The effect of phase-transfer catalysis in the 1,3-dipolar cycloaddition reactions of azomethine ylides - Synthesis of substituted prolines using AgOAc and inorganic base in substoichiometric amounts

Article abstract of DOI:10.1002/1099-0690(200105)2001:10<1971::AID-EJOC1971>3.0.CO;2-U

The 1,3-dipolar cycloaddition reaction between imino ester 1a and ethyl acrylate, employing phase-transfer catalysis (PTC) conditions in the presence of substoichiometric amounts of Lewis acids and inorganic bases, has been studied for the first time. Effects were analysed in the order: solvent, phase transfer agent, inorganic base, metal salt (Lewis acid), quantity of metal salt and the substituents on the 1,3-dipole. The two best methods found in this study [method A: THF, TBAC (10 mol-%), KOH (10 mol-%), AgOAc (10 mol-%), room temp.; method B: toluene, KOH (10 mol-%), AgOAc (10 mol-%), room temp.] were then applied to the cycloaddition reaction of the imino esters 1a and 5a (derived from alanine and glycine) with alkenes. These results were compared to those obtained under thermal 1,3-dipolar cycloaddition reaction conditions and to those previously reported using metallodipoles in the presence of organic bases.

Full text of DOI:10.1002/1099-0690(200105)2001:10<1971::AID-EJOC1971>3.0.CO;2-U

FULL PAPER
The Effect of Phase-Transfer Catalysis in the 1,3-Dipolar Cycloaddition
Reactions of Azomethine Ylides ؊ Synthesis of Substituted Prolines Using
AgOAc and Inorganic Base in Substoichiometric Amounts
[a]
[b]
[a]
[a]
´
´
´
Jesus Casas, Ronald Grigg, Carmen Najera,* and Jose M. Sansano*
Dedicated to Pierre and Lucette Duhamel on the occasion of their retirement
Keywords: Azomethine ylides / Cycloadditions / Phase-transfer catalysis / Prolines / Silver
The 1,3-dipolar cycloaddition reaction between imino ester
1a and ethyl acrylate, employing phase-transfer catalysis
AgOAc (10 mol-%), room temp.; method B: toluene, KOH (10
mol-%), AgOAc (10 mol-%), room temp.] were then applied
(PTC) conditions in the presence of substoichiometric to the cycloaddition reaction of the imino esters 1a and 5a
amounts of Lewis acids and inorganic bases, has been
studied for the first time. Effects were analysed in the order:
solvent, phase transfer agent, inorganic base, metal salt
(Lewis acid), quantity of metal salt and the substituents on
the 1,3-dipole. The two best methods found in this study
[method A: THF, TBAC (10 mol-%), KOH (10 mol-%),
(derived from alanine and glycine) with alkenes. These re-
sults were compared to those obtained under thermal 1,3-
dipolar cycloaddition reaction conditions and to those previ-
ously reported using metallodipoles in the presence of or-
ganic bases.
Introduction
inconvenience of this process is the generation of Michael
adducts in variable proportions, which can occasionally be
overcome by modifying certain reaction conditions. While
the regiochemistry is clearly dependent on the
HOMOϪLUMO interaction,[10] the yield, the diastereose-
lectivity and the Michael addition product/cycloadduct ra-
tio are strongly influenced by steric[11] and electronic ef-
fects.[10,12,13] In fact, semiempirical calculations employing
N-metallated azomethine ylides and nitroalkenes have
found that the coordination between metal cation, solvent,
dipolarophile and 1,3-dipole is a decisive factor in the reac-
tion course.[9,12] Silver(I) and lithium azomethine ylides are
widely used for this purpose.[2,7,8] Other metals have been
also tested, with variable results.[14] The common practice
is to employ excess or stoichiometric amounts of AgI or LiI
salts and excess of Et3N or 1,8-diazabicyclo[5.4.0]undec-7-
ene (DBU) as bases. As well as this, substoichiometric
quantities of metal salts have given good results, although
little attention has been paid to this fact. 1,3-Dipolar cyclo-
addition reactions between azomethine ylides and nitro-
olefins[12] and chiral enones[15] using 0.15 equiv. of AgOAc
and other examples using substoichiometric amounts of
LiBr[16] have been reported, but all involved an excess of
Et3N or DBU. Additionally, reactions performed in the
presence of AgI or LiI salts and triethylamine, all in sub-
stoichiometric quantities, gave moderate yields but no im-
provement in the diastereoselectivity and chemical yields
obtained using stoichiometric amounts both of AgI salt and
of base.[14e]
Cycloaddition reactions are very important transforma-
tions in synthesis, thanks to their simultaneous generation
of several stereogenic centres. Control over regioselectivity,
facial selectivity and endo/exo selectivity is crucial in order
to achieve high diastereoselectivities and enantioselectivi-
ties.[1] In this context, the 1,3-dipolar cycloaddition reaction
is one of the best and most useful methods for the construc-
tion of five-membered rings in a convergent and stereocon-
trolled manner.[2] In particular, the [3ϩ2] cycloaddition re-
action between azomethine ylides and alkenes is a direct
route to substituted prolines[1Ϫ3] Ϫ which are valuable sub-
strates in synthetic organic chemistry,[4] pharmacology,[5]
and biology[6] Ϫ and also to other structures with pyrrolid-
ine nuclei.[2,7c]
This cycloaddition reaction can be performed by using
various different reaction conditions,[2d,8] the more reliable
and elegant procedure being the in situ generation of stabil-
ized N-metallated azomethine ylides followed by further re-
action with alkenes at room temperature.[2a,2d,8] The reac-
tion with N-substituted azomethine ylides exhibits a high
degree of endo selectivity through a stepwise mechanism,
as has been recently reported in the literature.[9] The main
[a]
Department of Organic Chemistry, Faculty of Sciences,
University of Alicante,
Apdo. 99, 03080 Alicante, Spain
Fax: (internat.) ϩ 34-96/590-3549
E-mail: cnajera@ua.es and jmsansano@ua.es
[b]
Molecular Innovation, Diversity and Automated Synthesis
(MIDAS) Centre, School of Chemistry, Leeds University,
Leeds LS2 9JT, United Kingdom
Fax: (internat.) ϩ 44-113/233-6501
E-mail: r.grigg@chem.leeds.ac.uk
Excesses of tetraalkylammonium alkoxides have been
used for very clean syntheses of Michael adducts,[8a] but to
the best of our knowledge, phase-transfer catalysis (PTC)
Eur. J. Org. Chem. 2001, 1971Ϫ1982
WILEY-VCH Verlag GmbH, 69451 Weinheim, 2001
1434Ϫ193X/01/0510Ϫ1971 $ 17.50ϩ.50/0
1971

´
J. Casas, R. Grigg, C. Najera, J. M. Sansano
FULL PAPER
tions when using inorganic bases such as NaOH and
KOH.[20] They are easily prepared using known procedures,
starting from the corresponding α-amino acids, by trans-
formation into the isopropyl esters, followed by imine
formation in water.[7j][8c] These imino esters are suitable pre-
cursors for obtaining substituted prolines by means of 1,3-
dipolar cycloaddition reactions with electrophilic alkenes at
room temperature, either by using metal salts or thermally.
In search of the best reaction conditions for this kind of
cycloaddition reactions, we started with an initial reaction
(Scheme 1) and modified it in this order: solvent, PTC cata-
lyst, base, Lewis acid (metal salt), quantity of Lewis acid
and the substituents on the dipole.
Scheme 1
has not been applied to cycloaddition reactions between
1,3-metallodipoles and alkenes. PTC has become a widely
used tool for organic chemists and chemical engineers, who
recognize the potential profit opportunities likely to result
from implementing PTC. Non-asymmetric and asymmetric
organic transformations employing PTC conditions are in-
creasing very rapidly, together with discussions about their
mechanisms.[17] Asymmetric synthesis of α-amino acids by
CϪC bond formation using Schiff base esters and chiral
tetraalkylammonium salts constitutes one of the most im-
portant achievements in this field.[18]
In this article we will survey the influence of solid-liquid
phase-transfer catalysis in the 1,3-dipolar cycloaddition re-
actions of stabilized azomethine ylides and alkenes when
substoichiometric amounts of both inorganic base and AgI
salts are used. Substituted proline esters can be obtained
regioselectively and diastereoselectively by optimising each
component in the title reaction.[19]
This initial reaction studied was the 1,3-dipolar cycload-
dition between the dipole generated from 1a and ethyl ac-
rylate (1.1 equiv.), in the presence of AgOAc (10 mol-%)
and NaOH (10 mol-%) as base at room temperature
(Scheme 1 and Table 1), testing different solvents without
using any PTC agent. AgOAc was selected because it is gen-
erally the more useful Lewis acid in this type of reaction[14e]
and, on the other hand, an inorganic and economic base
like NaOH can be suited to a solid-liquid PTC system. Un-
der these reaction conditions the cycloaddition products
2aa were mainly obtained, rather than Michael adducts
3aa. Toluene and dichloromethane afforded almost the
same endo diastereoselectivity; however, the reaction in
toluene was slower (Table 1, Entries 1 and 3). With more
polar aprotic solvents, conversion was complete in only 2 h,
but in all these cases the diastereoselectivity would be al-
most identical and the chemoselectivity lower (Table 1, Ent-
ries 4Ϫ6). The yields of the reaction were quantitative in
all the examples shown in Table 1, except in the cases of
acetonitrile (70%) and DMF (68%). When acetonitrile was
used, the reaction was rapid at the beginning but never re-
Results and Discussion
The precursors of 1,3-dipoles are Schiff base esters de- ached total conversion, affording a 90:10 ratio of endo-2aa/
rived from glycine and alanine, and resistant to PTC condi- exo-2aa (Table 1, Entry 2). Thus, acetonitrile is unsuitable
Table 1. Solvent and PTC agent effects in the 1,3-dipolar cycloaddition reaction between 1a and ethyl acrylate in the presence of AgOAc
(10 mol-%) and NaOH (10 mol-%) at room temperature
Entry
Solvent
Ammoniumsalt
(10 mol-%)
Time
[h]
Conversion
(%)[a]
Product[a][b]
endo-2aa
exo-2aa
3aa
1
2
Toluene
MeCN
CH2Cl2
THF
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
85
70
48
2
100
70
100
100
100
68
100
100
63
100
15
100
100
100
100
100
100
53
92
90
91
82
82
88
33
51
59
73
4
94
90
2
94
71
90
59
8
10
6
0
0
3
3
4
4
14
14
4
5
Et2O
2
4
8
6
DMF
Ϫ
Ϫ
2
7
MeOH
Toluene
Toluene
Toluene
Toluene
THF
2
31
8
36
41
29
23
24
3
8
Adogen 464
TBAB
TBAC
TBAH
TBAC
Adogen 464
TBAH[c]
TBAA
TBAA[c]
TBAC
TBAC
5
9
48
3
12
4
10
11
12
13
14
15
16
17
18
24
7
72
3
THF
1
4
6
THF
0.5
9
18
5
80
1
THF
THF
5
10
4
19
6
CH2Cl2
MeCN
20
24
9
32
[a]
[b]
1
[c]
Determined by GC and based on product 1a. Ϫ
Stereochemistry determined by H NMR (NOESY) experiments. Ϫ Without
NaOH.
