcd for
4.2.1. Ethyl 1-(O,O-diethylthiophosphoryl)-2-phenyl-3-pyrroline-3-
carboxylate (1a)
C
17H23ClNO4PS: C, 50.56; H, 5.74; N, 3.47. Found: C, 50.30; H, 6.00;
N, 3.34.
The cycloaddition with N-thiophosphoryl phenylimine was
completed after stirred for 20 h. The pure title compound (180 mg,
yield 49%) was obtained as colorless viscous oil after work-up and
purification as described in the above general procedure. 1H NMR
4.2.5. Ethyl 1-(O,O-diethylthiophosphoryl)-2-(o-chlorophenyl)-3-
pyrroline-3-carboxylate (1e)
The cycloaddition with N-thiophosphoryl o-chlorophenylimine
was completed after stirred for 8 h. The title compound (165 mg,
yield 41%) was obtained as colorless viscous oil after work-up and
purification as described in the above general procedure. 1H NMR
(CDCl3, 400 MHz, TMS)
d 7.24 (m, 5H), 6.86 (s, 1H), 5.60 (pseudo t,
JP–N–C–H¼6.0 Hz, 1H), 4.45 (dq, JAB¼17.2 Hz, JP–N–C–H¼6.0 Hz, 2H),
4.10–3.78 (m, 5H), 3.34 (m, 1H), 1.21 (t, J¼7.2 Hz, 3H), 1.12 (t,
J¼7.0 Hz, 3H), 0.91 (t, J¼7.0 Hz, 3H); 13C NMR (CDCl3, 100 MHz,
(CDCl3, 400 MHz, TMS)
d 7.32–7.14 (m, 4H), 6.93 (s, 1H), 6.14
TMS)
d
162.2, 142.0, 136.7 (d, J¼9.3 Hz), 136.5 (d, J¼8.8 Hz), 127.9,
(pseudo t, JP–N–C–H¼6.4 Hz, 1H), 4.45 (dq, JAB¼17.6 Hz, JP–N–C–
127.7, 127.5, 68.0 (d, J¼4.5 Hz), 62.7 (d, J¼4.5 Hz, P–O–CH2), 62.6 (d,
J¼4.5 Hz, P–O–CH2), 60.5, 56.3 (d, J¼7.4 Hz), 15.7 (d, J¼7.8 Hz), 15.3
(d, J¼9.1 Hz), 13.9; 31P NMR (CDCl3, 160 MHz, 85% H3PO4)
¼6.4 Hz, 2H), 4.10–3.78 (m, 5H), 3.29 (m,1H),1.28 (t, J¼7.2 Hz, 3H),
H
1.12 (t, J¼7.2 Hz, 3H), 0.90 (t, J¼7.0 Hz, 3H); 13C NMR (CDCl3,
100 MHz, TMS)
d
162.1, 140.6, 139.5 (d, J¼7.8 Hz), 137.6 (d, J¼9.1 Hz),
d
71.0 ppm. Anal. Calcd for C17H24NO4PS: C, 55.27; H, 6.55; N, 3.79.
133.5, 129.7, 129.4, 128.6, 126.7, 64.0 (d, J¼4.5 Hz), 62.9 (d, J¼5.6 Hz,
P–O–CH2), 62.7 (d, J¼5.6 Hz, P–O–CH2), 60.6, 56.9 (d, J¼8.3 Hz), 15.8
(d, J¼8.0 Hz), 15.3 (d, J¼8.5 Hz), 13.8; 31P NMR (CDCl3, 160 MHz, 85%
Found: C, 54.91; H, 6.55; N, 3.58.
4.2.2. Ethyl 1-(O,O-diethylthiophosphoryl)-2-(p-methylphenyl)-3-
pyrroline-3-carboxylate (1b)
H3PO4) d 70.7 ppm. Anal. Calcd for C17H23ClNO4PS: C, 50.56; H, 5.74;
N, 3.47. Found: C, 50.55; H, 5.96; N, 3.45.
The cycloaddition with N-thiophosphoryl p-tolylimine was
completed after stirred for 24 h. The title compound (230 mg, yield
60%) was obtained as colorless viscous oil after work-up and
purification as described in the above general procedure. 1H NMR
4.2.6. Ethyl 1-(O,O-diethylthiophosphoryl)-2-(p-nitrophenyl)-3-
pyrroline-3-carboxylate (1f)
The cycloaddition with N-thiophosphoryl p-nitrophenylimine
was completed after stirred for 6 h. The title compound (315 mg,
yield 76%) was obtained as yellow viscous oil after work-up and
(CDCl3, 400 MHz, TMS)
d
7.18 (d, J¼8.0 Hz, 2H), 7.07 (d, J¼19.0 Hz,
2H), 6.85 (s, 1H), 5.59 (pseudo t, JP–N–C–H¼6.0 Hz, 1H), 4.45 (dq,

9476
B. Zhang et al. / Tetrahedron 64 (2008) 9471–9479
purification as described in the above general procedure. 1H NMR
(CDCl3, 400 MHz, TMS)
Anal. Calcd for C18H26NO4PS: C, 56.38; H, 6.83; N, 3.65. Found: C,
56.45; H, 6.75; N, 3.63.
