Enantioselective binaphthophosphepine-promoted [3+2] annulations of N-Ts- and N-DPP-imines with allenoates and 2-butynoates

Article abstract of DOI:10.1002/ejoc.200800598

The use of binaphthophosphepine 1a as a catalyst for the [3+2] cyclisation between allenoates or 2-butynoates and imines was investigated. The effects of the imine protecting group on both the catalytic activity and enantioselectivity were determined by c

Full text of DOI:10.1002/ejoc.200800598

FULL PAPER
DOI: 10.1002/ejoc.200800598
Enantioselective Binaphthophosphepine-Promoted [3+2] Annulations of N-Ts-
and N-DPP-Imines with Allenoates and 2-Butynoates
Nathalie Pinto,[a] Nicolas Fleury-Brégeot,[a] and Angela Marinetti*[a]
Keywords: Phosphanes / Asymmetric catalysis / [3+2] Cyclisations / Allenes / Imines
The use of binaphthophosphepine 1a as a catalyst for the
[3+2] cyclisation between allenoates or 2-butynoates and
imines was investigated. The effects of the imine protecting
group on both the catalytic activity and enantioselectivity
were determined by comparing the behaviour of N-tosyl-
and N-DPP-imines. The N-DPP-imines displayed lower reac-
tivity, but afforded the desired pyrrolines in higher enantio-
meric excess (73–92% ee). The DPP protecting group was
removed from the final pyrrolines under mild conditions to
afford the corresponding secondary amines.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
imines initially investigated, also N-p-nitrobenzenesulfonyl-
and N-β-(trimethylsilyl)ethanesulfonyl-benzaldimines had
been considered. The use of alternative protecting groups
was expected to expand the synthetic utility of these cyclisa-
tions, because such groups can usually be removed easier
than the N-Ts substituent. However, none of the protecting
groups could be removed from the [3+2] annulation prod-
ucts to afford the corresponding secondary 3-pyrrolines.
Not only did Ts deprotection with sodium methoxide fail,
but the removal of the Ts or SES group by fluoride ions,
under mild conditions, also unexpectedly led to concomi-
tant aromatization and isolation of the corresponding, un-
desired pyrroles.[5b,6b] The use of DPP as the removable N-
protecting group had not been considered in depth.[9]
In this context, after our initial studies on the enantiose-
lective [3+2] cyclisations of N-Ts-imines[4a,10] promoted no-
tably by phosphanes 1, we decided to check the suitability
of N-DPP-imines as starting materials in the same cyclisa-
tions. Parallel work from Jacobsen describes the use of
DPP-imines in analogous enantioselective [3+2] cyclisations
promoted by a phosphinothiourea catalyst.[11]
The N-DPP-imines 2a–f were prepared according to lit-
erature methods.[12] Their [3+2] cyclisations with both al-
lenoates and 2-butynoates were investigated in the presence
of achiral catalysts (PBu3 or PPh3) and the chiral binaph-
thophosphepine (S)-1a, according to Scheme 1.
Imines 2 were converted into the corresponding racemic
N-DPP-pyrrolines 3 or 4 by their reaction with ethyl or cy-
clohexyl 2-butynoate, respectively, in toluene, in the pres-
ence of 10 mol-% of PBu3 (Table 1, Entries 1, 3, 5 and 6).
Alternatively, we used ethyl 2,3-butadienoate as a suitable
starting material for these [3+2] cyclisations, with either
PPh3 or PBu3 as the catalyst (Table 1, Entries 2, 4 and 7–
9). Reagents and conditions are given in Table 1. Isolated
yields of 40–80% were obtained for reactions performed on
a 0.3–3 mmol scale.
Introduction
The binaphthophosphepines 1 initially described by Gla-
diali et al.[1] have been developed as efficient chiral ligands
in enantioselective organometallic catalysis.[2] Recently,
their suitability as chiral nucleophilic promoters for organo-
catalytic processes has been pointed out by Fu through
investigations on the [4+2] annulations of imines with all-
enes (ee = 75–98%),[3a] as well as on the [3+2] cyclisations
of allenes with enones (ee = 75–90%).[3b] Our group also
has been involved in studies on the use of 1 as an organoca-
talyst, in which the enantioselective [3+2] annulation of
various N-tosyl-arylimines with 2,3-butadienoates[4a] or al-
lenylphosphonates,[4b] leading to functionalised pyrrolines,
have been considered. Additional investigations on these re-
actions are reported here. The aim of this study is to dis-
close the effects of the imine protecting group on the
enantioselectivity of the [3+2] annulations promoted by 1a
by comparing N-Ts- and N-DPP-imines, as well as to out-
line suitable N-deprotection procedures for the final pyrrol-
ines. The stereochemical outcome of these cyclisations is
also discussed.
Results and Discussion
The phosphane-promoted [3+2] annulation of allenoates
(or 2-butynoates) with imines disclosed by Lu[5] represents
a useful strategy for the synthesis of functionalised 3-pyrro-
lines,[6] including biologically active compounds[7] and rel-
evant synthetic intermediates.[8] Suitable substrates are im-
ines activated toward nucleophilic additions by electron-
withdrawing nitrogen substituents. Thus, besides the N-Ts-
[a] Institut de Chimie des Substances Naturelles,
CNRS UPR 2301,
1, av. de la Terrasse, 91198 Gif-sur-Yvette Cedex, France
Fax: +33-1-69077247
E-mail: angela.marinetti@icsn.cnrs-gif.fr
146
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 146–151

Enantioselective Binaphthophosphepine-Promoted [3+2] Annulations
Scheme 2. Removal of the DPP protecting group from pyrrolines
3a–d,f.
Scheme 1. [3+2] annulation reactions of N-DPP-imines.
Table 2. Enantioselective [3+2] cyclisations of N-DPP-imines 2
with 2-butynoates promoted by binaphthophosphepine (S)-1a
(Scheme 1).
Table 1. [3+2] Cyclisations of N-DPP-imines 2a–f promoted by
achiral catalysts (Scheme 1).
Entry
Prod. R1
R2
Catalyst
T [°C] Yield
1
2
3
4
5
6
7
8
9
3a[a]
3a[b]
4a[a]
3b[b]
4b[a]
3c[a]
3d[b]
3e[b]
3f[b]
Ph
Ph
Ph
1-Naph
1-Naph
o-vinyl-C6H4 Et
CH=CH–Ph Et
m-Br-C6H4
p-NO2-Ph
Et
PBu3
PPh3
PBu3
PPh3
PBu3
PBu3
PPh3
PBu3
PBu3
110
110
110
50
50
110
50
72 %[c]
81 %
74 %
70 %
36 %
45 %
45 %[c]
46 %
60 %
Et
Cy[d]
Et
Cy
Et
Et
110
110
[a] From 2-butynoates. [b] From ethyl 2,3-butadienoate. [c] On 3-
mmol scale. [d] Cy = C6H11.