1972
Eur. J. Org. Chem. 2001, 1971Ϫ1982

Phase-Transfer Catalysis in the 1,3-Dipolar Cycloaddition Reactions of Azomethine Ylides
FULL PAPER
for use in the reaction under these conditions, unlike when Table 2. Base effect in the cycloaddition reaction between 1a and
ethyl acrylate in THF in the presence of AgOAc (10 mol-%) and
the reaction is carried out in the presence of an excess both
TBAC (10 mol-%) at room temperature
of AgI salt and of organic base.[14e] Polar protic solvents
Product[a][b]
such as methanol (Table 1, Entry 7) inhibited the formation
of the metallo-dipole, giving rise to a 1:1 mixture of diaster-
eomers[8a] and greater quantities of the Michael adduct.
The tendency of polar aprotic solvents to increase the reac-
tion rate is in agreement with previously reported semiem-
pirical calculations.[12] The influence of the temperature was
also studied in toluene, THF and acetonitrile; thus, when
the reaction was performed at 0 °C it became extremely
slow, but gave the same product ratio as the reaction per-
formed at room temperature.
Entry
Base
Time Conversion
(10 mol-%)
[h]
(%)[a]
endo-2aa exo-2aa 3aa
1
2
3
4
5
6
7
K2CO3
LiOH·H2O
NaOH
10
10
7
100
100
100
100
100
100
100
91
89
91
94
73
87
92
2
3
4
3
9
1
8
7
8
5
KOH
7
3
CsOH·H2O
5
24
10
14
12
0
Et3N[c]
DBU[c]
[a]
[b]
Determined by GC and based on product 1a. Ϫ Stereochem-
1
[c]
istry determined by H NMR (NOESY) experiments. Ϫ Reac-
tion run in absence of PTC agent and employing substoichiometric
amounts of base (10 mol-%).
In order to accelerate the reaction in the case of nonpolar
solvents we introduced substoichiometric amounts of some
PTC agents (10 mol-%) studying the effect of them in the
product ratios (Scheme 1 and Table 1). In general, when
Adogen 464 , tetrabutylammonium chloride (TBAC),
tetrabutylammonium hydroxide (TBAH), and tetrabu-
tylammonium acetate (TBAA) were used, the reaction rates
were increased. However, use of tetrabutylammonium
bromide (TBAB) resulted in very low reaction rates because
of the insolubility of the AgBr formed during the course of
the reaction (Table 1, Entry 9). Very disappointing results
were obtained with toluene and acetonitrile under PTC
conditions (Table 1, Entries 8Ϫ11, and 18). The reaction in
dichloromethane was diastereoselective but very slow
(Table 1, Entry 7). The best diastereoselectivities and yields,
in shorter reaction times, were achieved when using THF
as solvent (Table 1, Entries 12 and 15), TBAC and TBAA
being the best phase transfer agents. The reactions per-
formed in the presence of Adogen 464 and TBAH both
took place in 1 h. While Adogen 464 provided good endo
selectivity, TBAH generated a high proportion of Michael
adduct, as has been described[8a] (Table 1, Entries 13 and
14). Surprisingly, when TBAA was used without added
base, the process was faster than the analogous procedure
using NaOH, but with exo-2aa and Michael adduct 3aa
unfortunately being detected in significant amounts. TBAC
proved beneficial in terms of the reaction rates, but was
often detrimental in terms of cycloaddition/Michael addi-
tion product ratios. A significant decrease in stereoselectiv-
ity was observed, especially in Entries 8, 9, 11, and 14 in
Table 1. According to these results, THF proved to be the
best solvent in which to carry out cycloaddition reactions
between 1a and ethyl acrylate under typical PTC condi-
tions. Although TBAC or TBAA produced similar results,
TBAC afforded prolines in shorter reaction times, and so
was used as the PTC agent in subsequent experiments.
vided the best endo selectivity, while use of other bases
(K2CO3, LiOH, and CsOH) resulted in significant quantit-
ies of Michael adducts. Reaction conditions using KOH,
TBAC and AgOAc in THF (method A) resulted in im-
provements in the yield and diastereoselectivity of the reac-
tion with respect to those obtained in the presence of or-
ganic bases (Table 2, Entries 4, 6, and 7). The good diaster-
eoselectivity achieved when using NaOH in toluene without
a PTC agent (Table 1, Entry 1) prompted us to test other
bases such as K2CO3, LiOH, KOH, and CsOH·H2O in this
solvent. Again, the best diastereoselectivity (endo-2aa/exo-
2aa, 97:3) and the fastest reaction time (16 h) at room tem-
perature was obtained when using KOH (Method B).
According to the literature, lithium and silver(I) salts are
recommended for performing 1,3-dipolar cycloaddition re-
actions. Nevertheless, the influence of metal salts was also
examined. Thus, a 10 mol-% of a metal salt (MgCl2, ZnCl2,
MnCl2, LiCl, NiCl2, and CoCl2) was suspended in THF in
the presence of KOH (10 mol-%) and TBAC (10 mol-%).
This resulted in very low diastereoselectivities, providing
Michael adducts 3aa as the major products, with endo ad-
ducts 2aa being obtained in negligible quantities. Imidazoli-
dines, generated from cycloaddition reaction between two
molecules of imino ester 1a, were not detected when MgII,
ZnII, and CoII salts were examined,[8a,14d] again demon-
strating the influence of PTC conditions on the course of
the reaction. The differences in diastereoselection induced
by silver acetate and silver triflate versus that of the other
salts under this reaction conditions is impressive, and so for
this reason, that cation was used for all the cycloaddition
reactions between imino esters 1 and alkenes under solid-
liquid PTC conditions. Apparently, the counterion to the
metal salt did not affect the product ratios, as seen in the
cases of silver acetate and silver triflate.[8a,14d]
The effect of the base (10 mol-%) was also studied, and
Addition of variable quantities of AgOAc resulted in very
so different inorganic bases were examined in THF under significant changes in the cycloaddition reaction between
PTC conditions and in the presence of AgOAc. The results 1a and ethyl acrylate under PTC conditions (Table 3), in
were compared with those obtained using triethylamine and terms of reaction time, conversion and diastereoselectivity.
DBU, both in substoichiometric amounts. According to the Reaction times became shorter when the quantity of
product ratios and reaction times shown in Table 2, inor- AgOAc was increased (Table 3, Entries 1Ϫ4), while larger
ganic bases proved to deliver shorter reaction times. Sodium quantities of Michael adduct 3aa were formed in the ab-
and potassium hydroxides (Table 2, Entries 3 and 4) pro- sence of this salt (Table 3, Entry 7). These results, and those
Eur. J. Org. Chem. 2001, 1971Ϫ1982
1973

´
J. Casas, R. Grigg, C. Najera, J. M. Sansano
FULL PAPER
Table 3. 1,3-Dipolar cycloaddition reaction between 1a and ethyl
acrylate in THF under PTC conditions [TBAC (10 mol-%), KOH
(10 mol-%)], using variable amounts of AgOAc
Table 4. 1,3-Dipolar cycloaddition reaction between 1aϪ1e and
ethyl acrylate
Compound Method Time Conversion
Product[a][b]
Entry AgOAc PTC agent Time Conversion
Product[a][b]
endo-2aa exo-2aa 3aa
Entry
(mol-%) (mol-%)
[h]
(%)[a]
1
[h]
(%)[a]
endo-2aa exo-2aa 3aa
1
2
3
4
5
6
7
100 TBAC (10)
2
100
100
100
100
100
100
73
94
94
94
90
89
87
66
3
3
3
4
4
5
3
3
3
1
2
3
1a
1a
1a
A
B
C
7
100
100
100
94
97
84
3
3
3
0
1
15
10
5
TBAC (10) 5Ϫ6
TBAC (10) 6Ϫ7
TBAC (5) 17
TBAC (1) 65
TBAA (1) 16
10
24
3
15
6
endo-2ba exo-2ba 3ba
1
7
4
5
6
1b
1b
1b
A
B
C
4
33
19
100
100
100
93
100
87
4
0
9
3
0
4
1
0
8
Ϫ
48
31
endo-2ca exo-2ca 3ca
23[c]
Ϫ
Ϫ
0
Ϫ
Ϫ
[a]
[b]
7
8
9
1c
1c
1c
A
B[d]
C
1.5
24
19
100
100
0
70
Ϫ
Ϫ
Determined by GC and based on product 1a. Ϫ Stereochem-
istry determined by H NMR (NOESY) experiments.