d
8.15 (d, J¼7.6 Hz, 2H), 7.50 (d, J¼7.6 Hz,
2H), 6.92 (s, 1H), 5.73 (pseudo t, JP–N–C–H¼6.0 Hz, 1H), 4.46 (dq,
JAB¼17.6 Hz, JP–N–C–H¼6.0 Hz, 2H), 4.10–3.78 (m, 5H), 3.58 (m, 1H),
4.4.2. Ethyl 1-(O,O-diethylthiophosphoryl)-5-methyl-2-
(p-methylphenyl)-3-pyrroline-3-carboxylate (1h)
1.20 (t, J¼6.8 Hz, 3H),1.15 (t, J¼6.8 Hz, 3H),1.04 (t, J¼6.8 Hz, 3H); 13
C
NMR (CDCl3, 100 MHz, TMS)
d
161.8, 149.7, 147.2, 137.6 (d, J¼8.0 Hz),
By column chromatographic purification, the title compound 1h
(211 mg, yield 53%) from N-thiophosphoryl p-tolylimine was iso-
lated as colorless viscous oil with a ratio of cis- and trans-isomers of
46:1. It was then characterized as pure cis-1h without further
135.9 (d, J¼9.9 Hz), 128.7, 123.2, 67.8 (d, J¼6.1 Hz), 62.9 (d, J¼4.9 Hz,
P–O–CH2), 60.9, 55.8 (d, J¼6.1 Hz), 15.8 (d, J¼7.6 Hz), 15.5 (d,
J¼8.5 Hz), 13.9; 31P NMR (CDCl3, 160 MHz, 85% H3PO4)
d 70.8 ppm.
Anal. Calcd for C17H23N2O6PS: C, 49.27; H, 5.59; N, 6.76. Found: C,
49.25; H, 5.55; N, 6.64.
purification. For cis-1h, 1H NMR (CDCl3, 400 MHz, TMS)
d 7.23 (d,
J¼8.0 Hz, 2H), 7.08 (d, J¼8.0 Hz, 2H), 6.75 (m, 1H), 5.62 (m, 1H), 4.80
(m, 1H), 4.10–3.75 (m, 5H), 3.32 (m, 1H), 2.29 (s, 3H), 1.52
(d, J¼6.8 Hz, 3H), 1.23 (t, J¼7.2 Hz, 3H), 1.12 (t, J¼7.2 Hz, 3H), 0.90
4.3. The PPh3-catalyzed [3D2] cycloaddition of ethyl 2,3-
butadienoate with N-(O,O-diethylphosphoryl) phenylimine
(t, J¼7.2 Hz, 3H); 13C NMR (CDCl3, 100 MHz, TMS)
d 162.5, 141.6 (d,
J¼9.1 Hz), 138.6, 137.0, 134.1 (d, J¼8.6 Hz), 128.6, 128.0, 68.5
(d, J¼4.0 Hz), 63.0 (d, J¼7.3 Hz), 62.5 (d, J¼5.3 Hz, P–O–CH2), 62.2
(d, J¼4.5 Hz, P–O–CH2), 60.4, 23.2, 21.0, 15.7 (d, J¼7.9 Hz), 15.1 (d,
According to the general procedure for N-thiophosphoryl
imines, instead of its thio-analogue, N-(O,O-diethylphosphoryl)
phenylimine (242 mg, 1 mmol) was similarly reacted with ethyl
2,3-butadienoate (224 mg, 2 mmol) under the mediation of PPh3
(52 mg, 0.2 mmol). After a similar work-up, the crude product was
isolated by silica gel column chromatography (petroleum ether–
ethyl acetate, 10:1), giving the corresponding normal adduct 1a0
(142 mg, yield 40%) as colorless viscous oil.
J¼9.1 Hz), 13.8; 31P NMR (CDCl3, 160 MHz, 85% H3PO4)
d 72.4 ppm.
Anal. Calcd for C19H28NO4PS: C, 57.41; H, 7.10; N, 3.52. Found: C,
57.35; H, 7.12; N, 3.49.