[a] From ref.[4a]; N-Ts-pyrrolines were obtained from the corre-
sponding allenoates. [b] 72 h. [c] Enantiomeric excesses were mea-
sured by chiral HPLC. Absolute configurations were assumed to
be (S) (see below).
Although good conversion rates were attained in these
reactions, it must be mentioned here that the isolation of
the N-DPP-pyrrolines 3 and 4 by column chromatography
occasionally suffered from partial decomposition, leading observed when starting from the corresponding allenoates.
[16]
to lower isolated yields. We were unable to identify the ori- These reactions were routinely performed in CH2Cl2
at
gin of this randomly observed decomposition process. Thus, r.t. for 24 h to give isolated yields of 25–74% and enantio-
it is recommend that pyrrolines be purified by flash meric excesses of 73–88%. Conversion rates increased at a
chromatography shortly after their synthesis and be stored higher temperature, but the enantioselectivity decreased
at low temperature.[13]
concomitantly. For instance, for substrate 3a, the reaction
With respect to the Ts group, the DPP protecting group in refluxing CH2Cl2 provided an 81% conversion and a
offers the major advantage of being easily removed.[14] 77% ee, while the same reaction at room temperature pro-
Thus, pyrrolines 3a–d,f were converted into the correspond- vided a 50% conversion and an 85% ee. Imines 2d and 2f
[15]
ing secondary amines by treatment with BF3·OEt2
(for failed to react in the presence of phosphane 1a either at
the synthesis of 5a and 5b) or aqueous HCl (for 5c,d,f), at room temperature or at 50 °C.
r.t. Under such mild conditions, aromatization into pyrroles
As a general trend, the use of the DPP protecting group
was suitably prevented. Pyrrolines 5 were isolated after decreased the reactivity of the imine relative to the pre-
aqueous workup and extraction from the aqueous phases at viously reported N-Ts-imines, as a result of a combination
pH ≈ 10 (Scheme 2). Occasionally, purification by column of steric effects and a lower electrophilicity of the imine
chromatography provided a suitable alternative to these carbon.[5b] However, the DPP group induces higher levels
workup conditions. Yields were moderate for reactions per- of asymmetric induction.[17] We found additional evidence
formed on a 0.2–0.5 mmol scale (compounds 5b–d,f), while for this trend from experiments on the diastereoselective an-
5a could be prepared in 95% yield on a 3 mmol scale.
nulations between l-menthyl or d-menthyl 2-butynoates and
In a second series of experiments, the [3+2] cyclisations N-DPP- or N-Ts-benzaldimines (2a and 2aЈ, respectively).
described above were performed in the presence of phos- In these annulation reactions, mixtures of the epimeric
phepine (S)-1a. The results are reported in Table 2. For pyrrolines 6 (or 6Ј) and 7 (or 7Ј) were formed (Scheme 3).
comparison purposes, the enantiomeric excesses obtained
previously[4a] in the analogous cyclisations of N-Ts-imines expected epimeric pyrrolines were obtained (Scheme 3, En-
are recalled in the table. tries 1 and 4), showing that the menthyl group had a minor
With achiral catalysts [e.g. P(iBu)3], 1:1 mixtures of the
2-Butynoates proved to be the most suitable reactants, effect on the stereoselectivity of these reactions. With the
giving clean conversions into the desired pyrrolines 3 and chiral phosphane 1a, starting from N-DPP-imines and men-
4, whereas the formation of unidentified side-products was thyl butynoates, high diastereomeric excesses were obtained
Eur. J. Org. Chem. 2009, 146–151
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147

N. Pinto, N. Fleury-Brégeot, A. Marinetti
FULL PAPER
tecting group. The subsequent tosylation of the crude mix-
ture of epimeric pyrrolines with tosyl chloride in aqueous
NaOH/CH2Cl2 afforded the N-Ts-imines 7Ј and 6Ј in a
Ͼ9:1 ratio. The 1H NMR spectroscopic data of 7Ј from
this reaction fit with those of the pyrroline CS-7Ј, whose
configuration was determined from X-ray crystal data. Im-
portantly, it must be noted that, under the reaction condi-
tions of Scheme 4, only a very small change in the initial
ratio of epimers was observed, which showed that the
stereochemical integrity of pyrroline 7 was essentially re-
tained through the deprotection/tosylation process.
These experiments demonstrated that phosphane (S)-1a
induced the same direction of asymmetric induction [i.e.,
(S) configuration of the α carbon], in the annulation reac-
tions of both N-DPP-imine 2a and N-Ts-imine 2aЈ with
menthyl butynoates. Based on these results, we tentatively
assumed that (S)-configured pyrrolines are always produced
from N-Ts-imines and N-DPP-imines in the presence of (S)-
1a. This assignment was applied in Table 2.
Altogether, this work emphasizes the potential utility of
the asymmetric [3+2] annulations of N-DPP-imines pro-
moted by phosphepine 1a, which combine fairly high levels
of asymmetric induction with synthetically valuable meth-
ods for the removal of the nitrogen protecting group.
Scheme 3. Diastereoselective [3+2] annulation reactions of menthyl
2-butynoates with benzaldimines 2a and 2aЈ.
and a small variation in the product ratios (6/7) was noticed
for chiral menthyl units with opposite configurations; the
diastereomeric excesses were 82% and Ͼ90% for the l-men-
thyl and d-menthyl esters, respectively (Scheme 3, Entries 2
and 3). The chiral catalyst definitely controls the stereo-
chemical outcome of these cyclisations, with only small
match-mismatch effects observed between the chiral cata-
lyst and the chiral substrate. We observed lower diastereo-
selectivities and a more pronounced match-mismatch effect
when analogous experiments were performed on the N-Ts-
benzaldimine 2aЈ (Scheme 3, Entries 5, 6); with (S)-1a as
the catalyst, mixtures of the epimeric pyrrolines 6Ј and 7Ј
were obtained in 34% and 56% de from l-menthyl and d-
menthyl 2-butynoate, respectively. N-Ts-imines give higher
conversion rates than did the corresponding N-DPP-imines.
In order to determine the direction of chiral induction
from phosphane (S)-1a, we previously performed an X-ray
analysis on crystals of the major epimer, 7Ј, obtained from
d-menthyl 2-butynoate and N-Ts-imine 2aЈ.[4a] This allowed
for the assignment of the α carbon of this pyrroline as (S)-
configured. The configurations of the other N-Ts-pyrrolines
6Ј and 7Ј could be inferred from this assignment. The same
(S) configuration was thus assigned to the major epimer, 6Ј,
obtained from l-menthyl 2-butynoate and imine 2aЈ.