1
endo-2da exo-2da 3da
0
100
Ϫ
10
11
12
1d
1d
1d
A[e]
B[e]
C
3
8
19
82
0
0
Ϫ
100[f]
0
previously obtained, confirmed that silver cation is neces-
sary for achieving good diastereoselectivities in short reac-
tion times. TBAC and TBAA (1 mol-%) were added, to-
gether with AgOAc (1 mol-%); both reactions were com-
pleted at the same time (Table 3, Entries 5 and 6) and no
improvement in the diastereoselection was observed. This
result and those in Table 1 confirm that noncolloidal AgCl
was formed in the heterogeneous reaction media. In all
100
100[g]
Ϫ
endo-2ea exo-2ea 3ea
13
14
15
1e
1e
1e
A[e]
B[e]
C
4
72
19
100
100
0
0
Ϫ
0
0
Ϫ
100
100
Ϫ
100[g]
[a]
[b]
Determined by GC and based on product 1. Ϫ
Stereochem-
[c]
1
istry determined by H NMR (NOESY) experiments. Ϫ Other
diastereomer was detected in 7% yield. Ϫ [d] 1.1 equiv. of KOH was
[e]
[f]
cases (with TBAC and TBAA), a fine black suspension was required. Ϫ 4 equiv. of KOH were required. Ϫ Amino ester
was obtained in 61% yield due to hydrolysis of 1d under reaction
conditions. Ϫ
served.
observed at the end of the reaction, presumably due to the
[g]
Only decomposition of the imino ester was ob-
formation of AgOH. The optimal quantity of AgI salt for
this reaction was settled as 10 mol-%, since the results ob-
tained were similar when 15 mol-% of AgI salt was used
(Table 3, Entries 2 and 3).
ries 4Ϫ6). Under these particular reaction conditions, the
o-hydroxybenzaldimine 1c was not a useful substituent be-
cause it required stoichiometric amounts of base to produce
total conversion (Table 4, Entry 8, Method B) and only de-
composition products were obtained, as also occurred in
the thermal reaction. In THF, the reaction was very fast,
with an improved exo-2ca ratio, as semiempirical calcula-
tions with imino esters and nitroalkenes had predicted.[12]
The reaction between 1d (R ϭ Cy) and ethyl acrylate illus-
trated the feasibility of selectively producing either pure
cycloadduct endo-2da or pure Michael adduct 3da by chan-
ging the reaction conditions. Methods A and B, employing
an excess of base, afforded endo-2da in 95% and 3da in 39%
isolated yield, respectively (Table 4, Entries 11 and 10). A
bulkier group, such as tert-butyl, on the imine function
quantitatively afforded the Michael adduct 3ea, whether
method A or method B was employed (Table 4, Entries 13
and 14). This result was in accordance to that previously
reported for imino esters, using LiCl as catalyst.[11,16] Ther-
mal reaction conditions improved neither yield nor diaster-
Scheme 2
Activated aromatic and nonaromatic aldimines of the al- eoselectivity in any case (Table 4, Entries 3, 6, 9, 12, and
anine isopropyl ester were prepared, so as to study the in- 15). All the experiments demonstrated that it was beneficial
fluence of the imine substituent (Scheme 2 and Table 4). to apply PTC to 1,3-dipolar cycloaddition reactions using
Three different reaction conditions were used (Method A: catalytic amounts of AgOAc and KOH. Substituted pro-
THF, TBAC, KOH, AgOAc; Method B: toluene, KOH and lines were accessible by following this methodology, and so
AgOAc; Method C: thermal reaction), on the basis of the the next step was to investigate the reaction between 1a and
best results achieved previously.
several alkenes using the three methods mentioned and to
The presence of the chloro substituent at the para posi- compare the results obtained (Scheme 3 and Table 5).
tion in the corresponding arylaldimine 1b accelerated the
A bulky, electron-withdrawing group such as p-tolylsul-
reaction in all cases, as previously described,[14e,20d] af- fonyl produced a behaviour different to that with ethyl ac-
fording good to excellent diastereoselectivity (Table 4, Ent- rylate. Reaction times at room temperature (methods A and
1974
Eur. J. Org. Chem. 2001, 1971Ϫ1982

Phase-Transfer Catalysis in the 1,3-Dipolar Cycloaddition Reactions of Azomethine Ylides
FULL PAPER
Here, the cycloaddition reaction between 1a and 3-buten-2-
one under PTC conditions (Table 5, method A) proved to
be a very valuable route, achieving a good yield (66%) and
a high endo selectivity. In contrast, complex mixtures of ste-
reoisomers were obtained when using methods B and C.
Acrolein, when very long reaction times were employed, af-
forded significant quantities of stereomutated compound
4af, together with the endo-2af adduct (Table 5). Less react-
ive vinylphosphonate also required 80 °C and very long re-
action times (Table 5) to achieve high degrees of conversion.
In this case, major compound exo-2ah was isolated and no
traces of stereomutated 4ah were detected. As shown in
Table 5, thermal cycloaddition reactions were only useful
when vinyl sulfone was employed as dipolarophile.
Nitrostyrene was used as the dipolarophile in this 1,3-
cycloaddition reaction in the presence of an excess of base,
furnishing a complex mixture of diastereomeric cycload-
ducts and Michael addition products, while it has been re-
ported that exo products are mainly obtained when using
organic bases and silver(I) salts.[12,21] The cycloaddition re-
action under PTC conditions was very sensitive to steric
hindrance. For example, trans-cinnamaldehyde or methyl
crotonate did not give the desired products. Attempts to
perform cycloaddition reactions with electron-rich alkenes
such as cyclohexene, styrene and ethyl vinyl ether were un-
successful even when the temperature of the reaction mix-
ture was raised to 110 °C in a sealed tube.
Glycine derivative 5a was also employed as 1,3-dipole
with some representative alkenes in the 1,3-dipolar cycload-
dition reactions, using methods A, B and C, (Scheme 4 and
Table 6). As expected, the reaction times were shorter than
when the alanine derivative had been used. The diastereose-
lectivity was very high when ethyl acrylate (methods A and
B), N-phenylmaleimide (method A and B) and acrylonitrile
(method B) were employed (see Table 6). Again, the thermal
cycloaddition reaction (method C) did not represent any
improvement over methods A and B. Stereomutated com-
pounds 8 were detected in all thermal tests, even when using
methods A and B, in the reaction with methyl vinyl ketone.
In this last example, use of method A afforded compound
8ae in 58% yield.
Scheme 3
B) were rather long in the case of p-tolyl vinyl sulfone and
the diastereoselectivity depended on how stabilized the in-
termediates of the reaction were. Thus, in a nonpolar solv-
ent (method B), the major product was the cycloadduct
exo-2ab. However, method A, which incorporated higher
concentrations of salts, afforded Michael product 3ab and
endo-2ab as a 5:4 mixture. This vinyl sulfone afforded the
best endo selectivity when using thermal cycloaddition con-
ditions (method C), whereas N-phenylmaleimide (NPM) af-
forded the best endo diastereoselectivity, in almost quantit-
ative yield, in all the examples given in Table 5. In this last
case, endo-2ac was exclusively obtained in high yields after
1 d, independently of the selected method. In the case of
acrylonitrile, the best diastereoselectivities were again
achieved using method B. The other two procedures fur-
nished mixtures with significant quantities of exo-2ad prod-
uct. These results are in agreement with those previously
reported, in which the low endo selectivity of acrylonitrile
was evidenced.[16b] In the absence of silver acetate, it was
possible to obtain the Michael adduct 3ad as a major prod-
uct. The reaction between 1a and dimethyl fumarate at
room temperature resulted in similar diastereoselectivities
for methods A and B; however, a 58:42 mixture of endo-
2ag/exo-2ag was isolated from the thermal cycloaddition re-
action (method C).
Many factors, ions and reaction conditions, are involved
in the formation or rupture of the intermediate complexes
in the reaction. For glycine and alanine imino esters 1a and
5a, respectively, the stereomutation could be promoted by
the interaction of a Lewis base (aldehyde or ketone) with
the (1,3-dipole)metal complex I and IЈ. This interaction
would transform the structure of the chelate I and IЈ of the
imino esters 1a and 5a, generating new chelates II and IIЈ
α,β-Unsaturated ketones and aldehydes generated a new (Scheme 5). The steric hindrance of the intermediate com-
diastereomer 4, which had not been detected previously. Ac- plexes II and IIЈ would be partially avoided by rotation
1
cording to H NMR experiments (NOESY), product 4 was around NϪC2 bond, producing the intermediate complexes
the stereomutated compound, generated by C2ϪN bond ro- III and IIIЈ. As illustrated in Scheme 5, the methyl group
tation in the (E,E)-metallodipole. This behaviour has been in IIIЈ would cause slightly less hindrance than the isopro-
described for 1,3-dipoles with bulky imine substituents poxycarbonyl group in IIЈ; presumably the stabilization en-
when using less reactive dipolarophiles.[14e] As reported, the ergy gap between them is very small. However, organic
yields of the cycloadducts were very poor when using 3- complex III should experience fewer interactions than the
buten-2-one in the presence of LiBr and triethylamine.[16b] corresponding aggregate II, so we would expect larger
Eur. J. Org. Chem. 2001, 1971Ϫ1982
1975

´
J. Casas, R. Grigg, C. Najera, J. M. Sansano
FULL PAPER
Table 5. 1,3-Dipolar cycloaddition reaction of 1a and dipolarophiles
[a]
[b]
1
[c]
Determined by GC and based on product 1a. Ϫ
Stereochemistry determined by H NMR (NOESY) experiments. Ϫ Without
[e] [f]
[d]
AgOAc. Ϫ
column chromatography (flash silica gel).
In the presence of 1.5 equiv. of KOH. Ϫ The reaction was carried out at 80 °C. Ϫ Decomposition took place after
amounts of stereomutated products for glycine than for al- reckon that complexes II and IIЈ would act as kinetic
anine derivatives (see methyl vinyl ketone examples in pseudometallo-dipoles, while III and IIIЈ would work as
Table 5 and Table 6). On the other hand, acrolein has a thermodynamic pseudometallo-dipoles. The result obtained
higher energy LUMO than methyl vinyl ketone,[22] which with another high energy LUMO alkene such as diethyl vi-
justifies its longer reaction times (Table 5). We can also nylphosphonate, heating the reaction at 80 °C, is not con-
1976
Eur. J. Org. Chem. 2001, 1971Ϫ1982

Phase-Transfer Catalysis in the 1,3-Dipolar Cycloaddition Reactions of Azomethine Ylides
FULL PAPER
Table 6. 1,3-Dipolar cycloaddition reaction of 5a and alkenes
[a]
[b]
[c]
Determined by GC and based on product 5a. Ϫ
presence of 1.5 equiv. of KOH.
Stereochemistry determined by 1H NMR (NOESY) experiments. Ϫ
In the
Scheme 4
Scheme 5
Conclusion
tradictory with these hypothesis because the kinetic pseudo-
metallo-dipole IIЈ is favoured at this temperature and is
It has been demonstrated that PTC conditions can also
more reactive than IIIЈ. The exo adduct is formed preferen- be applied to 1,3-dipolar cycloaddition reactions between
tially, due to the volume of the electron-withdrawing group, imino esters of glycine and alanine and electrophilic al-
as had occurred with the vinyl sulfone, where significant kenes. This regioselective and diastereoselective process,
amounts of exo product were detected.
carried out in the presence of substoichiometric amounts
Eur. J. Org. Chem. 2001, 1971Ϫ1982
1977

´
J. Casas, R. Grigg, C. Najera, J. M. Sansano
FULL PAPER
[CH(CH3)2], 67.8, 68.4 [NCHCH3, CH(CH3)2], 128.8, 129.6, 130.9,
137.0 (ArC), 161.3 (CϭN), 171.9 (CϭO). Ϫ MS (EI): m/z (%) ϭ
210 (10) [Mϩ Ϫ 43], 166 [Mϩ Ϫ 87, 100), 139 (17), 43 (39). Ϫ
HRMS calcd. for [C13H16ClNO2 Ϫ C4H7O2]: 166.0423; found
166.0420.
of both an inorganic base (KOH) and of silver acetate, is
economically more viable than others using excesses of or-
ganic bases and metal salts. α,β-Unsaturated aldehydes and
ketones react under these conditions, affording good yields
of cycloadducts, as does diethyl vinylphosphonate. The re-
activity of the imino ester derived from alanine allows this
procedure to be applied to imino esters derived from other
amino acids, taking into account the sensitivity of this reac-
tion to steric hindrance.