4.4.3. Ethyl 1-(O,O-diethylthiophosphoryl)-2-(p-chlorophenyl)-5-
methyl-3-pyrroline-3-carboxylate (1i)
By once column chromatographic purification, the normal cy-
cloaddition product 1i (380 mg, yield 76%) from N-thiophosphoryl
p-chlorophenylimine was obtained as colorless viscous oil with
a ratio of cis- and trans-isomer of 11:1. It was not further purified
before identified as pure cis-1i by NMR. For cis-1i, 1H NMR (CDCl3,
4.3.1. Ethyl 1-(O,O-diethylphosphoryl)-2-phenyl-3-pyrroline-3-
carboxylate (1a0)
1H NMR (CDCl3, 400 MHz, TMS)
d 7.65–7.18 (m, 5H), 6.87 (br s,
1H), 5.47 (m, 1H), 4.38 (m, 2H), 4.06–3.74 (m, 5H), 3.32 (m, 1H), 1.20
(t, J¼6.8 Hz, 3H), 1.08 (t, J¼7.2 Hz, 3H), 0.90 (t, J¼6.8 Hz, 3H); 13C
400 MHz, TMS)
d
7.32 (d, J¼8.4 Hz, 2H), 7.28 (d, J¼8.4 Hz, 2H), 6.80
NMR (CDCl3, 75 MHz, TMS)
d
162.3, 142.0, 137.0 (d, J¼8.9 Hz), 132.1
(s, 1H), 5.66 (d, JP–N–C–H¼8.8 Hz, 1H), 4.83 (m, 1H), 4.10–3.75 (m,
5H), 3.46 (m, 1H), 1.55 (d, J¼6.4 Hz, 3H),1.25 (t, J¼7.2 Hz, 3H), 1.15 (t,
J¼7.2 Hz, 3H),1.00 (t, J¼7.2 Hz, 3H); 13C NMR (CDCl3,100 MHz, TMS)
(d, J¼9.9 Hz), 128.1, 127.7, 127.6, 68.2 (d, J¼5.8 Hz), 62.2 (d, J¼5.4 Hz,
P–O–CH2), 62.1 (d, J¼4.8 Hz, P–O–CH2), 60.6, 55.2 (d, J¼6.4 Hz), 16.1
(d, J¼6.8 Hz), 15.6 (d, J¼7.6 Hz), 13.9; 31P NMR (CDCl3, 160 MHz, 85%
d
162.3, 142.2 (d, J¼9.0 Hz), 140.4, 133.8 (d, J¼8.9 Hz), 133.2, 129.6,
H3PO4)
d
6.9 ppm. Anal. Calcd for C17H24NO5P: C, 57.78; H, 6.85; N,
128.1, 68.3 (d, J¼4.5 Hz), 63.0 (d, J¼6.7 Hz), 62.7 (d, J¼4.8 Hz, P–O–
CH2), 62.5 (d, J¼4.6 Hz, P–O–CH2), 60.6, 23.2, 15.7 (d, J¼7.8 Hz), 15.3
(d, J¼8.9 Hz), 13.9; 31P NMR (CDCl3, 160 MHz, 85% H3PO4)
3.96. Found: C, 57.56; H, 7.03; N, 3.87.
4.4. General procedure for the PTA-catalyzed [3D2]
cycloaddition of ethyl 2,3-pentadienoate with N-(O,O-
diethylthiophosphoryl) imines
d 72.5 ppm. Anal. Calcd for C18H25ClNO4PS: C, 51.73; H, 6.03; N, 3.35.
Found: C, 51.91; H, 6.25; N, 3.30.
4.4.4. Ethyl 1-(O,O-diethylthiophosphoryl)-2-(o-chlorophenyl)-5-
methyl-3-pyrroline-3-carboxylate (1j)
To a stirred solution of the substrate imine (1 mmol) and PTA
(32 mg, 0.2 mmol) in anhydrous CH2Cl2 (10 mL), neat ethyl 2,3-
pentadienoate (315 mg, 2.5 mmol) was dropwise added by the
means of microsyringe over 10 min at room temperature. The so-
lution was further stirred for 48 h. After evaporation of the solvent
and volatile components, the crude product was purified by silica
gel column chromatography (petroleum ether–ethyl acetate, 35:1),
affording the corresponding adduct 1, which contained a pair of
diastereomers with the cis-isomer being predominant. The ratio of
cis- and trans-isomers in 1 was determined by 31P NMR.
By once column chromatographic purification as described in
the above general procedure, the normal cycloaddition product 1j
(290 mg, yield 70%) from N-thiophosphoryl o-chlorophenylimine
was obtained as colorless viscous oil with a ratio of cis- and trans-
isomers of 7:1. This diastereomeric mixture was further isolated by
careful column chromatography (petroleum ether as eluant),
affording a small amount of pure cis-1j associated with a major
fraction of cis- and trans-isomer mixture. For cis-1j, 1H NMR (CDCl3,
300 MHz, TMS) d 7.34–7.13 (m, 4H), 6.82 (m, 1H), 6.29 (m, 1H), 4.86
(m, 1H), 4.02 (m, 4H), 3.78 (m, 1H), 3.20 (m, 1H), 1.61 (d, J¼6.6 Hz,
4.4.1. Ethyl 1-(O,O-diethylthiophosphoryl)-5-methyl-2-phenyl-3-
pyrroline-3-carboxylate (1g)
3H), 1.29 (t, J¼6.9 Hz, 3H), 1.09 (t, J¼6.9 Hz, 3H), 0.84 (t, J¼6.9 Hz,
3H); 13C NMR (CDCl3, 100 MHz, TMS)
d
162.0, 142.4 (d, J¼9.7 Hz),
By once column chromatographic purification, the normal cy-
cloaddition product 1g (295 mg, yield 77%) from N-thiophosphoryl
phenylimine was obtained as colorless viscous oil with a ratio of
cis- and trans-isomers of 25:1. It was then characterized as pure cis-
1g without further purification. For cis-1g, 1H NMR (CDCl3,
139.4, 134.2, 133.8 (d, J¼8.5 Hz), 129.2, 129.1, 128.4, 126.6, 64.0, 63.3
(d, J¼8.1 Hz), 62.7 (d, J¼5.8 Hz, P–O–CH2), 62.2 (d, J¼4.7 Hz, P–O–
CH2), 60.4, 23.4, 15.7 (d, J¼7.7 Hz), 14.9 (d, J¼10.0 Hz), 13.7; 31P NMR
(CDCl3, 120 MHz, 85% H3PO4)
d 71.1 ppm. Anal. Calcd for
C18H25ClNO4PS: C, 51.73; H, 6.03; N, 3.35. Found: C, 51.84; H, 6.17; N,
400 MHz, TMS)
d 7.37–7.10 (m, 5H), 6.78 (br s, 1H), 5.65 (d, JP–N–C–
3.32.