Experimental Section
General: Imines 2a–f[12,18] were prepared from the corresponding
aldehydes and diphenylphosphinamide in the presence of TiCl4, ac-
cording to the reported method.[12] Characterization data for the
new imine 2c: 1H NMR (CDCl3, 500 MHz): δ = 5.49 (d, 3J =
11.0 Hz, 1 H, =CH2), 5.66 (d, 3J = 18.0 Hz, 1 H, CH2), 7.4–7.5 (10
3
H), 7.9 (4 H), 8.18 (d, J = 8.0 Hz, 1 H), 9.66 (d, JH,P = 32.0 Hz,
1 H, N=CH) ppm. HRMS: calcd. for C21H18NNaOP 354.1024;
found 354.1015. Menthyl butynoates were prepared from butynoic
acid and (–)- or (+)-menthol by esterification with DCC/DMAP,
according to the reported procedure.[19]
Phosphane-Catalysed Annulations of Imines 2 with 2-Butynoate. Ge-
neral Procedure A: PBu3 (33 µL, 1  in toluene) was added to a
solution of 2-butynoate (0.39 mmol) and imine 2 (0.33 mmol) in
degassed toluene (1 mL) under argon. The mixture was refluxed
for 24 h. The solvent was removed under reduced pressure, and the
The stereochemical course of reactions involving N-DPP-
imine 2a and menthyl butynoates was established by chemi- residue was purified by column chromatography on silica gel to
afford 3.
cal correlation between the final product 6 and the N-Ts-
pyrroline CS-7Ј of known configuration, as follows
(Scheme 4).
General Procedure B: A solution containing 2-butynoate (42 µL,
0.36 mmol), imine 2 (0.30 mmol) and phosphane 1a (11 mg,
0.03 mmol) in degassed CH2Cl2 (1 mL) was stirred under argon at
r.t. for 24 h. The solvent was removed under reduced pressure, and
the residue was purified by column chromatography.
Ethyl 1-(Diphenylphosphinoyl)-2,5-dihydro-2-phenylpyrrole-3-car-
boxylate (3a):[5b] The purification of 3a was performed by column
chromatography on silica gel with heptane/EtOAc (4:6) as the elu-
ent (Rf = 0.2). Colourless oil. 1H NMR (CDCl3, 300 MHz): δ =
1.09 (t, J = 7.2 Hz, 3 H, Me), 3.91–4.09 (m, 2 H, OCH2), 4.31 (dtd,
J = 17.1, 6.0, 1.8 Hz, 1 H, NCH2), 4.42 (ddt, J = 17.1, 10.8, 2.4 Hz
1 H, NCH2), 5.51 (m, 1 H, NCH), 6.87 (3 H), 7.1–7.3 (5 H), 7.5–
7.7 (4 H), 7.8 (2 H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 13.9
Scheme 4. Assignment of the α carbon configuration of pyrroline
7 by chemical correlation to 7Ј.
We treated the 95:5 mixture of epimeric pyrrolines 7 and
6, obtained from d-menthyl 2-butynoate, imine 2a and (S)-
2
2
(Me), 54.7 (d, JC,P = 2.8 Hz, NCH2), 60.5 (OCH2), 68.3 (d, JC,P
1a as the catalyst, with BF3·OEt2 to remove the DPP pro- = 3.5 Hz, NCH), 127.2, 127.4, 127.8, 128.0, 128.2, 128.5, 128.7,
148
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Eur. J. Org. Chem. 2009, 146–151

Enantioselective Binaphthophosphepine-Promoted [3+2] Annulations
1
130.2 (d, JC,P = 79 Hz, C-P), 131.6 (d, JC,P = 2.7 Hz, CH), 131.9
NCH2CH=), 162.3 (CO2Et) ppm. 31P NMR (CDCl3, 121 MHz): δ
= 26 ppm. MS (ESI): m/z = 490 [M + Na]+. HPLC: Chiracel AD
3
(d, JC,P = 2.6 Hz, CH), 132.4, 132.5, 137.0 (d, JC,P = 5.1 Hz,
NCH2CH=), 137.6 (d, JC,P = 5.4 Hz, C), 142.4 (d, JC,P = 2.6 Hz, heptane/iPrOH (80:20), 1 mL/min, tR = 11.0 min for the (R) enanti-
C), 162.2 (CO2Et) ppm. 31P NMR (CDCl3, 121 MHz): δ = 26 ppm. omer, tR = 16.8 min for the (S) enantiomer.
MS (ESI): m/z = 440 [M + Na]+. HPLC: Chiracel AD, heptane/
Cyclohexyl 1-(Diphenylphosphinoyl)-2,5-dihydro-2-(1-naphthyl)pyr-
iPrOH (80:20), 1 mL/min, tR = 7.5 min for the (R) enantiomer, tR
role-3-carboxylate (4b): Purification of 4b was performed by col-
= 8.5 min for the (S) enantiomer. [α]2D0 = +126 (c = 1, CHCl3, 75%
umn chromatography with heptanes/EtOAc (3:7) as the eluent (Rf
ee).
= 0.2). Colourless oil. 1H NMR (CDCl3, 300 MHz): δ = 0.6–1.6
Pyrroline 3a slowly converted into the corresponding pyrrole when
stored at r.t. An authentic sample of ethyl 1-(diphenylphosphinoyl)-
2-phenylpyrrole-3-carboxylate was obtained by the DDQ oxi-
dation[20] of 3a: 1H NMR (CDCl3, 300 MHz): δ = 0.94 (t, J =
(10 H), 4.2–4.5 (m, 2 H, NCH2), 6.37 (br., 1 H, NCH), 6.7 (2 H),
6.8 (2 H), 7.1 (1 H), 7.2–7.3 (8 H), 7.5 (3 H), 7.7 (2 H) ppm. 13C
NMR (CDCl3, 75 MHz): δ = 23.4 (CH2), 23.5 (CH2), 25.0 (CH2),
30.7 (CH2), 31.2 (CH2), 54.9 (NCH2), 73.0 (OCH), 123.2, 124.9,
125.0, 125.5, 127.4, 127.6, 128.0, 128.5, 128.7, 131.1 (d), 131.8 (d),
7.2 Hz, 3 H, Me), 3.96 (q, J = 7.2 Hz, 2 H, OCH2), 6.49 (t, JH,H
≈
3
JH,P = 3.6 Hz, 1 H), 6.64 (t, JH,H ≈ JH,P = 3.0 Hz, 1 H), 6.9–7.1 (5
132.2, 132.3, 136.7 (d, JC,P = 4.6 Hz, NCH2CH=), 161.8 (CO2Cy)
H), 7.3–7.4 (4 H), 7.4–7.5 (6 H) ppm. 13C NMR (CDCl3, 75 MHz): ppm. 31P NMR (CDCl3, 121 MHz): δ = 27 ppm. MS (ESI): m/z =
δ = 13.9 (Me), 59.7 (OCH2), 111.9 (d, JC,P = 7.4 Hz, CH), 119.4
(d, JC,P = 6.3 Hz, C), 124.6 (d, JC,P = 5.9 Hz, CH), 126.7, 128.0,
544 [M + Na]+. HPLC: Chiracel AD, heptane/iPrOH (85:15),
1 mL/min, tR = 10.4 min for the (R) enantiomer, tR = 13.6 min for
128.5, 128.7, 128.9 (C), 129.0 (C), 130.7 (C), 131.7, 131.96, 132.10, the (S) enantiomer.