Isopropyl 2-[(E)-1-(2-Hydroxyphenyl)methylideneamino]propanoate
(1c): Colourless oil, 91%. Ϫ TLC: Rf ϭ 0.75 (n-hexane/ethyl acet-
ate, 3:2). Ϫ IR (film): ν˜ ϭ 1747, 1636 cmϪ1. Ϫ 1H NMR
(300 MHz): δ ϭ 1.24, 1.25 [2 ϫ d, J ϭ 6.3 Hz, 6 H, CH(CH3)2],
1.52 (d, J ϭ 6.8 Hz, 3 H, NCHCH3), 4.09 (q, J ϭ 6.8 Hz, 1 H,
NCHCH3), 5.03 [sept, J ϭ 6.3 Hz, 1 H, CH(CH3)2], 6.84Ϫ6.97 (m,
2 H, ArH), 7.24Ϫ7.34 (m, 2 H, ArH), 8.37 (s, 1 H, CHϭN), 13.06
(s, 1 H, OH). Ϫ 13C NMR (75 MHz): δ ϭ 19.4 (NCHCH3), 21.6
[C(CH3)2], 66.1, 68.7 [NCCH3, C(CH3)2], 117.0, 118.5, 118.6,
131.5, 132.5, 160.9 (ArC), 163.7 (CϭN), 171.2 (CϭO). Ϫ MS (EI):
m/z (%) ϭ 235 (19) [Mϩ], 192 (2), 148 (100). Ϫ HRMS calcd. for
[C13H17NO3]: 235.1208; found 235.1205.
Experimental Section
General: Melting points were determined with a Reichert Thermo-
var hot plate apparatus and are uncorrected. Ϫ IR spectra were
recorded with a Nicolet 510 P-FT and only the structurally most
important peaks are listed. Ϫ NMR spectra were performed with
a Bruker AC 300 and DRX 500 by the NMR Service of the Univer-
sity of Alicante, using CDCl3 as solvent and TMS as internal
standard unless otherwise stated. Ϫ Low resolution electron impact
(EI) mass spectra were obtained at 70 eV with a Shimadzu QP-
5000, and low resolution electrospray ionisation (ESI) mass spectra
were obtained with a Finnigan VG platform. HRMS (EI) were
recorded with a Finnigan MAT 95S (MS Service of the University
of Alicante). Ϫ Microanalyses were performed by the Microana-
lysis Service of the University of Alicante. Ϫ Analytical TLC was
performed on Schleicher & Schuell F1400/LS silica gel plates and
the spots visualised with UV light at 254 nm. Flash chromato-
graphy used Merck silica gel 60 (0.040Ϫ0.063 mm). Ϫ Commer-
cially available TBAC hydrate was dehydrated in vacuo (2 Torr) at
60 °C prior to use.
Isopropyl 2-[(E)-1-Cyclohexylmethylideneamino]propanoate (1d):
Colourless oil, 73%. Ϫ TLC: Rf ϭ 0.73 (n-hexane/ethyl acetate,
1
3:2). Ϫ IR (film): ν˜ ϭ 1736, 1665 cmϪ1. Ϫ H NMR (300 MHz):
δ ϭ 1.20Ϫ1.41 [m with 2 ϫ d at 1.23, 1.24, 12 H, (CH2)3CH2CH,
(CH3)2CH], 1.39 (d, J ϭ 6.8 Hz, 3 H, NCHCH3), 1.66Ϫ1.90 (m, 4
H, 2 ϫ CH2CH), 2.24 [m, 1 H, CH(CH3)2], 3.80 (q, J ϭ 6.8 Hz, 1
H, NCHCH3), 5.02 [sept, J ϭ 6.3 Hz, 1 H, CH(CH3)2], 7.53 (d,
J ϭ 5.5 Hz, 1 H, CHϭN). Ϫ 13C NMR (75 MHz): δ ϭ 19.1
(CH3CN), 21.5, 21.6 [CH(CH3)2], 25.1, 25.8, 29.4, 29.5 [(CH2)5],
43.4, (CHCH2), 67.6, 68.0 [CH(CH3)2, NCHCH3], 171.0 (CϭN),
172.0 (CϭO). Ϫ MS (EI): m/z (%) ϭ 225 (0.2) [Mϩ], 138 [Mϩ
Ϫ 87] (47), 55 (20). Ϫ HRMS calcd. for [C13H23NO2]: 225.1728;
found 225.1721.
Isopropyl 2-[(E)-2,2-Dimethylpropylideneamino]propanoate (1e):
Colourless oil, 36%. Ϫ TLC: Rf ϭ 0.55 (n-hexane/ethyl acetate,
Synthesis of Imino Esters 1. ؊ General Procedure: SOCl2 (20 mmol,
1.45 mL) was added dropwise to a suspension of amino acid (gly-
cine or alanine, 10 mmol) in 2-propanol (15 mL) at 0 °C. The reac-
tion mixture was refluxed for 16 h and the solvent was evaporated
in vacuo (15 Torr). Water (30 mL), Na2CO3 (10 mmol, 1.06 g), and
the corresponding aldehyde (10 mmol) were added and the mixture
was stirred vigorously for 18 h. The aqueous phase was extracted
with ethyl acetate (3 ϫ 20 mL); the organic phase was dried
(Na2SO4) and concentrated in vacuo (15 Torr) to afford imino es-
ters 1aϪf. Physical and analytical data see below.
1
3:2). Ϫ IR (film): ν˜ ϭ 1736, 1665 cmϪ1. Ϫ H NMR (300 MHz):
δ ϭ 1.08 [s, 9 H, CH(CH3)3], 1.21, 1.23 [2 ϫ d, J ϭ 6.3 Hz, 6 H,
CH(CH3)2], 1.39 (d, J ϭ 6.8 Hz, 3 H, NCHCH3], 3.82 (q, J ϭ
6.8 Hz, 1 H, NCHCH3), 5.02 [sept, J ϭ 6.3 Hz, 1 H, CH(CH3)2],
7.56 (s, 1 H, CHϭN). Ϫ 13C NMR (75 MHz): δ ϭ 18.8, (NCCH3),
22.6, 22.7 [CH(CH3)2], 26.7 [C(CH3)3], 36.1 [C(CH3)3], 67.4, 67.9
[NCCH3, C(CH3)2], 172.0 (CϭO), 173.9 (CϭN). Ϫ MS (EI): m/z
(%) ϭ 200 (0.7) [Mϩ ϩ 1], 112 (100) [Mϩ Ϫ 87], 43 (45). Ϫ HRMS
calcd. for [C11H21NO2]: 199.1522; found 199.1565.
Isopropyl 2-[(E)-1-Phenylmethylideneamino]propanoate (1a): Col-
ourless oil, 81%. Ϫ TLC: Rf ϭ 0.71 (n-hexane/ethyl acetate, 3:2).
Isopropyl 2-[(E)-1-Phenylmethylideneamino]acetate (5a): Colourless
oil, 83%. Ϫ TLC: Rf ϭ 0.70 (n-hexane/ethyl acetate, 3:2). Ϫ IR
1
Ϫ IR (film): ν˜ ϭ 1735, 1644 cmϪ1. Ϫ H NMR (300 MHz): δ ϭ
1
(film): ν˜ ϭ 1739, 1648 cmϪ1. Ϫ H NMR (300 MHz): δ ϭ 1.27 [d,
1.24, 1.26 [2 ϫ d, J ϭ 6.1 Hz, 6 H, CH(CH3)2], 1.51 (d, J ϭ 6.7 Hz,
3 H, NCHCH3), 4.10 (q, J ϭ 6.7 Hz, 1 H, NCHCH3), 5.06 [sept,
J ϭ 6.1 Hz, 1H CH(CH3)], 7.41 (m, 3 H, ArH), 7.78 (m, 2 H,
ArH), 8.31 (s, 1 H, NϭCH). Ϫ 13C NMR (75 MHz): δ ϭ 19.2
(NCHCH3), 21.6 [CH(CH3)2], 67.9, 68.3 [NCHCH3 and
CH(CH3)2], 128.4, 128.5, 130.9, 135.8 (ArC), 162.6 (CϭN), 172.0
(CϭO). ϪMS (EI): m/z (%) ϭ 220 (0.11) [Mϩ ϩ 1], 176 (21), 133
(19), 132 (100), 105 (43), 43 (26). Ϫ HRMS calcd. for [C13H17NO2
Ϫ C3H7]: 176.0711; found 176.0714.
J ϭ 6.3 Hz, 6 H, CH(CH3)2], 4.35 (s, 2 H, NCH2), 5.09 [sept, J ϭ
6.3 Hz, 1 H, CH(CH3)2], 7.41 (m, 3 H, ArH), 7.77 (m, 2 H, ArH),
8.27 (s, 1 H, CHϭN). Ϫ 13C NMR (75 MHz): δ ϭ 21.6 [C(CH3)2],
62.0 (NCH2), 68.3 [CH(CH3)2], 128.3, 128.4, 131.0 (ArC), 135.5
(CϭN), 169.4 (CϭO). Ϫ MS (EI): m/z (%) ϭ 162 (37) [Mϩ Ϫ 43],
118 (81), 91 (100), 43 (37). Ϫ HRMS calcd. for [C12H15NO2
Ϫ
C3H7]: 162.0555; found 162.0566.
1,3-Dipolar Cycloaddition Reaction between Imino Esters 1 and 5a
2-[(E)-1-(4-Chlorophenyl)methylideneamino]propanoate and Alkenes. ؊ Method A: Potassium hydroxide (0.025 mmol,
Isopropyl
(1b): Colourless oil, 79%. Ϫ TLC: Rf ϭ 0.73 (n-hexane/ethyl acet-
2 mg) was added to a suspension of the imino ester 1 (0.25 mmol),
ate, 3:2). Ϫ IR (film): ν˜ ϭ 1735, 1644 cmϪ1. Ϫ 1H NMR alkene (0.3 mmol), silver acetate (0.025 mmol, 4 mg), and previ-
(300 MHz): δ ϭ 1.24, 1.25 [2 ϫ d, J ϭ 6.4 Hz, 6 H, CH(CH3)2],
ously dehydrated tetrabutylammonium chloride (0.025 mmol,
1.50 (d, J ϭ 6.1 Hz, 3 H, NCHCH3), 4.09 (q, J ϭ 6.8 Hz, 1 H, 7 mg) in THF (3 mL), and the resulting mixture was vigorously
NCHCH3), 5.05 [sept, J ϭ 6.4 Hz, 1 H, CH(CH3)2], 7.37 (d, J ϭ stirred for the times indicated in the corresponding tables. The solv-
8.3 Hz, 2 H, ArH), 7.71 (d, J ϭ 8.3 Hz, 2 H, ArH), 8.26 (s, 1 H,
ent was evaporated in vacuo (15 Torr), ethyl acetate added, and the
NϭCH). Ϫ 13C NMR (75 MHz): δ ϭ 19.3 (NCCH3), 21.7, 21.8 mixture was percolated through silica gel, eluting with ethyl acetate.