¼8.4 Hz, 1H), 4.82 (m, 1H), 4.10–3.75 (m, 5H), 3.29 (m, 1H), 1.55
H
(d, J¼6.4 Hz, 3H), 1.24 (t, J¼7.2 Hz, 3H), 1.11 (t, J¼7.2 Hz, 3H), 0.89 (t,
4.4.5. Ethyl 1-(O,O-diethylthiophosphoryl)-5-methyl-2-
(p-nitrophenyl)-3-pyrroline-3-carboxylate (1k)
By once column chromatographic purification as described in
the above general procedure, the normal cycloaddition product 1k
(424 mg, yield 99%) from N-thiophosphoryl p-nitrophenylimine
was obtained as colorless viscous oil with a ratio of cis- and
J¼7.2 Hz, 3H); 13C NMR (CDCl3, 100 MHz, TMS)
d
162.6, 142.0
(d, J¼8.9 Hz), 141.7, 134.2 (d, J¼8.5 Hz), 128.2, 128.0, 127.5, 68.8 (d,
J¼4.0 Hz), 63.2 (d, J¼7.3 Hz), 62.7 (d, J¼5.5 Hz, P–O–CH2), 62.4
(d, J¼4.7 Hz, P–O–CH2), 60.5, 23.3, 15.8 (d, J¼7.8 Hz), 15.2 (d,
J¼9.3 Hz), 13.9; 31P NMR (CDCl3, 160 MHz, 85% H3PO4)
d 72.4 ppm.

B. Zhang et al. / Tetrahedron 64 (2008) 9471–9479
9477
trans-isomers of 6:1. This diastereomeric mixture was further
isolated by careful column chromatography (petroleum ether as
eluant), affording a small amount of pure cis-1k associated with
a major fraction of cis- and trans-isomer mixture. For cis-1k, 1H
1H), 3.58 (s, 3H), 2.23 (br s, 1H); 13C NMR (CDCl3, 100 MHz, TMS)
d
163.6, 143.4, 141.2, 137.2, 128.4, 127.4, 126.8, 68.0, 53.8, 51.3 ppm;
HRMS (ESI) calcd for
204.1023.
C
12H14NO2 [(MþH)þ] 204.1024, found
NMR (CDCl3, 300 MHz, TMS)
d
8.18 (d, J¼7.8 Hz, 2H), 7.57 (d,
J¼7.8 Hz, 2H), 6.82 (br s, 1H), 5.78 (d, JP–N–C–H¼9.0 Hz, 1H), 4.84 (m,
1H), 4.10–3.85 (m, 5H), 3.59 (m, 1H), 1.56 (d, J¼6.6 Hz, 3H), 1.21 (t,
J¼6.9 Hz, 3H), 1.14 (t, J¼6.9 Hz, 3H), 1.02 (t, J¼6.9 Hz, 3H); 13C NMR
4.6.2. Methyl 2-(p-methylphenyl)-3-pyrroline-3-carboxylate (2b)
From 1b (192 mg, 0.5 mmol), the title compound (83 mg, yield
76%) was obtained as pale yellow liquid after silica gel chroma-
(CDCl3,100 MHz, TMS)
d
162.1,149.3,147.2,142.9 (d, J¼9.1 Hz),133.4
tography. 1H NMR (CDCl3, 400 MHz, TMS)
d
7.16 (d, J¼8.0 Hz, 2H),
(d, J¼9.0 Hz), 129.2, 123.2, 68.5 (d, J¼5.0 Hz), 63.0 (d, J¼6.1 Hz),
62.9 (d, J¼5.1 Hz, P–O–CH2), 62.8 (d, J¼5.1 Hz, P–O–CH2), 60.9, 23.1,
15.7 (d, J¼7.9 Hz),15.4 (d, J¼8.7 Hz),13.9; 31P NMR (CDCl3,120 MHz,
7.10 (d, J¼8.0 Hz, 2H), 6.96 (br s, 1H), 5.16 (br s, 1H), 4.12 (m, 1H),
3.90 (m, 1H), 3.60 (s, 3H), 2.35 (br s, 1H), 2.30 (s, 3H); 13C NMR
(CDCl3, 100 MHz, TMS) d 163.6,141.0, 140.4,137.2, 136.9,129.1, 126.7,
67.7, 53.7, 51.2, 20.9 ppm; HRMS (ESI) calcd for C13H16NO2
85% H3PO4)
d
71.7 ppm. Anal. Calcd for C18H25N2O6PS: C, 50.46; H,
5.88; N, 6.54. Found: C, 50.51; H, 6.02; N, 6.38.