132.80, 132.83, 142.6 (d, JC,P = 7.4 Hz, C), 164.1 (CO2Et) ppm. 31
P
Ethyl 1-(Diphenylphosphinoyl)-2,5-dihydro-2-(2-vinylphenyl)pyrrole-
3-carboxylate (3c): Compound 3c was purified by chromatography
on TLC plates (silica gel) with heptanes/EtOAc (3:7) as the eluent.
NMR (CDCl3, 121 MHz): δ = 25 ppm. MS (ESI): m/z = 438 [M
+ Na]+.
Cyclohexyl 1-(Diphenylphosphinoyl)-2,5-dihydro-2-phenylpyrrole-3- 1H NMR (CDCl3, 500 MHz): δ = 1.07 (t, J = 7.0 Hz, 3 H, Me),
carboxylate (4a): The purification of 4a was performed by column
3.97 (m, 2 H, OCH2), 4.29 (dt, 2J = 17.0, 5.5 Hz, 1 H, NCH2), 4.43
(br. dd, 2J ≈ 17 Hz, 1 H, NCH2), 4.96 (d, 3J = 11.0 Hz, 1 H, =CH2),
chromatography with a heptane/EtOAc gradient (40:60 to 0:100)
1
3
as the eluent (Rf = 0.2, EtOAc). Colourless oil. H NMR (CDCl3,
5.19 (d, J = 17.5 Hz, 1 H, =CH2), 5.99 (m, 1 H, NCH), 6.60 (dd,
500 MHz): δ = 1.1–1.7 (10 H), 4.29 (dt, J = 17.5, 4.5 Hz, 1 H, 3J = 17.5, 11.0 Hz, 1 H, =CHAr), 6.89 (s, 1 H, NCH2CH=), 7.1–
NCH2), 4.39 (dd, J = 17.5, 11.0 Hz, 1 H, NCH2), 4.61 (m, 1 H, 7.5 (12 H), 7.8 (2 H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 13.9
2
OCH), 5.52 (m, 1 H, NCH), 6.85 (3 H), 7.108 (3 H), 7.19 (2 H), (Me), 55.1 (d, JC,P = 2.6 Hz, NCH2), 60.5 (OCH2), 63.6 (NCH),
7.3–7.5 (4 H), 7.55 (2 H), 7.81 (2 H) ppm. 13C NMR (CDCl3,
115.7 (=CH2), 125.7, 127.4, 127.7, 127.9, 128.1, 128.6, 128.7, 129.1
75 MHz): δ = 23.3 (CH2), 23.5 (CH2), 25.2 (CH2), 31.0 (CH2), 31.4 (C), 130.8 (C), 131.1 (C), 131.6 (d, JC,P = 2.6 Hz, CH), 131.9 (d,
2
2
(CH2), 54.7 (d, JC,P = 2.9 Hz, NCH2), 68.2 (d, JC,P = 3.3 Hz, JC,P = 2.6 Hz, CH), 132.1, 132.3, 132.5, 132.6, 132.8 (C), 133.9
3
NCH), 73.0 (OCH), 126.7, 127.1, 127.4, 127.8, 128.0, 128.1, 128.5,
(=CHPh), 136.9 (C), 137.2 (d, JC,P = 4.8 Hz, NCH2CH=), 137.8
1
130.2 (d, JC,P = 81 Hz, C-P), 131.5 (d, JC,P = 2.6 Hz, CH), 131.9
(C), 137.9 (C), 139.9 (C), 162.2 (CO2Et) ppm. 31P NMR (CDCl3,
(d, JC,P = 2.5 Hz, CH), 132.35, 132.40, 132.47, 132.53, 137.0 (d, 121 MHz): δ = 27 ppm. HRMS: calcd. for C27H26NNaO3P
3JC,P = 5.1 Hz, NCH2CH=),138.0 (d, JC,P = 5.6 Hz, C), 142.4 (d,
JC,P = 2.4 Hz, C), 161.7 (CO2Cy) ppm. 31P NMR (CDCl3,
121 MHz): δ = 27 ppm. HPLC: Chiracel AD, heptane/iPrOH
466.1548; found 466.1553. HPLC: Chiracel AD, heptane/iPrOH
(80:20), 1 mL/min, tR = 6.7 min for the major (R) enantiomer, tR
= 9.7 min for the (S) enantiomer.
(80:20), 1 mL/min, tR = 6.6 min for the (R) enantiomer, tR
8.8 min for the (S) enantiomer.
=
Ethyl 1-(Diphenylphosphinoyl)-2,5-dihydro-2-(2-styryl)pyrrole-3-car-
boxylate (3d): Purification of 3d was performed by column
chromatography on alumina with heptanes/EtOAc (1:1) as the elu-
ent. 1H NMR (CDCl3, 300 MHz): δ = 1.14 (t, J = 7.2 Hz, 3 H,
Me), 4.0–4.2 (m, 4 H, OCH2 + NCH2), 5.04 (m, 1 H, NCH), 5.78
Pyrroline 4a slowly dehydrogenated into the corresponding pyrrole.