1978
Eur. J. Org. Chem. 2001, 1971Ϫ1982

Phase-Transfer Catalysis in the 1,3-Dipolar Cycloaddition Reactions of Azomethine Ylides
FULL PAPER
The solvent was evaporated (15 Torr) to obtain pyrrolidines or
Michael adduct, depending on the reaction (see text and tables).
7.07 (m, 2 H ArH), 7.28Ϫ7.39 (m, 8 H, ArH). Ϫ 13C NMR
(75 MHz): δ ϭ 21.6, 21.8 [CH(CH3)2], 24.0 (NCCH3), 50.4
(COCHCPh), 55.7 (COCHCN), 62.1 (PhC), 67.6, 69.7 [CH3CCO2-
iPr, CH(CH3)2], 126.1, 127.0, 128.1, 128.3, 128.4, 128.9, 131.5,
136.8 (ArC), 171.7, 173.6, 174.4 (3 ϫ CϭO). Ϫ MS (EI): m/z (%) ϭ
392 (0.5) [Mϩ], 306 (16), 305 (100), 219 (17), 131 (17), 43 (14). Ϫ
HRMS calcd. for [C23H24N2O4]: 392.1736; found 392.1727.
Method B: Potassium hydroxide (0.025 mmol, 2 mg) was added to
a suspension of the imino ester 1 (0.25 mmol), alkene (0.3 mmol),
and silver acetate (0.025 mmol, 4 mg) in toluene (3 mL), and the
resulting mixture was vigorously stirred for the times shown in the
corresponding tables. The solvent was evaporated in vacuo (15
Torr), ethyl acetate was added, and the mixture was percolated
through silica gel, eluting with ethyl acetate. The solvent was evap-
orated (15 Torr) to obtain pyrrolidines or Michael adduct, de-
pending on the reaction (see text and tables).
Isopropyl (2R*,4R*,5S*)-4-Cyano-2-methyl-5-phenylpyrrolidine-2-
carboxylate (endo-2ad, Method B, Table 5): Colourless oil, 89%. Ϫ
C16H20N2O2 (272.1): calcd. C 70.5, H 7.4, N 10.3; found C 70.2,
H 7.5, N 9.9. Ϫ TLC: Rf ϭ 0.64 (n-hexane/ethyl acetate, 3:2). Ϫ
IR (film): ν˜ ϭ 2240, 1724 cmϪ1. Ϫ 1H NMR (300 MHz): δ ϭ 1.31,
1.32 [2 ϫ d, J ϭ 6.3 Hz, 6 H, CH(CH3)2], 1.48 (s, 3 H, NCCH3),
2.18, (dd, J ϭ 13.6, 7.5 Hz, 1 H, CO2CCHH), 2.82 (dd, J ϭ 13.6,
3.1 Hz, 1 H, CO2CCHH), 3.28 (ddd, J ϭ 7.5, 5.9, 3.1 Hz, 1 H,
CNCH), 4.50 (d, J ϭ 5.9 Hz, 1 H, PhCH), 5.15 [sept, J ϭ 6.3 Hz,
1 H, CH(CH3)2], 7.25Ϫ7.48 (m, 5 H, ArH). Ϫ 13C NMR
(75 MHz): δ ϭ 21.5, 21.6 [CH(CH3)2], 27.0 (HNCCH3), 37.4
(NCCH), 41.5 (CH2CHCN), 64.1, 64.7 (PhC, HNCCH3), 69.4
[CH(CH3)2], 119.0 (CN), 126.8, 128.3, 128.5, 137.7 (ArC), 174.8
(CϭO). Ϫ MS (EI): m/z (%) ϭ 185 (100) [Mϩ Ϫ 87], 43 (13), 42
(18), 41 (12). Ϫ HRMS calcd. for [C16H20N2O2]: 272.1524; found
272.1531.
Method C: A solution of the imino ester 1 (0.25 mmol) and the
alkene (0.3 mmol) in toluene (3 mL) was heated in a sealed tube at
110 °C (see tables and text for reaction times). The solvent was
evaporated in vacuo (15 Torr) to give the crude products. Physical
and analytical data follow.
4-Ethyl 2-Isopropyl (2R*,4R*,5S*)-2-Methyl-5-phenylpyrrolidine-
2,4-dicarboxylate (endo-2aa, Method A or B, Table 4): Colourless
solid, 95%, m.p. 92Ϫ93 °C (ethyl acetate/n-hexane). Ϫ C18H25NO4
(319.2): calcd. C 67.7, H 7.9, N 4.4; found C 67.6, H 7.9, N 4.2. Ϫ
TLC: Rf ϭ 0.55 (n-hexane/ethyl acetate, 3:2). Ϫ IR (KBr): ν˜ ϭ
1
1731 cmϪ1. Ϫ H NMR (300 MHz): δ ϭ 0.73 (t, J ϭ 7.3 Hz, 3 H,
CH2CH3), 1.22, 1.23 [2 ϫ d, J ϭ 6.1 Hz, 6 H, CH(CH3)2], 1.41 (s,
3 H, NCCH3), 1.97 (dd, J ϭ 13.4, 7.9 Hz, 1 H, NCCHH), 2.60
(dd, J ϭ 13.4, 6.0 Hz, 1 H, NCCHH), 3.10 (s, 1 H, NH), 3.25 (m,
1 H, CHCO2Et), 3.59 (m, 2 H, CH2O), 4.57 (d, J ϭ 7.3 Hz, 1 H,
PhCH), 5.06 [sept, J ϭ 6.1 Hz, 1 H, CH(CH3)2], 7.10Ϫ7.26 (m,
5 H, ArH). Ϫ 13C NMR (75 MHz): δ ϭ 13.5 (CH3CH2O), 21.5
[(CH3)2CH], 27.5 (CH3CN), 40.3 (CH2CHCO2Et), 50.4
(CHCO2Et), 60.0 (CH2O), 65.0, 65.5 (PhCH, CCO2iPr), 68.6
[C(CH3)2], 126.0, 127.0, 128.0, 139.1 (ArC), 172.5, 175.4 (2 ϫ Cϭ
Isopropyl (2R*,4R*,5S*)-4-Acetyl-2-methyl-5-phenylpyrrolidine-2-
carboxylate (endo-2ae, Method A, Table 5): Pale yellow oil, 66%. Ϫ
C17H23NO3 (289.1): calcd. C 70.6, H 8.0, N 4.8; found C 70.2, H
7.9, N 4.8. Ϫ TLC: Rf ϭ 0.69 (n-hexane/ethyl acetate, 3:2). Ϫ IR
1
(film): ν˜ ϭ 1720 cmϪ1. Ϫ H NMR (300 MHz): δ ϭ 1.26, 1.28 [2
ϫ d, J ϭ 6.3 Hz, 6 H, CH(CH3)2], 1.46 (s, 3 H, NCCH3), 1.97 (s,
3 H, COCH3), 2.08 (dd, J ϭ 13.1, 10.0 Hz, 1 H, NCCHH), 2.60
(dd, J ϭ 13.1, 7.0 Hz, 1 H, NCCHH), 3.06 (ddd, J ϭ 10.0, 8.3,
7.0 Hz, 1 H, CH3COCH), 4.40 (d, J ϭ 8.3 Hz, 1 H, PhCH), 5.04
[sept, J ϭ 6.3 Hz, 1 H, CH(CH3)2], 7.23Ϫ7.43 (m, 5 H, ArH). Ϫ
13C NMR (75 MHz): δ ϭ 21.6 [CH(CH3)2], 27.0 (CH3CN), 30.0
(CH3CO), 38.6 (CH2CHO), 59.7 (CHPh), 63.8 (CHCOCH3), 65.0
(CH3CCO2iPr), 68.7 [CH(CH3)2], 126.9, 127.0, 128.3, 128.4, 143.0
(ArC), 176.5 (OCϭO), 207.7 (CϭO). Ϫ MS (EI): m/z (%) ϭ 289
(0.2) [Mϩ], 202 (100) [Mϩ Ϫ 87], 160 (22), 158 (21), 106 (28). Ϫ
HRMS calcd. for [C17H23NO3 Ϫ C4H7O2]: 202.1231; found
202.1228.
O). Ϫ MS (EI): m/z (%) ϭ 320 (0.1) [Mϩ ϩ 1], 232 (100) [Mϩ
Ϫ
87], 158 (27), 42 (23). Ϫ HRMS calcd. for [C18H25NO4 Ϫ C4H7O2]:
232.1337; found 232.1335.
Isopropyl
(2R*,4R*,5R*)-2-Methyl-4-(4-methylphenylsulfonyl)-5-
phenylpyrrolidine-2-carboxylate (endo-2ab, Method C, Table 5):
Colourless solid, 80%, m.p. 92 °C (ethyl acetate/n-hexane). Ϫ
C22H27NO4S (433.3): calcd. C 63.5, H 6.8, N 3.5; found C 63.4, H
6.9, N 3.4. Ϫ TLC: Rf ϭ 0.50 (n-hexane/ethyl acetate, 3:2). Ϫ IR
1
(KBr): ν˜ ϭ 1732, 1310, 1150 cmϪ1. Ϫ H NMR (300 MHz): δ ϭ
2-Isopropyl 3,4-Dimethyl (2R*,3R*,4R*,5S*)-2-Methyl-5-phenyl-
pyrrolidine-2,3,4-tricarboxylate (endo-2ag, Method A or B, Table 5):
Pale yellow oil, 92%. Ϫ C19H25NO6 (363.2): calcd. C 62.8, H 6.9,
N 3.9; found C 63.1, H 7.1, N 3.9. Ϫ TLC: Rf ϭ 0.60 (n-hexane/
ethyl acetate, 3:2). Ϫ IR (film): ν˜ ϭ 1732 cmϪ1. Ϫ 1H NMR
(300 MHz): δ ϭ 1.32, 1.34 [2 ϫ d, J ϭ 6.7 Hz, 6 H, CH(CH3)2]
1.37 (s, 3 H, NCCH3), 3.17 (s, 3 H, PhCHCHCO2CH3), 3.71 (s, 3
H, NCCHCO2CH3), 3.85Ϫ3.94 [m, 2 H, (CH3O2CH)2], 4.79 (d,
J ϭ 7.9 Hz, 1 H, PhCH), 5.17 (sept, J ϭ 6.7 Hz, 1 H, CH(CH3)2],
7.23Ϫ7.31 (m, 5 H, ArH). Ϫ 13C NMR (75 MHz): δ ϭ 21.0
(NCCH3), 21.5, 21.6 [CH(CH3)2], 51.3, 51.9 (2 ϫ CO2CH3), 52.6,
53.8 (COCH)2, 62.8 (PhC), 67.1 (NCCO), 69.3 [CH(CH3)2], 127.2,
127.7, 128.1, 139.0 (ArC), 171.1, 171.3, 173.2 (3 ϫ CϭO). Ϫ MS
(EI): m/z (%) ϭ 363 (0.1) [Mϩ], 276 (37) [Mϩ Ϫ 87], 244 (47), 216
(100), 184 (47), 158 (22), 157 (17), 131 (33), 43 (48), 42 (85). Ϫ
HRMS calcd. for [C19H25NO6]: 363.1681; found 363.1673.