[(MþH)þ] 218.1180, found 218.1170.
4.5. The PTA-catalyzed [3D2] cycloaddition of ethyl 2,3-
pentadienoate with N-(O,O-diethylphosphoryl) phenylimine
4.6.3. Methyl 2-(p-methoxyphenyl)-3-pyrroline-3-carboxylate (2c)
From 1c (198 mg, 0.5 mmol), the title compound (75 mg, yield
64%) was obtained as pale yellow liquid after work-up and purifi-
cation as described in the above general procedure. 1H NMR (CDCl3,
By the procedure for its thio-analogue, N-(O,O-diethyl-
phosphoryl) phenylimine (242 mg, 1 mmol) was similarly reacted
with ethyl 2,3-pentadienoate (315 mg, 2.5 mmol) under the me-
diation of PTA (32 mg, 0.2 mmol) for 24 h. After a similar work-up,
the crude product was isolated by silica gel column chromatogra-
phy (petroleum ether–ethyl acetate, 10:1), giving the correspond-
ing adduct 1g0 (198 mg, yield 54%) as colorless viscous oil. The
product 1g0, with a ratio (9:1) of cis- and trans-isomer, was
identified as cis-1g0 by NMR without further isolation.
400 MHz, TMS)
d
7.17 (d, J¼8.4 Hz, 2H), 6.94 (br s, 1H), 6.80 (d,
J¼8.4 Hz, 2H), 5.13 (br s, 1H), 4.12 (dd, J¼17.2, 5.0 Hz, 1H), 3.88 (d,
J¼17.2 Hz, 1H), 3.73 (s, 3H), 3.58 (s, 3H), 2.15 (br s, 1H); 13C NMR
(CDCl3,100 MHz, TMS) d 163.6,158.8,140.9,137.2,135.6,127.9,113.7,
67.4, 55.0, 53.6, 51.2 ppm; HRMS (ESI) calcd for
C13H16NO3
[(MþH)þ] 234.1130, found 234.1123.
4.6.4. Methyl 2-(p-chlorophenyl)-3-pyrroline-3-carboxylate (2d)
Methanolysis of 1d (202 mg, 0.5 mmol) yielded the title com-
pound (102 mg, yield 86%) as pale yellow liquid after work-up and
purification as described in the above general procedure. Also,
a small amount of aromatization by-product 3d (9 mg, 5%) was
isolated as the first fraction from the crude product. For 2d, 1H NMR
4.5.1. Ethyl 1-(O,O-diethylphosphoryl)-5-methyl-2-phenyl-3-
pyrroline-3-carboxylate (1g0)
For cis-1g0, 1H NMR (CDCl3, 400 MHz, TMS)
d 7.43–7.21 (m, 5H),
6.79 (br s, 1H), 5.48 (m, 1H), 4.75 (m, 1H), 4.10–3.90 (m, 5H), 3.73
(m, 1H), 3.23 (m, 1H), 1.52 (d, J¼6.4 Hz, 3H), 1.28 (t, J¼7.2 Hz, 3H),
1.10 (t, J¼7.2 Hz, 3H), 0.86 (t, J¼6.8 Hz, 3H); 13C NMR (CDCl3,
(CDCl3, 400 MHz, TMS)
d
7.25 (d, J¼8.4 Hz, 2H), 7.20 (d, J¼8.4 Hz,
2H), 6.96 (br s, 1H), 5.17 (br s, 1H), 4.10 (ddd, J¼17.6, 5.6, 2.0 Hz, 1H),
100 MHz, TMS)
d
162.5, 142.0 (d, J¼9.3 Hz), 141.8, 134.5 (d,
3.92 (m, 1H), 3.59 (s, 3H), 2.13 (br s, 1H); 13C NMR (CDCl3, 100 MHz,
J¼9.9 Hz), 128.0, 127.9, 127.5, 68.8 (d, J¼4.4 Hz), 62.3 (d, J¼5.9 Hz,
P–O–CH2), 62.1 (d, J¼5.9 Hz, P–O–CH2), 61.7 (d, J¼5.5 Hz), 60.4, 22.9,
16.1 (d, J¼7.0 Hz), 15.4 (d, J¼7.7 Hz), 13.8; 31P NMR (CDCl3, 160 MHz,
TMS) d 163.5, 142.2, 141.4, 137.0, 133.0, 128.5, 128.4, 67.3, 53.9,
51.4 ppm; HRMS (ESI) calcd for C12H13ClNO2 [(MþH)þ] 238.0634,
found 238.0627 (100) and 240.0597 (33).