An authentic sample of cyclohexyl 1-(diphenylphosphinoyl)-2-
phenylpyrrole-3-carboxylate was obtained by the DDQ oxidation
of 4a: 1H NMR (CDCl3, 500 MHz): δ = 1.0–1.6 (10 H), 4.66 (d, JA,B = 15.6 Hz, 1 H, =CHPh), 5.91 (dd, J = 15.6, 7.8 Hz, 1
3
3
(OCH), 6.55 (t, J = 3.5 Hz, 1 H, CH), 6.72 (t, J = 3.0 Hz, 1 H,
H, CH=CHPh), 6.74 (s, 1 H, NCH2CH=), 7.0–7.9 (Ph) ppm. 13C
CH), 6.98–7.05 (4 H), 7.1 (1 H), 7.4 (4 H), 7.5–7.6 (6 H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 14.1 (Me), 53.6 (NCH2), 60.4
NMR (CDCl3, 125 MHz): δ = 23.2 (CH2), 25.3 (CH2), 31.2 (CH2), (OCH2), 66.9 (NCH), 126.6, 127.5, 128.1–128.7, 131.6, 131.9–
2
2
71.9 (OCH), 112.0 (d, JC,P = 7.4 Hz, NCH), 120.0 (d, JC,P
=
132.1, 132.5, 132.6, 132.7, 136.0 (d, JC,P = 5.6 Hz, C), 136.6 (C),
6.0 Hz, C), 124.5 (d, 3JC,P = 5.7 Hz, CH), 126.7, 128.0, 128.6, 128.7,
129.4 (C), 130.4 (C), 131.2 (C), 131.7, 132.0, 132.1, 132.8, 142.2 (d,
JC,P = 4.3 Hz, C), 163.7 (CO2Cy) ppm. 31P NMR (CDCl3,
121 MHz): δ = 22 ppm.
137.9 (d, JC,P = 5.6 Hz, NCH2CH=), 162.4 (CO2Et) ppm. 31P
3
NMR (CDCl3, 121 MHz): δ = 26 ppm. HRMS: calcd. for
C27H26NNaO3P 466.1548; found 466.1539.
Ethyl 2-(3-Bromophenyl)-1-(diphenylphosphinoyl)-2,5-dihydropyr-
Ethyl 1-(Diphenylphosphinoyl)-2,5-dihydro-2-(1-naphthyl)pyrrole-3- role-3-carboxylate (3e): Purification of 3e was performed by col-
carboxylate (3b): Purification of 3b was performed by column
umn chromatography on silica gel with EtOAc as the eluent. 1H
chromatography on silica gel with heptanes/EtOAc (3:7) as the elu-
NMR (CDCl3, 500 MHz): δ = 1.11 (t, J = 7.0 Hz, 3 H, Me), 3.9–
ent (Rf = 0.2). Colourless oil. 1H NMR (CDCl3, 300 MHz): δ = 4.1 (m, 2 H, OCH2), 4.31 (dm, 2J = 17.1, J = 7, 5, 1.9 Hz, 1 H,
2
0.81 (t, J = 7.2 Hz, 3 H, Me), 3.82 (q, J = 7.2 Hz, 2 H, OCH2), NCH2), 4.42 (dm, J = 17, J = 11 Hz, 1 H, NCH2), 5.47 (m, 1 H,
4.40 (dm, J = 17.1 Hz, 1 H, NCH2), 4.47 (m, 1 H, NCH2), 6.42 NCH), 6.84 (t, J = 1.5 Hz, 1 H), 6.87 (d, J = 8.0 Hz, 1 H), 6.91 (s,
(br., 1 H, NCH), 6.7 (2 H), 6.9 (2 H), 7.1 (1 H), 7.2–7.4 (8 H), 7.6 1 H), 7.0 (t, J = 7.5 Hz, 1 H), 7.2–7.3 (3 H), 7.4–7.5 (3 H), 7.5–7.6
(3 H), 7.7 (2 H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 13.6 (Me),
(3 H), 7.8 (2 H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 13.9 (Me),
54.8 (NCH2), 60.5 (OCH2), 123.16, 124.95, 125.07, 125.44, 127.50, 54.7 (NCH2), 60.9 (OCH2), 68.1 (NCH), 122.0 (C), 126.1, 128.1,
127.67, 128.02, 128.49, 128.66, 131.2 (d, JC,P = 2 Hz, CH), 131.8 (d, 128.3, 128.6, 128.8, 129.5, 130.3, 130.6, 131.9–132.5, 136.8 (C),
3
3
JC,P = 2 Hz, CH), 132.10, 132.22, 132.34, 136.8 (d, JC,P = 5.0 Hz,
137.7 (d, JC,P = 4.7 Hz, NCH2CH=), 144.7 (C), 162.2 (CO2Et)
Eur. J. Org. Chem. 2009, 146–151
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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149

N. Pinto, N. Fleury-Brégeot, A. Marinetti
FULL PAPER
ppm. 31P NMR (CDCl3, 121 MHz): δ = 27 ppm. HRMS: calcd.
for C25H23BrNNaO3P 518.0497; found 518.0489. HPLC: Chiracel
AD, heptane/iPrOH (80:20), 1 mL/min, tR = 7.9 min for the major
(R) enantiomer, tR = 8.9 min for the (S) enantiomer.
60.4 (OCH2), 63.8 (NCH), 116.9 (CH2=CHAr), 126.4 (CH), 126.6
(CH), 127.8 (CH), 128.1 (CH), 134.5 (CH), 137.1 (C), 139.5 (C),
141.3 (NCH2CH=), 163.2 (CO2Et) ppm. HRMS: calcd. for
C15H18NO2 244.1338; found 244.1331.
Ethyl 1-(Diphenylphosphinoyl)-2,5-dihydro-2-(4-nitrophenyl)pyrrole- Ethyl 2,5-Dihydro-2-(2-styryl)-1H-pyrrole-3-carboxylate (5d):
A
3-carboxylate (3f): Purification of 3f was performed by column
chromatography on silica gel with EtOAc as the eluent. H NMR
(CDCl3, 500 MHz): δ = 1.12 (t, J = 7.0 Hz, 3 H, Me), 3.9–4.1 (m,
2 H, OCH2), 4.3–4.4 (m, 2 H, NCH2), 5.65 (br., 1 H, NCH), 6.94
(s, 1 H, HC=), 7.06 (d, J = 8.5 Hz, 2 H), 7.23 (m, 2 H), 7.4–7.5
(m, 3 H), 7.5–7.6 (m, 3 H), 7.8 (2 H), 7.96 (d, J = 8.3 Hz, 2 H)
solution of pyrroline 3d (0.22 g, 0.5 mmol) in MeOH (4 mL) was
1
treated with aqueous HCl (1 mL, 12 ). The mixture was stirred
overnight, the solvent was evaporated, and the residue was diluted
with aqueous HCl. The aqueous mixture was extracted with EtOAc
and then treated with NaOH until pH ≈ 10. The aqueous layer was
extracted with EtOAc, and evaporation of the solvent afforded pure
ppm. 13C NMR (CDCl3, 75 MHz): δ = 13.9 (Me), 55.0 (NCH2), 5d (51 mg, 41%). 1H NMR (CDCl3, 300 MHz): δ = 1.18 (t, J =
60.9 (OCH2), 67.8 (NCH), 123.2, 128.3, 128.4, 128.7, 128.8, 129.5 7.2 Hz, 3 H, Me), 3.83 (br. d, J = 17.1 Hz, 1 H, NCH2), 3.9 (br. d,
(C), 129.8 (C), 131.2 (C), 131.6 (C), 132.0, 132.1, 132.3, 136.4 (d,
1 H, NCH2), 4.1–4.2 (2 H, OCH2), 4.78 (br., 1 H, NCH), 6.16 (dd,
JC,P = 4.9 Hz, C) 138.3 (d, JC,P = 5.0 Hz, NCH2CH=), 146.9 (C), 3J = 15.9, 7.5 Hz, 1 H, CH=CHPh), 6.55 (d, 3J = 15.9 Hz, 1 H,
149.8 (C), 161.7 (CO2Et) ppm. 31P NMR (CDCl3, 121 MHz): δ CH=CHPh), 6.81 (1 H, NCH2CH=), 7.1–7.3 (5 H, Ph) ppm. 13C
= 26 ppm. HRMS: calcd. for C25H23N2NaO5P 485.1242; found
485.1241.