1.22, 1.23 [2 ϫ d, J ϭ 6.3 Hz, 6 H, CH(CH3)2], 1.52 (s, 3 H,
NCCH3), 2.30 (s, 3 H, CH3Ar), 2.41 (dd, J ϭ 13.6, 9.5 Hz, 1 H,
NCCHH), 2.74 (dd, Jϭ13.6, 8.4 Hz, 1 H, NCHH) 3.78Ϫ3.87 (m,
1 H, SCH), 4.60 (d, J ϭ 8.4 Hz, 1 H, PhCH), 5.00 [sept, J ϭ 6.3 Hz,
1 H, CH(CH3)2], 7.15 (m, 7 H, ArH), 7.57 (m, 2 H, ArH). Ϫ 13C
NMR (75 MHz): δ ϭ 21.4, 21.5 [CH(CH3)2, NCCH3), 26.1
(CH3Ph), 38.3 (CH2CHS), 63.4, 64.9 (PhC, NCCH3), 69.2, 69.9
[SCH, CH(CH3)2], 127.2, 127.6, 128.2, 128.3, 129.5, 135.3, 139.9
144.5 (ArC), 175.2 (CϭO). Ϫ MS (EI): m/z (%) ϭ 314 (11) [Mϩ
Ϫ
87], 158 (100), 42 (25). Ϫ HRMS calcd. for [C22H27NO4S Ϫ
C7H8O2S]: 245.1415; found 244.1418.
Isopropyl (1R*,3S*,3aR*,6aS*)-1-Methyl-4,6-dioxo-3,5-diphenyl-
perhydropyrrolo[3,4-c]pyrrole-1-carboxylate (endo-2ac, Method A or
B, Table 5): Colourless solid, 87%, m.p. 184Ϫ185 °C (ethyl acetate/
n-hexane). Ϫ C23H24N2O4 (392.1): calcd. C 70.4, H 6.2, N 7.1;
found C 70.3, H 6.1, N 7.1. Ϫ TLC: Rf ϭ 0.27 (n-hexane/ethyl
acetate, 3:2). Ϫ IR (KBr): ν˜ ϭ 1723 cmϪ1. Ϫ 1H NMR (300 MHz):
Diethyl (2R*,3S*,5R*)-5-Isopropyloxycarbonyl-5-methyl-2-phenyl-
δ ϭ 1.31, 1.37 (2 ϫ d, J ϭ 6.2 Hz, 6 H, CH(CH3)2], 1.61 (s, 3 H, tetrahydro-1H-pyrrol-3-ylphosphonate (exo-2ah,
NCCH3), 2.73 (d, J ϭ 8.3 Hz, 1 H, NH), 3.40 (d, J ϭ 7.5, 1 H, Table 5): Pale yellow oil, 90%. Ϫ TLC: Rf ϭ 0.81 (n-hexane/ethyl
CH3CCH), 5.65 (dd, J ϭ 9.1, 7.6 Hz, 1 H, PhCCH), 4.83 (dd, J ϭ acetate, 3:2). Ϫ IR (film): ν˜ ϭ 1724, 1247 cmϪ1. Ϫ 1H NMR
Method
C,
9.1, 8.3 Hz, 1 H, PhCH), 5.16 [sept, J ϭ 6.2 Hz, 1 H, CH(CH3)2],
(300 MHz): δ ϭ 1.05 [t, J ϭ 7.3 Hz, 6 H, (CH3CH2O)2], 1.24Ϫ1.33
Eur. J. Org. Chem. 2001, 1971Ϫ1982
1979

´
J. Casas, R. Grigg, C. Najera, J. M. Sansano
FULL PAPER
[m, 6 H, CH(CH3)2], 1.46, (s, 3 H, NCCH3), 2.07Ϫ2.20 (m, 1 H, 60%. Ϫ TLC: Rf ϭ 0.62 (n-hexane/ethyl acetate, 3:2). Ϫ IR (film):
NCCHH), 2.39Ϫ2.50 (m, 1 H, PCH), 2.63Ϫ2.68 (m, 1 H, PhCH), ν˜ ϭ 1729 cmϪ1. Ϫ 1H NMR (300 MHz): δ ϭ 1.18Ϫ1.23 [m, 15
5.03 [sept, J ϭ 6.7 Hz, 1 H, CH(CH3)2], 7.22Ϫ7.42 (m, 5 H,
H, (CH2)3CH2CH, CH3CH2O, CH(CH3)2], 1.36 (s, 3 H, NCCH3),
1.52Ϫ1.72 [m, 4 H, (CH2)2CH], 1.79Ϫ1.86 (m, 1 H, NCCHH), 2.02
ArCH). Ϫ 13C NMR (75 MHz): δ ϭ 15.9, 16.0, 16.1, 16.2, 16.3
(CH3CH2O)2, 21.6 [CH(CH3)2], 26.2 (NCCH3), 39.9 (PCHCH2), (m, 1 H, CH2CH), 2.50 (d, J ϭ 13.4 Hz, 1 H, NCCHH), 2.90 (m,
43.4, 45.3 (PCH), 61.4, 61.5, 61.6, 61.7, 61.8 [(CH3CH2O)2], 64.2 2 H, CyCH, CHCO2Et), 3.96Ϫ4.19 (m, 2 H, CH3CH2O), 5.07
(PhCH), 65.3, 65.5 (NCCH3), 68.9 [CH(CH3)2], 127.5, 127.7, 128.3,
[sept, J ϭ 6.4 Hz, 1 H, CH(CH3)2]. Ϫ 13C NMR (75 MHz): δ ϭ
14.2 (CH3CH2O), 21.6 [CH(CH3)2], 25.8, 25.9, 26.3 [(CH2)3CH2],
28.4 (NCCH3), 30.9, 31.6 [(CH2)2CH], 39.7 (CyCH), 42.2
(NCCH2), 47.4 (CHCO2Et), 60.0 (CH3CH2O), 65.5 (NCCH3),
68.2, 68.3 [CH(CH3)2], 174.1, 175.7 (2 ϫ CϭO). Ϫ MS (EI): m/z
(%) ϭ 238 (100) [Mϩ Ϫ 87], 82 (69), 67 (17), 55 (33), 44 (15), 43
(35), 42 (31), 41 (47). Ϫ HRMS calcd. for [C18H31NO4 Ϫ C4H7O2]:
238.1807; found 238.1801.
135.3 (ArC), 176.1 (CϭO). Ϫ MS (EI): m/z (%) ϭ 296 (14) [Mϩ
Ϫ
87], 158 (100), 44 (56), 43 (24), 42 (34), 41 (17), 40 (42). Ϫ HRMS
calcd. for [C19H30NO5P Ϫ C4H7O2]: 296.1415; found 296.1416.
Isopropyl 4-Cyano-2-methyl-2-[(E)-1-phenylmethylideneamino]but-
anoate (3ad, Table 5): Pale yellow oil, 95%. Ϫ TLC: Rf ϭ 0.71 (n-
hexane/ethyl acetate, 3:2). Ϫ C16H20N2O2 (272.1): calcd. C 70.6, H
7.4, N 10.3; found C 70.2, H 7.3, N 10.7. Ϫ IR (film): ν˜ ϭ 2249,
1725, 1644 cmϪ1. Ϫ 1H NMR (300 MHz): δ ϭ 1.25 [d, J ϭ 6.4 Hz,
6 H, CH(CH3)2], 1.50 (s, 3 H, NCHCH3), 2.07Ϫ2.13 (m, 1 H,
COCCHH), 2.39Ϫ2.45 (m, 1 H, COCCHH), 2.53Ϫ2.66 (m, 2 H,
CNCH2), 5.07 [sept, J ϭ 6.4 Hz, 1 H, CH(CH3)2], 7.44 (m, 3 H,
ArH), 7.75 (m, 2 H, ArH), 8.30 (s, 1 H, NϭCH). Ϫ 13C NMR
(75 MHz): δ ϭ 12.5 (CH2CCO), 21.6, 21.7 [CH(CH3)2], 23.4
(NCHCH3), 35.9 (CH2CN), 66.5 (COCH3), 69.1 [CH(CH3)2], 120.3
(CN), 128.3, 128.5, 131.2, 135.9 (ArC), 160.8 (HCϭN), 172.8 (Cϭ
O). Ϫ MS (EI): m/z (%) ϭ 185 (100) [Mϩ Ϫ 87], 104 (18), 103 (17),
90 (21), 51 (24), 44 (67), 43 (30), 42 (26), 41 (32). Ϫ HRMS calcd.
for [C16H20N2O2 Ϫ C3H7]: 229.0977; found 229.0980.
5-Ethyl 1-Isopropyl 2-[(E)-2,2-Dimethylpropylideneamino]-2-methyl-
pentanedioate (3ea, Method A or B, Table 4): Colourless oil, 67%.