85% H3PO4) d 7.6 ppm. Anal. Calcd for C18H26NO5P: C, 58.85; H, 7.13;
N, 3.81. Found: C, 58.79; H, 7.25; N, 3.73.
4.6.5. Methyl 1-(O,O-diethylthiophosphoryl)-2-(p-chlorophenyl)-
1H-pyrrole-3-carboxylate (3d)
4.6. General procedure for the HCl-catalyzed methanolysis of
adducts 1 and the synthesis of free amine 3-pyrrolines 2
Colorless oil; 1H NMR (CDCl3, 400 MHz, TMS)
d
7.33 (m, 5H), 6.67
(m, 1H), 4.02 (m, 2H), 3.88 (m, 2H), 3.63 (s, 3H), 1.16 (t, J¼6.8 Hz,
6H); 13C NMR (CDCl3, 100 MHz, TMS)
164.2, 140.6, 138.7, 134.6,
d
A solution of 1 (0.5 mmol) in anhydrous hydrochloric methanol
(3.5 M, 20 mL) was stirred at room temperature for 12 h, followed
by gentle reflux (ca. 60 ꢀC) for additional 24 h. The solution was
then concentrated to about one tenth of its original volume under
reduced pressure. The residue, after being taken into CH2Cl2
(20 mL), was basified with Et3N (1 mL, in excess) and stirred at
room temperature for 1 h. Removal of solvents and other volatile
components on a rotary evaporator gave a syrupy stuff, which was
mixed with ether (20 mL) and thoroughly stirred to precipitate the
by-product hydrochloric Et3N salt. The amine salt was filtered off
and rinsed with ether (5 mLꢁ2). The combined ethereal filtrate was
evaporated to afford the crude deprotected 3-pyrroline 2, which
was subsequently purified by silica gel column chromatography via
gradient elution with petroleum ether–ethyl acetate (30:1, then
10:1, finally ethyl acetate only).
132.5, 130.6, 127.3, 125.4 (d, J¼9.6 Hz), 111.3 (d, J¼10.2 Hz), 64.7 (d,
J¼4.8 Hz), 51.1, 15.5 (d, J¼8.1 Hz); 31P NMR (CDCl3, 160 MHz, 85%
H3PO4)
d 63.9 ppm.
4.6.6. Methyl 2-(o-chlorophenyl)-3-pyrroline-3-carboxylate (2e)
The title compound (75 mg, yield 63%) as pale yellow liquid was
obtained from the methanolysis of 1e (202 mg, 0.5 mmol), after
work-up and purification as described in the above general pro-
cedure. 1H NMR (CDCl3, 400 MHz, TMS)
d
7.34–7.12 (m, 4H), 7.08 (br
s, 1H), 5.72 (m, 1H), 3.99 (m, 2H), 3.61 (s, 3H), 2.29 (br s, 1H); 13C
NMR (CDCl3,100 MHz, TMS) 163.5,142.7, 140.3,136.0,133.4, 129.6,
d
128.5, 127.8, 127.0, 64.0, 53.5, 51.4 ppm; HRMS (ESI) calcd for
C
12H13ClNO2 [(MþH)þ] 238.0634, found 238.0631 (100) and
240.0602 (33).
4.6.7. Methyl 2-(p-nitrophenyl)-3-pyrroline-3-carboxylate (2f)
The title compound (88 mg, yield 71%) as pale yellow liquid was
obtained from the methanolysis of 1f (207 mg, 0.5 mmol), after
work-up and purification as described in the above general pro-
cedure. Also, a small amount of aromatization by-product 3f (7 mg,
4%) was isolated as the first fraction in the column chromatography.
4.6.1. Methyl 2-phenyl-3-pyrroline-3-carboxylate (2a)
From the substrate 1a (185 mg, 0.5 mmol), the pure title com-
pound (70 mg, yield 69%) was obtained as pale yellow liquid after
work-up and purification as described in the above general pro-
cedure. 1H NMR (CDCl3, 400 MHz, TMS)
d
7.24 (m, 5H), 6.98 (br s,
1H), 5.12 (br s, 1H), 4.12 (dd, J¼17.2, 5.0 Hz, 1H), 4.10 (d, J¼17.2 Hz,
For 2f, 1H NMR (CDCl3, 400 MHz, TMS)
d
8.13 (d, J¼8.4 Hz, 2H), 7.48

9478
B. Zhang et al. / Tetrahedron 64 (2008) 9471–9479
(d, J¼8.4 Hz, 2H), 7.02 (br s, 1H), 5.34 (br s, 1H), 4.16 (dd, J¼17.6,
of a solution of cis-2k and equivalent picric acid in CH2Cl2–ethanol
(50:50) yielded yellow crystals of the cis-2k picrate salt (mp 166–
168 ꢀC), which were used for the X-ray diffraction. For cis-2k, 1H
5.2 Hz, 1H), 4.06 (d, J¼17.6 Hz, 1H), 3.61 (s, 3H), 2.24 (br s, 1H); 13
C
NMR (CDCl3, 100 MHz, TMS) d 163.3, 151.2, 142.0, 140.6, 136.6, 128.1,
123.6, 67.2, 54.2, 51.6 ppm; HRMS (ESI) calcd for C12H13N2O4
NMR (CDCl3, 400 MHz, TMS)
d
8.17 (d, J¼8.8 Hz, 2H), 7.53 (d,
[(MþH)þ] 249.0875, found 249.0876.