NMR (CDCl3, 75 MHz): δ = 14.2 (Me), 53.3 (NCH2), 60.4
(OCH2), 65.8 (NCH), 126.5 (CH), 127.2 (CH), 128.5 (CH), 129.7
(CH=CHPh), 130.7 (CH=CHPh), 136.9 (C), 140.9 (NCH2CH=),
163.5 (CO2Et) ppm. MS (ESI): m/z = 244 [M + H]+ (100%).
Removal of the DPP Protecting Group from Pyrrolines 3
Ethyl 2,5-Dihydro-2-phenyl-1H-pyrrole-3-carboxylate (5a): To a
solution of pyrroline 3a (1.0 g, 2.4 mmol) in CH2Cl2 (25 mL) at
0 °C were added successively MeOH and BF3·OEt2 (3 mL,
24 mmol). The mixture was stirred at 0 °C for 30 min and then at
r.t. for 4 h. After hydrolysis, the aqueous layer was separated,
treated with K2CO3 until pH ≈ 10 and extracted with CH2Cl2. The
evaporation of the solvent afforded pyrroline 5a as a pale yellow
Ethyl 2,5-Dihydro-2-(4-nitrophenyl)-1H-pyrrole-3-carboxylate (5f):
A solution of pyrroline 3f (0.20 g, 0.43 mmol) in MeOH (6 mL) was
treated with aqueous HCl (1 mL, 12 ). The mixture was stirred
overnight, the solvent was evaporated, and the residue was taken
up in CH2Cl2/Et3N. The volatiles were evaporated, and the residue
was purified by column chromatography with EtOAc as the eluent.
1
Yield 45 mg (40%). H NMR (CDCl3, 300 MHz): δ = 1.16 (t, J =
1
oil. Yield 0.49 g (95%). H NMR (D2O, 300 MHz): δ = 1.04 (t, J
7.2 Hz, 3 H, Me), 4.0–4.2 (4 H, NCH2 + OCH2), 5.38 (br., 1 H,
= 7.2 Hz, 3 H, Me), 4.04 (q, J = 7.2 Hz, 2 H, OCH2), 4.29 (dt, J
= 17.4, J ≈ 1.8 Hz, 1 H, NCH2), 4.37 (dt, J = 17.4, J ≈ 2.5 Hz, 1
H, NCH2), 5.74 (t, J ≈ 1.5 Hz, 1 H, NCH), 7.12 (q, J ≈ 2.0 Hz, 1
H, NCH2CH=), 7.4–7.5 (5 H, Ph) ppm. 13C NMR (D2O, 75 MHz):
δ = 13.0 (Me), 51.4 (NCH2), 62.4 (OCH2), 67.5 (NCH), 128.0 (CH),
129.5 (CH), 130.3 (CH), 132.95 (C), 133.07 (C), 138.2
(NCH2CH=), 163.1 (CO2Et) ppm. MS (ESI): m/z = 218 [M +
H]+.
NCH), 7.04 (1 H, NCH2CH=), 7.51 (d, 3J = 8.7 Hz, 2 H, Ar), 8.18
3
(d, J = 8.7 Hz, 2 H, Ar) ppm. 13C NMR (CDCl3, 75 MHz): δ =
14.2 (Me), 53.3 (NCH2), 60.8 (OCH2), 67.4 (NCH), 123.9 (CH),
128.4 (CH), 137.0 (C), 141.6 (NCH2CH=), 147.5 (C), 151.1 (C),
163.0 (CO2Et) ppm. HRMS: calcd. for C13H15N2O4 263.1032;
found 263.1026.
Studies on the Diastereoselective [3+2] Cyclisation Reactions Be-
tween Menthyl 2-Butynoate and Imines: Scheme 3. All reactions
were performed in CH2Cl2 at r.t., according to the General Pro-
cedure B, with either P(iBu)3 or phosphepine (S)-1a as the catalyst.
Reactions of N-DPP-imine 2a with d- or l-menthyl butynoate (En-
tries 2 and 3 in Scheme 3) were performed on a 0.3 mmol scale.
Ethyl 2,5-Dihydro-2-(1-naphthyl)-1H-pyrrole-3-carboxylate (5b):
The method described above for the deprotection of 3a was applied
to the synthesis of 5b from 3b on a 0.5 mmol scale. Compound 5b
was obtained in 42% isolated yield (55 mg) as a pale yellow oil. 1H
NMR (CDCl3, 300 MHz): δ = 0.97 (t, J = 7.2 Hz, 3 H, Me), 3.85
(dm, J = 17.5 Hz, 1 H, NCH2), 3.9–4.0 (3 H, OCH2 + NCH2), 5.92
(br., 1 H, NCH), 7.05 (q, J ≈ 2.0 Hz, 1 H, NCH2CH=), 7.17 (dd,
J = 7.2, 1.2 Hz, 1 H), 7.31 (t, J = 7.7 Hz, 1 H), 7.39 (t, J = 7.5 Hz,
1 H), 7.45 (t, J = 7.0 Hz, 1 H), 7.67 (d, J = 8.5 Hz, 1 H), 7.76 (d,
J = 8.0 Hz, 1 H), 8.18 (d, J = 8.5 Hz, 1 H) ppm. 13C NMR (CDCl3,
75 MHz): δ = 14.0 (Me), 53.6 (NCH2), 60.3 (OCH2), 63.8 (NCH),
123.5, 123.7, 125.4, 125.7, 126.3, 128.1, 128.7 (CH), 131.6 (C),
134.1 (C), 137.1 (C), 138.7 (C), 142.3 (NCH2CH=), 163.6 (CO2Et)
ppm. MS (ESI): m/z = 290 [M + Na]+ (30%), 268 [M + H]+
(100%).