Ϫ TLC: Rf ϭ 0.19 (n-hexane/ethyl acetate, 3:2). Ϫ IR (film): ν˜ ϭ
1
1736, 1665 cmϪ1. Ϫ H NMR (300 MHz): δ ϭ 0.96, 1.01 [s, 9 H,
C(CH3)3], 1.13Ϫ1.20 [m, 9 H, CH(CH3)2, OCH2CH3], 1.24, 1.25
(s, 3 H, NCCH3), 1.91Ϫ1.99 (m, 1 H, NCCHH), 2.06Ϫ2.16 (m, 1
H, NCCHH), 2.22Ϫ2.35 (m, 2 H, NCCH2CH2), 4.04 (q, J ϭ
7.2 Hz, 2 H, OCH2CH3), 5.01 [sept, J ϭ 6.3 Hz, 1 H, CH(CH3)2],
7.49 (s, 1 H, CHϭN). Ϫ 13C NMR (75 MHz): δ ϭ 14.1
(CH3CH2O), 21.6, 21.7 [CH(CH3)2], 23.2, 23.3 (NCCH3), 26.0,
26.5 [C(CH3)3], 29.3, 29.4 (NCCH2CH2), 35.2, 36.5 (NCCH2), 37.6
[C(CH3)3], 60.2, 60.3 (OCH2CH3), 66.3 (NCCH3), 68.0, 68.5
[CH(CH3)2], 170.3 (CϭN), 173.2, 173.3, 173.6, 173.9 (2 ϫ CϭO).
Ϫ MS (EI): m/z (%) ϭ 256 (4) [Mϩ Ϫ 43], 212 (81) [Mϩ Ϫ 87], 98
(21), 96 (22), 82 (41), 69 (16), 57 (19), 55 (49), 44 (37), 43 (71), 42
4-Ethyl 2-Isopropyl (2R*,4R*,5S*)-5-(4-Chlorophenyl)-2-methylpyr-
rolidine-2,4-dicarboxylate (endo-2ba, Method B, Table 4): Colour-
less needles, 92%, m.p. 93 °C (n-hexane/ethyl acetate).
Ϫ
C19H24ClNO4 (353.6): calcd. C 61.1, H 6.8, N 4.0; found C 61.4,
H 6.9, N 4.2. Ϫ TLC: Rf ϭ 0.77 (n-hexane/ethyl acetate, 3:2). Ϫ
IR (KBr): ν˜ ϭ 1732 cmϪ1. Ϫ 1H NMR (300 MHz): δ ϭ 0.86 (t,
J ϭ 7 Hz, 3 H, COCH2CH3), 1.28, 1.29 [2 ϫ d, J ϭ 6.3 Hz, 6 H,
CH(CH3)2], 1.46 (s, 3 H, NCCH3), 2.02 (dd, J ϭ 13.4, 9.5 Hz, 1
H, NCCHH), 2.64 (dd, J ϭ 13.4, 5.7 Hz, 1 H, NCCHH),
3.29Ϫ3.36 (m, 1 H, CHCO), 3.70 (m, 2 H, CH2O), 4.60 (d, J ϭ
7.5 Hz, 1 H, PhCH), 5.11 [sept, J ϭ 6.3 Hz, 1 H, CH(CH3)2], 7.24
(s, 4 H, ArH). Ϫ 13C NMR (75 MHz): δ ϭ 13.6 (CH3CH2O), 21.6,
21.7 [(CH3)2CH], 27.3 (CH3CN), 40.1 (CH2CHCO2Et), 50.2
(CHCO2Et), 60.2 (CH2O), 64.0 (PhC), 65.5 (CH3CCO2iPr), 68.7
[CH(CH3)2], 128.1, 128.2, 133.1, 137.9 (ArC), 172.2 (CO2Et), 175.3
(CO2iPr). Ϫ MS (EI): m/z (%) ϭ 310 (0.4) [Mϩ Ϫ 43], 266 (100)
[Mϩ Ϫ 87], 165 (16), 57 (15), 43 (45), 42 (71), 41 (26). Ϫ HRMS
calcd. for [C18H24ClNO4 Ϫ C4H7O2]: 266.0947; found 266.0945.
(48), 41 (100), 40 (37). Ϫ HRMS calcd. for [C16H29NO4
C4H7O2]: 212.1650; found 212.1660.
Ϫ
Isopropyl (2R*,4S*,5R*)-4-Formyl-2-methyl-5-phenylpyrrolidine-2-
carboxylate (4af, Method B, Table 5): Colourless oil, 81%. Ϫ
C16H21NO3 (275.1): calcd. C 69.8, H 7.7, N 5.1; found C 70.0, H
7.5, N 5.3. Ϫ TLC: Rf ϭ 0.58 (n-hexane/ethyl acetate, 3:2). Ϫ IR
1
(film): ν˜ ϭ 1732 cmϪ1. Ϫ H NMR (300 MHz): δ ϭ 1.26, 1.27 [2
ϫ d, J ϭ 6.3 Hz, 6 H, CH(CH3)2], 1.52 (s, 3 H, NCCH3), 2.21 (dd,
J ϭ 13.6, 5.5 Hz, 1 H, NCCHH), 2.50 (dd, J ϭ 13.6, 8.6 Hz, 1 H,
NCCHH), 2.98Ϫ3.06 (m, 1 H, HCOCH), 4.62 (d, J ϭ 7.9 Hz, 1
H, PhCH), 5.00 [sept, J ϭ 6.3 Hz, 1 H, CH(CH3)2], 7.30 (m, 5 H,
ArH), 9.19 (d, J ϭ 2.8 Hz, 1 H, CHO). Ϫ 13C NMR (75 MHz):
δ ϭ 21.6, 21.7 [CH(CH3)2], 26.1, (NCCH3), 34.9 (CH2CHCHO),
62.8 (PhCH), 64.6 (NCCH3), 68.7 [CH(CH3)2], 126.8, 126.9, 128.5,
138.8 (ArC), 176.7 (CO2iPr), 202.4 (CHO). Ϫ MS (EI): m/z (%) ϭ
232 (2) [Mϩ Ϫ 43], 188 (100) [Mϩ Ϫ 87], 158 (15), 106 (41), 91
(17), 44 (24), 43 (38), 42 (60), 41 (36). Ϫ HRMS calcd. for
[C16H21NO3 Ϫ C4H7O2]: 188.1075; found 188.1078.
4-Ethyl 2-Isopropyl (2R*,4R*,5S*)-5-(2-Hydroxyphenyl)-2-methyl-
pyrrolidine-2,4-dicarboxylate (endo-2ca, Method A, Table 4): Pale
yellow oil, 85%. Ϫ C18H25N2O5 (335.2): calcd. C 64.5, H 7.5, N
4.2; found C 64.1, H 7.3, N 4.4. Ϫ TLC: Rf ϭ 0.71 (n-hexane/ethyl
acetate, 3:2). Ϫ IR (film): ν˜ ϭ 1736 cmϪ1. Ϫ 1H NMR (300 MHz):
δ ϭ 0.88 (t, J ϭ 7.2 Hz, 3 H, CH3CH2O), 1.29, 1.31 [2 ϫ d, J ϭ
6.3 Hz, 6 H, CH(CH3)2], 1.52 (s, 3 H, NCCH3), 2.02, (dd, J ϭ 13.4,
7.7 Hz, 1 H, NCCHH), 2.88 (dd, J ϭ 13.4, 4.0 Hz, 1 H, NCCHH),
3.75 (m, 1 H, CHCO2Et), 4.80 (d, J ϭ 7.9 Hz, 1 H, PhCH), 5.10
[sept, J ϭ 6.3 Hz, 1 H, CH(CH3)2], 6.70Ϫ7.14 (m, 4 H, ArH). Ϫ
13C NMR (75 MHz): δ ϭ 13.4 (CH3CH2O), 21.4, 21.6 [(CH3)2CH],
26.4 (CH3CN), 39.0 (CH2CHCO2Et), 48.9 (CHCO2Et), 60.7
(CH2O), 64.1 (PhC), 65.2 (CH3CCO2iPr), 68.8 [CH(CH3)2], 117.1,
118.4, 118.7, 121.1, 122.6, 128.5, 128.8, 136.5, 158.0 (ArC), 172.4,
174.5, (2 ϫ CϭO). Ϫ MS (EI): m/z (%) ϭ 202 (100) [Mϩ Ϫ 133],
77 (17), 51 (16), 44 (30), 43 (39), 42 (66), 41 (46), 40 (25). Ϫ HRMS
calcd. for [C18H25NO5 Ϫ C6H13O3]: 202.0868; found 202.0859.
4-Ethyl 2-Isopropyl (2R*,4R*,5S*)-5-phenylpyrrolidine-2,4-dicarb-
oxylate (endo-6aa, Method A or B, Table 6): Colourless oil, 92%. Ϫ
TLC: Rf ϭ 0.67 (n-hexane/ethyl acetate, 3:2). Ϫ IR (film): ν˜ ϭ
1
1732 cmϪ1. Ϫ H NMR (300 MHz): δ ϭ 0.82 (t, J ϭ 7.2 Hz, 3 H,
CH3CH2O), 1.30 [d, J ϭ 6.3 Hz, 6 H, CH(CH3)2], 2.30 (m, 2 H,
NCHCH2), 2.77 (s, 1 H, NH), 3.30 (m, 1 H, CHCO2Et), 3.57Ϫ3.77
(m, 2 H, CH3CH2O), 3.92 (dd, J ϭ 8.3 Hz, 1 H, CHCO2iPr), 4.52
(d, J ϭ 7.9 Hz, 1 H, PhCH), 5.15 [sept, J ϭ 6.3 Hz, 1 H,
CH(CH3)2], 7.31 (m, 5 H, ArH). Ϫ 13C NMR (75 MHz): δ ϭ 13.6
(CH3CH2O), 21.7, 21.8 [CH(CH3)2], 33.6 (NCCH2), 49.7
(CHCO2Et), 60.1 (CH3CH2O), 65.8 (PhCH), 68.6 [CH(CH3)2],
126.8, 127.4, 128.1, 139.1 (ArC), 172.5, 172.7 (2 ϫ CϭO). Ϫ MS
(EI): m/z (%) ϭ 305 (0.6) [Mϩ], 218 (100) [Mϩ Ϫ 87], 172 (17),
145 (16), 144 (49), 117 (36), 43 (42), 41 (28). Ϫ HRMS calcd. for
4-Ethyl 2-Isopropyl (2R*,4R*,5R*)-5-Cyclohexyl-2-methylpyrrolid-
ine-2,4-dicarboxylate (endo-2da, Method B, Table 4): Colourless oil, [C17H23NO4]: 305.1627; found 305.1620.