J¼8.8 Hz, 2H), 6.87 (br s, 1H), 5.35 (m, 1H), 4.39 (m, 1H), 3.60 (s, 3H),
2.27 (br s, 1H), 1.37 (d, J¼6.8 Hz, 3H); 13C NMR (CDCl3, 100 MHz,
4.6.8. Methyl 1-(O,O-diethylthiophosphoryl)-2-(p-nitrophenyl)-1H-
TMS) d 163.4, 151.2, 147.0, 146.6, 135.0, 128.5, 123.4, 67.2, 60.2, 51.4,
pyrrole-3-carboxylate (3f)
22.4 ppm; HRMS (ESI) calcd for C13H15N2O4 [(MþH)þ] 263.1031,
Colorless oil; 1H NMR (CDCl3, 400 MHz, TMS)
d
8.24 (d, J¼8.8 Hz,
found 263.1029.
2H), 7.57 (d, J¼8.8 Hz, 2H), 7.38 (m, 1H), 6.71 (m, 1H), 4.10–3.88 (m,
4H), 3.64 (s, 3H), 1.16 (t, J¼6.8 Hz, 6H); 31P NMR (CDCl3, 160 MHz,
4.6.14. Methyl trans-1-(O,O-diethylthiophosphoryl)-5-methyl-2-
85% H3PO4)
d
63.6 ppm.
(p-nitrophenyl)-3-pyrroline-3-carboxylate (trans-4k)
Yellow viscous oil; 1H NMR (CDCl3, 400 MHz, TMS)
d 8.14 (d,
4.6.9. Methyl 5-methyl-2-phenyl-3-pyrroline-3-carboxylate (2g)
From 1g (192 mg, 0.5 mmol, cis/trans 25:1), the cis-isomer
(cis-2g) of the title compound (77 mg, yield 71%) was only obtained
as pale yellow liquid after work-up and purification in the above
general procedure. For cis-2g, 1H NMR (CDCl3, 400 MHz, TMS)
J¼8.8 Hz, 2H), 7.49 (d, J¼8.8 Hz, 2H), 6.74 (br s, 1H), 5.73 (m, 1H),
4.98 (m, 1H), 3.90 (m, 3H), 3.60 (s, 3H), 3.35 (m, 1H), 1.56 (d,
J¼6.4 Hz, 3H), 1.22 (t, J¼6.8 Hz, 3H), 0.97 (t, J¼7.2 Hz, 3H); 13C NMR
(CDCl3, 100 MHz, TMS)
d
162.4, 149.9, 147.1, 143.3 (d, J¼10.4 Hz),
133.9 (d, J¼11.3 Hz), 128.8, 123.1, 69.0 (d, J¼6.6 Hz), 63.3 (d,
J¼6.6 Hz), 63.0 (d, J¼4.5 Hz, P–O–CH2), 62.7 (d, J¼5.5 Hz, P–O–CH2),
51.8, 21.5, 15.8 (d, J¼7.8 Hz), 15.6 (d, J¼8.2 Hz); 31P NMR (CDCl3,
d
7.30–7.10 (m, 5H), 6.77 (br s, 1H), 5.10 (br s, 1H), 4.16 (m, 1H), 3.49
(s, 3H), 2.34 (br s, 1H), 1.25 (d, J¼6.8 Hz, 3H); 13C NMR (CDCl3,
100 MHz, TMS)
d
163.8, 145.9, 143.4, 136.2, 128.2, 127.2, 127.1, 68.3,
160 MHz, 85% H3PO4) d 68.5 ppm.
60.2, 51.2, 22.0 ppm; HRMS (ESI) calcd for C13H16NO2 [(MþH)þ]
218.1180, found 218.1174.
4.7. The HCl-catalyzed methanolysis of N-(O,O-diethyl-
phosphoryl) cycloaddition product 1g0
4.6.10. Methyl 5-methyl-2-(p-methylphenyl)-3-pyrroline-3-
carboxylate (2h)
From the methanolysis of 1h (200 mg, 0.5 mmol, cis/trans 46:1),
the cis isomer of the title compound (44 mg, yield 38%) was isolated
as pale yellow liquid. For cis-2h, 1H NMR (CDCl3, 400 MHz, TMS)
By the above general procedure, the methanolysis of ethyl
1-(O,O-diethylphosphoryl)-5-methyl-2-phenyl-3-pyrroline-3-car-
boxylate (1g0) (184 mg, 0.5 mmol, cis/trans 9:1) yielded a mixture
of the corresponding cis and trans free amines 2g (61 mg, overall
yield 56%) as pale yellow oil. Further careful column chromato-
graphic isolation gave a small amount of pure cis-2g, which was
identical to the sample from the methanolysis of 1g by their NMR
spectra.