1
The crude reaction mixtures were analyzed by H NMR to deter-
mine the diastereomeric ratios. The filtration of the reaction mix-
ture on a short silica gel column (heptanes/EtOAc, 30:70, as the
eluent, Rf = 0.2) afforded samples of pyrrolines 6 (or 7), which
contained variable amounts of the starting imine 2a. These samples
allowed for the characterisation of pyrrolines CS-6 and CS-7 by 1H
NMR spectroscopy. MS (ESI) m/z 550 [M + Na]. Diastereomeric
ratios were measured from the integration of the menthyl OCH
signals.
Pyrroline CS-6 was obtained as the major epimer of the 91:9 mix-
ture from the reaction of l-menthyl 2-butynoate with 2a promoted
by (S)-1a. 1H NMR (500 MHz, CDCl3, selected data): δ = 0.61 (d,
3J = 7.0 Hz, 3 H, CHMe2), 0.80 (d, 3J = 6.5 Hz, 3 H, CHMe2),
Ethyl 2,5-Dihydro-2-(2-vinylphenyl)-1H-pyrrole-3-carboxylate (5c):
A solution of pyrroline 3c (108 mg, 0.24 mmol) in MeOH (3 mL)
was treated with aqueous HCl (0.5 mL, 12 ) at r.t. The mixture
was stirred overnight, the volatiles were removed, and the crude
reaction mixture was purified by column chromatography with
EtOAc as the eluent. Compound 5c (Rf = 0.3) was obtained in
3
0.83 (d, J = 7.0 Hz, 3 H, CHMe), 0.8–1.7 (9 H), 4.28–4.35 (m, 1
H, NCH2), 4.40–4.46 (m, 1 H, NCH2), 4.52 (td, J = 11.0, 4.0 Hz,
1 H, OCH), 5.55 (1 H, NCH), 6.82 (2 H), 7.0–7.6 (12 H), 7.8 (2
H) ppm.
1
55% isolated yield (33 mg) as a colourless oil. H NMR (CDCl3,
300 MHz): δ = 1.03 (t, J = 7.2 Hz, 3 H, Me), 3.1 (br., 1 H, NH), Pyrroline CS-7 was obtained as the major epimer of the Ͼ95:5 mix-
3
2
4.0–4.1 (4 H, NCH2 + OCH2), 5.29 (dd, J = 11.1, J = 1.5 Hz, 1
ture from the reaction of d-menthyl 2-butynoate with 2a promoted
3
2
H, CH2=CHAr), 5.50 (br., 1 H, NCH), 5.58 (dd, J = 17.4, J =
by (S)-1a. 1H NMR (500 MHz, CDCl3, selected data): δ = 0.47 (d,
1.5 Hz, 1 H, CH2=CHAr), 6.97 (1 H, NCH2CH=), 7.0–7.4 (5 H) 3J = 6.5 Hz, 3 H, CHMe2), 0.57 (d, 3J = 7.0 Hz, 3 H, CHMe2),
ppm. 13C NMR (CDCl3, 75 MHz): δ = 14.0 (Me), 53.4 (NCH2), 0.87 (d, 3J = 6.5 Hz, 3 H, CHMe), 0.8–1.4 (6 H), 1.5–1.6 (2 H),
150
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Eur. J. Org. Chem. 2009, 146–151

Enantioselective Binaphthophosphepine-Promoted [3+2] Annulations
1.84 (1 H), 4.24–4.42 (m, 2 H, NCH2), 4.60 (td, J = 10.5, 4.0 Hz,
1 H, OCH), 5.55 (1 H, NCH), 6.8 (m, 2 H), 6.9–7.9 (14 H) ppm.
[1]
[2]
S. Gladiali, A. Dore, D. Fabbri, O. De Lucchi, M. Manassero,
Tetrahedron: Asymmetry 1994, 5, 511–514.
The configuration of pyrroline CS-7 was assigned as follows. The
crude mixture of pyrrolines obtained from d-menthyl butynoate
and imine 2a was submitted to the N-deprotection procedure with
BF3·OEt2, according to the procedure described for the deprotec-
tion of 3a above. The crude secondary pyrroline thus obtained was
reacted with excess tosyl chloride in aqueous NaOH/CH2Cl2, with
BnEt3NCl as the catalyst, at r.t. for 4 h. The organic phase was
separated, washed with water, dried with MgSO4, and the solvents
were evaporated. 1H NMR analysis showed the presence of the
known pyrrolines CS-7 and CR-6 (see below) in a 9:1 ratio.
For representative references, see: a) K. Junge, G. Oehme, A.
Monsees, T. Riermeier, U. Dingerdissen, M. Beller, Tetrahedron
Lett. 2002, 43, 4977–4980; b) K. Junge, B. Hagemann, S. En-
thaler, G. Oehme, M. Michalik, A. Monsees, T. Riermeier, U.
Dingerdissen, M. Beller, Angew. Chem. Int. Ed. 2004, 43, 5066–
5069; c) K. Junge, B. Hagemann, S. Enthaler, A. Spannenberg,
M. Michalik, G. Oehme, A. Monsees, T. Riermeier, M. Beller,
Tetrahedron: Asymmetry 2004, 15, 2621–2631; d) E. Alberico,
I. Nieddu, R. Taras, S. Gladiali, Helv. Chim. Acta 2006, 89,
1716–1729; e) S. Enthaler, G. Erre, K. Junge, J. Holz, A.
Börner, E. Alberico, I. Nieddu, S. Gladiali, M. Beller, Org. Pro-
cess Res. Dev. 2007, 11, 568–577.
a) R. P. Wurz, G. C. Fu, J. Am. Chem. Soc. 2005, 127, 12234–
12235; b) J. E. Wilson, G. C. Fu, Angew. Chem. Int. Ed. 2006,
45, 1426–1429.
a) N. Fleury-Brégeot, L. Jean, P. Retailleau, A. Marinetti, Tet-
rahedron 2007, 63, 11920–11927; b) A. Panossian, N. Fleury-
Brégeot, A. Marinetti, Eur. J. Org. Chem. 2008, 3826–3833.
a) Z. Xu, X. Lu, Tetrahedron Lett. 1997, 38, 3461–3464; b) Z.
Xu, X. Lu, J. Org. Chem. 1998, 63, 5031–5041.
The reactions of the N-Ts-imine 2aЈ with d- or l-menthyl butynoate
(Scheme 3) were performed on a 0.3 mmol scale with a 1:1 alkyne/
imine ratio, in CH2Cl2 (1 mL), at r.t.
[3]
[4]
Starting from l-menthyl 2-butynoate, imine 2aЈ and P(iBu)3 as the
catalyst (10 mol-%), a 54:46 mixture of 6Ј and 7Ј was obtained
(Scheme 3, Entry 4). The mixture was purified by column
chromatography on silica gel with heptane/EtOAc (7:3, Rf = 0.4).