1980 Eur. J. Org. Chem. 2001, 1971Ϫ1982

Phase-Transfer Catalysis in the 1,3-Dipolar Cycloaddition Reactions of Azomethine Ylides
FULL PAPER
´
T. Abellan, R. Chinchilla, N. Galindo, G.
[2c]
2475Ϫ2486. Ϫ
Isopropyl (1R*,3S*,3aR*,6aS*)-4,6-Dioxo-3,5-diphenylperhydropyr-
rolo[3,4-c]pyrrole-1-carboxylate (endo-6ac, Method A or B, Table 6):
Colourless solid, 92%, m.p. 214 °C (n-hexane/ethyl acetate). Ϫ
C22H22N2O4 (378.3): calcd. C 69.8, H 5.9, N 7.4; found C, 69.5, H
5.8, N 7.5. Ϫ TLC: Rf ϭ 0.33 (n-hexane/ethyl acetate, 3:2). Ϫ IR
´
Guillena, C. Najera, J. M. Sansano, Targets in Heterocyclic Sys-
tems, vol. 4, in press. For reviews of 1,3-dipolar cycloaddition
[2d]
reactions see:
A. Padwa (Ed.), 1,3-Dipolar Cycloaddition
[2e]
Chemistry; Wiley, New York, 1984. Ϫ
H. Waldmann, Syn-
[2f]
lett 1995, 133Ϫ141. Ϫ
A. Padwa, Comprehensive Organic
Synthesis (Eds.: B. M. Trost, I. Fleming); Pergamon Press,
Oxford, 1991, vol. 4, pp. 1069Ϫ1109.
1
(KBr): ν˜ ϭ 1716 cmϪ1. Ϫ H NMR (300 MHz): δ ϭ 1.31, 1.37 [2
ϫ d, J ϭ 6.3 Hz, 6 H, CH(CH3)2], 2.50 (s, 1 H, NH), 3.52 (dd,
J ϭ 8.9, 7.6 Hz, 1 H, PhCHCH), 3.67 (dd, J ϭ 7.6, 6.9 Hz, 1 H,
CHCHCO2iPr), 4.04 (d, J ϭ 6.9 Hz, 1 H CHCO2iPr), 4.55 (d, J ϭ
8.9 Hz, 1 H, PhCH), 5.20 [sept, J ϭ 6.3 Hz, 1 H, CH(CH3)2],
7.12Ϫ7.44 (m, 10 H, ArH). Ϫ 13C NMR (75 MHz): δ ϭ 21.6, 21.9
[CH(CH3)2], 48.2 (PhCHCH), 49.5 (NCHCH), 62.2 (NCHCO),
64.1 (PhC), 69.2 [CH(CH3)2], 125.9, 126.1, 127.0, 128.3, 128.9,
129.0, 131.6, 136.6 (ArC), 168.9, 173.6, 174.7 (3 ϫ CϭO). Ϫ MS
(EI): m/z (%) ϭ 291 (23) [Mϩ Ϫ 87], 205 (21), 144 (52), 117 (20),
90 (15), 44 (100), 43 (47), 42 (17), 41 (30), 40 (99).
[3]
`
M. Pichon, B. Frigadiere, Tetrahedron: Asymmetry 1996, 7,
927Ϫ964.
[4] [4a]
F. J. Sardina, H. Rapopport, Chem. Rev. 1996, 96,
[4b]
1825Ϫ1872. Ϫ
J. Seyden-Penne, Chiral Auxiliaries and Li-
[4c]
gands in Asymmetric Synthesis, Wiley, New York, 1996. Ϫ
G. R. Stephenson, Advanced Asymmetric Catalysis in Organic
Synthesis, Chapman and Hall, London, 1996. Ϫ [4d] R. Noyori,
Asymmetric Catalysis in Organic Synthesis, Wiley, New York,
1994.
[5]
[6]
[5a]
See for example:
P. P. Waid, G. A. Flynn, E. W. Huber, J.
[5b]
S. Sabol, Tetrahedron Lett. 1996, 37, 4091Ϫ4094. Ϫ
V. V.
Khau, M. J. Martinelli, Tetrahedron Lett. 1996, 37, 4323Ϫ4326.
See for example: [6a] C. W. G. Fishwick, R. J. Foster, R. E. Carr,
Isopropyl
(2R*,4R*,5S*)-4-Cyano-5-phenylpyrrolidine-2-carb-
[6b]
Tetrahedron Lett. 1996, 37, 3915Ϫ3918. Ϫ
A. Bianco, M.
oxylate (endo-6ad, Method B, Table 6): Colourless oil, 97%. Ϫ
C15H18N2O2 (258.1): calcd. C 69.7, H 7.0, N 10.8; found C 70.0,
H 7.2, N 10.9. Ϫ TLC: Rf ϭ 0.69 (n-hexane/ethyl acetate, 3:2). Ϫ
IR (film): ν˜ ϭ 1735, 2243 cmϪ1. Ϫ 1H NMR (300 MHz): δ ϭ 1.30
[d, J ϭ 6.3 Hz, 6 H, CH(CH3)2], 2.42Ϫ2.63 (m, 2 H, NCCHCH2),
2.73, (s, 1 H, NH), 3.25 (m, 1 H, NCCH), 3.10 (dd, J ϭ 8.8, 6.3 Hz,
1 H, CHCO2iPr), 4.40 (d, J ϭ 6.4 Hz, 1 H, PhCH), 5.14 [sept, J ϭ
6.25 Hz, 1 H, CH(CH3)2], 7.15Ϫ7.49 (m, 5 H, ArH). Ϫ 13C NMR
(75 MHz): δ ϭ 21.6, 21.7 [CH(CH3)2], 34.4 (CNCHCH2), 35.9
(CNC), 58.5 (CCO2iPr), 64.8 (PhC), 62.2 [CH(CH3)2], 119.1 (CN),
126.9, 128.4, 128.5, 137.6 (ArC), 172.0 (CϭO). Ϫ MS (EI): m/z
(%) ϭ 258 (2) [Mϩ], 171 (100) [Mϩ Ϫ 87], 154 (27), 117 (27), 43
(30), 41 (21). Ϫ HRMS calcd. for [C15H18N2O2]: 258.1368; found
258.1365.
Maggini, G. Scorrano, C. Toniolo, G. Marconi, C. Villani, M.
Prato, J. Am. Chem. Soc. 1996, 118, 4072Ϫ4080.
[7]
Pyrrolizidine and indolizidine alkaloids can be prepared by this
[7a]
route:
G. Broggini, G. Zecchi, Synthesis 1999, 905Ϫ917. Ϫ
[7b]
R. Grigg, S. Hargreaves, J. Redpath, S. Turchi, G. Yogana-
than, Synthesis 1999, 441Ϫ446. Ϫ Pyrroles, polycyclic struc-
[7c]
tures and natural products are also obtained:
I. Fejes, L.
´
Töke, G. Blasco, M. Nyerges, C. S. Pak, Tetrahedron 2000, 56,
[7d]
8545Ϫ8553. Ϫ
Lett. 2000, 41, 7951Ϫ7954. Ϫ
Visintin, E. Valentin, Helv. Chim. Acta 1997, 80, 1457Ϫ1472.
M. Nyerges, I. Fejes, L. Töke, Tetrahedron
[7e]
F. Felluga, G. Pitacco, C.
[7f]
[7g]
Ϫ
C. S. Pak, M. Nyerges, Synlett 1999, 1271Ϫ1273. Ϫ
H. A. Dondas, J. Duraisingham, R. Grigg, W. S. MacLachlan,
D. T. MacPherson, M. Thornton-Pett, V. Sridharan, S. Sugan-
[7h]
than, Tetrahedron 2000, 56, 4063Ϫ4070. Ϫ
H. A. Dondas,
J. Duraisingham, R. Grigg, W. S. MacLachlan, D. T. MacPher-
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[7i]
ron Lett. 2000, 41, 967Ϫ970. Ϫ
R. Grigg, M. Thornton-
Isopropyl
(2R*,4S*,5R*)-4-Acetyl-5-phenylpyrrolidine-2-carb-
[7j]
Pett, G. Yoganathan, Tetrahedron 1999, 55, 8129Ϫ8140. Ϫ
oxylate (8ae, Method A, Table 6): Pale yellow oil, 58%. Ϫ
C16H21NO3 (275.1): calcd. C 69.8, H 7.7, N 5.1; found C 70.1, H
7.7, N 4.7. Ϫ TLC: Rf ϭ 0.75 (n-hexane/ethyl acetate, 3:2). Ϫ IR
D. J. Denhart, D. A. Griffith, C. H. Heathcock, J. Org. Chem.
[7k]
1998, 63, 9616Ϫ9617. Ϫ
M. Nyerges, M. Rudas, I. Bitter,
[7l]
L. Töke, Tetrahedron 1997, 53, 3269Ϫ3280.
Ϫ
K.
1
(film): ν˜ ϭ 1716 cmϪ1. Ϫ H NMR (300 MHz): δ ϭ 1.29 [d, J ϭ
Amornraksa, R. Grigg, H. Q. N. Gunaratne, J. Kemp, V. Srid-
haran, J. Chem. Soc., Perkin Trans. 1 1987, 2285Ϫ2296.
6.3 Hz, 6 H, CH(CH3)2], 1.97 (s, 3 H, CH3CO), 2.28 (m, 1 H,
NCCHH), 2.48 (m, 1 H, NCCHH), 3.12 (m, 1 H, CH3COCH),
3.94 (dd, J ϭ 9.0, 5.1 Hz, 1 H, NCHCO), 4.27 (d, J ϭ 8.6 Hz, 1
H, PhCH), 5.10 [sept, J ϭ 6.3 Hz, 1 H, CH(CH3)2], 7.26Ϫ7.44 (m,
5 H, ArH). Ϫ 13C NMR (75 MHz): δ ϭ 21.7, 21.8 [CH(CH3)2],
30.6 (CH3CO), 33.9 (CH2CHCO2iPr), 59.2 (CHCO2iPr), 59.4
(CH3COC), 66.6 (Ph), 68.7 [CH(CH3)2], 126.8, 127.9, 128.7, 141.4
(ArC), 173.9 (CO2iPr), 207.1 (CϭO). Ϫ MS (EI): m/z (%) ϭ 232
(4) [Mϩ Ϫ 43], 188 (16) [Mϩ Ϫ 87], 146 (15), 44 (17), 43 (100), 41
(15), 40 (30). Ϫ HRMS calcd. for [C16H21NO3 Ϫ C3H7]: 232.0973;
found 232.0970.
[8a]R. Grigg, V. Sridharan, Advances in Cycloaddition, JAI Press
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´
This work was supported by the Direccion General de Ensen˜anza
´
´
Superior e Investigacion Cientıfica (Project PB97-0123) and by
Generalitat Valenciana (Project GVDOC00-14-02). J. M. S. thanks
the M.E.C. (Spanish Ministry of Education and Culture) for a con-
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D. A. Barr, M. J. Dorrity, R. Grigg, S. Hargreaves, J. F.
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Received November 10, 2000
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Part of these results have been reported in the 4th International
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