d
7.18 (d, J¼7.6 Hz, 2H), 7.10 (d, J¼7.6 Hz, 2H), 6.83 (br s, 1H), 5.13 (br
s,1H), 4.20 (br s,1H), 3.56 (s, 3H), 2.30 (s, 3H), 2.01 (br s, 1H),1.31 (d,
J¼6.4 Hz, 3H); 13C NMR (CDCl3, 100 MHz, TMS)
d 163.8, 145.8, 140.3,
136.8, 136.2, 129.0, 127.1, 68.0, 60.2, 51.1, 21.9, 20.9 ppm; HRMS (ESI)
calcd for C14H18NO2 [(MþH)þ] 232.1337, found 232.1333.
Acknowledgements
4.6.11. Methyl 2-(p-chlorophenyl)-5-methyl-3-pyrroline-3-
carboxylate (2i)
Financial support from National Natural Science Foundation of
China (Grant Nos. 20672057; 20421202) and Scientific Research
Foundation of State Education Ministry for the Returned Overseas
Chinese Scholars is gratefully acknowledged.
The cis-isomer of the title compound (62 mg, yield 49%) was
obtained as pale yellow liquid from the methanolysis of 1i (210 mg,
0.5 mmol, cis/trans 11:1) after work-up and purification in the
above general procedure. For cis-2i, 1H NMR (CDCl3, 400 MHz, TMS)
d
7.19 (m, 4H), 6.77 (br s, 1H), 5.11 (br s, 1H), 4.20 (m, 1H), 3.52 (s,
Supplementary data
3H), 2.16 (br s,1H), 1.26 (d, J¼6.8 Hz, 3H); 13C NMR (CDCl3,100 MHz,
TMS)
d 163.8, 146.2, 142.1, 135.8, 133.0, 128.8, 128.5, 67.5, 60.2, 51.4,
General experimental remarks; a general procedure for the
preparation of N-(O,O-diethyl(thio)phosphoryl)imines and their 1H
NMR spectra; NMR (1H, 13C, 31P) spectra for 1, 2, 3, and 4 are pro-
vided. Supplementary data associated with this article can be found
in the online version, at doi:10.1016/j.tet.2008.07.075.
22.2 ppm; HRMS (ESI) calcd for C13H15ClNO2 [(MþH)þ] 252.0791,
found 252.0788 (100) and 254.0758 (33).
4.6.12. Methyl 2-(o-chlorophenyl)-5-methyl-3-pyrroline-3-
carboxylate (2j)
The cis-isomer of the title compound (69 mg, yield 55%) was
isolated as pale yellow liquid from the methanolysis of 1j (210 mg,
0.5 mmol, cis/trans 7:1). For cis-2j, 1H NMR (CDCl3, 400 MHz, TMS)
References and notes
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d
7.35–7.10 (m, 4H), 6.92 (br s, 1H), 5.72 (m, 1H), 4.30 (m, 1H), 3.60
(s, 3H), 2.13 (br s, 1H), 1.28 (d, J¼6.8 Hz, 3H); 13C NMR (CDCl3,
100 MHz, TMS) d 163.8, 147.0, 141.0, 135.4, 133.7, 129.5, 128.4, 128.3,
127.1, 64.0, 60.2, 51.5, 22.2 ppm; HRMS (ESI) calcd for C13H15ClNO2
[(MþH)þ] 252.0791, found 252.0788 (100) and 254.0758 (33).
4.6.13. Methyl 5-methyl-2-(p-nitrophenyl)-3-pyrroline-3-
carboxylate (2k)
From the methanolysis of 1k (214 mg, 0.5 mmol, cis/trans 6:1),
the cis-isomer of the title compound cis-2k (103 mg, yield 79%) as
a yellow semi-solid was isolated after work-up and purification as
described in the above general procedure. Also, a small amount of
transesterification product trans-4k (22 mg, 11%) was obtained as
the first fraction in the column chromatography. Slow evaporation
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6. Selected crystal data for 2k conjugate with picric acid (CCDC 684846): em-
pirical formula: C19H17N5O11. Formula weight: 491.38. Crystal space group:
triclinic, P-1. Unit cell dimensions: a¼8.250(2) Å, b¼10.100(3) Å, c¼13.805(4) Å,
a
¼87.412(5)ꢀ,
b
¼80.926(5)ꢀ,
g
¼74.698(4)ꢀ. F000¼508, Z¼2, Dcalcd¼1.
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490 g cmꢂ3, U¼1095.5(5) Å3, T¼294(2) K,
l
(Mo K
a
)¼0.7107 Å. 5715 reflections
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collected in the range of 1.49ꢃ
q
ꢃ25.02ꢀ, Rint¼0.0229. Refinement method: full-
matrix least-squares on F2 to R1¼0.0507, wR2¼0.1314. The supplementary