[5]
[6]
Starting from l-menthyl 2-butynoate, imine 2aЈ and phosphane (S)-
1a as the catalyst (10 mol-%), a 33:67 mixture of 7Ј and 6Ј was
obtained (Scheme 3, Entry 5).
a) G.-L. Zhao, M. Shi, J. Org. Chem. 2005, 70, 9975–9984; b)
X.-F. Zhu, C. E. Henry, O. Kwon, Tetrahedron 2005, 61, 6276–
6282.
Starting from d-menthyl 2-butynoate, imine 2aЈ and phosphane (S)-
1a as the catalyst (10 mol-%), a 78:22 mixture of 7Ј and 6Ј was
obtained (Scheme 3, Entry 6).
[7]
[8]
S. Castellano, H. D. G. Fiji, S. S. Kinderman, M. Watanabe, P.
de Leon, F. Tamanoi, O. Kwon, J. Am. Chem. Soc. 2007, 129,
5843–5845.
a) B. E. Segelstein, T. T. Wager, W. M. Welch (Pfizer Inc.), US
Patent Appl. 2005/272800, 2005; b) T. T. Wager, W. M. Welch,
B. T. O’Neill (Pfizer Prod. Inc.), WO 2004/110996, 2004; c)
J. M. Humphrey, T. A. Chappie (Pfizer Prod. Inc.), WO 2005/
115976, 2005.
The use of N-DPP-benzaldimine in the [3+2] cyclisation reac-
tion with ethyl 2,3-butadienoate was mentioned by Lu in his
initial report. Low conversion rates were observed. See ref.[5b]
For additional examples of enantioselective cyclisations of N-
Ts-imines promoted by chiral phosphanes, see: a) L. Jean, A.
Marinetti, Tetrahedron Lett. 2006, 47, 2141–2145; b) Scherer,
A. Gladysz, J. A. J. Gladysz, Tetrahedron Lett. 2006, 47, 6335–
6337.
D-Menthyl 2,5-Dihydro-2-phenyl-1-tosylpyrrole-3-carboxylate (CS-
7Ј): Compound CS-7Ј was isolated in diastereomerically pure form
by crystallization of the enriched mixtures obtained from d-menthyl
2-butynoate. The NMR spectroscopic data for CS-7Ј have been re-
1
ported previously. Selected, representative H NMR spectroscopic
[9]
3
data: (300 MHz, CDCl3): δ = 0.43 (d, J = 7.0 Hz, 3 H, CHMe2),
3
0.56 (d, J = 6.8 Hz, 3 H, CHMe2), 6.89 (1 H, NCH2CH=) ppm.
[10]
C28H35NO4S (481.65): calcd. C 69.82, H 7.32; found C 69.63, H
7.15.
D-Menthyl 2,5-Dihydro-2-phenyl-1-tosylpyrrole-3-carboxylate (CR-
6Ј): Compound CR-6Ј was isolated from a 9:1 mixture with CS-7Ј.
This sample was isolated by crystallization of the epimeric mixture
obtained from d-menthyl 2-butynoate and P(iBu)3 as the catalyst.
1H NMR (500 MHz, CDCl3): δ = 0.64 (d, 3J = 6.9 Hz, 3 H,
[11] Y.-Q. Fang, E. N. Jacobsen, J. Am. Chem. Soc. 2008, 130,
5660–5661.
[12] W. B. Jennings, C. J. Lovely, Tetrahedron 1991, 47, 5561–5568.
[13] We also observed the conversion of pyrrolines into pyrroles
when pyrrolines were stored with contact to air at room temp.
NMR spectroscopic data for pyrroles derived from 3a and 4a
are given in the experimental section.
[14] After the submission of this manuscript, the use of thiophos-
phoryls as easily removable N-protecting groups in imine-allene
[3+2] cyclizations has been reported: B. Zhang, Z. He, S. Xu,
G. Wu, Z. He, Tetrahedron 2008, 64, 9471–9479.
[15] H. M. I. Osborn, J. B. Sweeney, B. Howson, Synlett 1994, 145–
147.
[16] Toluene afforded lower enantioselectivity than did CH2Cl2.
[17] A similar trend was noticed by Jacobsen in analogous cyclisa-
tions promoted by a phosphinothiourea catalyst. See ref.[11]
[18] a) J. B. Sweeney, A. A. Cantrill, A. B. McLaren, S. Thobhani,
Tetrahedron 2006, 62, 3681–3693; b) D. M. Ballweg, R. C.
Miller, D. L. Gray, K. A. Scheidt, Org. Lett. 2005, 7, 1403–
1406.
3
3
CHMe2), 0.79 (d, J = 6.7 Hz, 3 H, CHMe2), 0.86 (d, J = 7.4 Hz,
3 H, CHMe), 0.8–1.3 (4 H), 1.6–1.7 (5 H), 2.38 (s, 3 H, Me), 4.37
2
3
4
(ddd, JA,B = 16.9, J = 5.8, J = 1.7 Hz, 1 H, NCH2), 4.5–4.6 (2
H, NCH2 + OCH), 5.75 (1 H, NCH), 6.76 (1 H, NCH2CH=), 7.14
(d, J = 8.1 Hz, 2 H, Ts), 7.2–7.3 (5 H, Ph), 7.42 (d, J = 8.1 Hz, 2
H, Ts) ppm. 13C NMR (CDCl3): δ = 16.4 (Me), 20.6 (Me), 21.4
(Me), 21.9 (Me), 23.6 (CH2), 26.5 (CHMe2), 31.2 (CHMe), 34.0
(CH2), 40.1 (CH2), 46.9 (CH), 54.9 (NCH2), 69.1 (NCH), 75.0
(OCH), 127.1, 127.8, 128.1, 129.4, 134.8 (NCH2CH=), 135.7 (C),
136.5 (C), 139.4 (C), 143.2 (C), 161.5 (CO2Men) ppm. MS (ESI):
m/z = 504 [M + Na]+. HRMS: calcd. for C28H35NNaO4S 504.2185;
found 504.2184.
Acknowledgments
[19] J. W. J. Kennedy, D. G. Hall, J. Org. Chem. 2004, 69, 4412–
We are grateful to Dr. Thomas Riermeier and Dr. Renat Kadyrov
(Evonik Degussa GmbH, Hanau, Germany) for a generous gift of
the chiral phosphane 1a. This work was performed within the
CP2D program, 2007, of the Agence Nationale de la Recherche
(ANR).
4428.
[20] Y. K. Shim, J. I. Youn, J. S. Chun, T. H. Park, M. H. Kim, W. J.
Kim, Synthesis 1990, 753–754.
Received: June 20, 2008
Published Online: November 25, 2008
Eur. J. Org. Chem. 2009, 146–151
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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