Stereoselective synthesis of substituted pyrrolidines by a domino Michael addition/carbocyclization reaction

Article abstract of DOI:10.1002/1099-0690(200211)2002:21<3536::AID-EJOC3536>3.0.CO;2-L

The domino 1,4-addition/carbocyclization/functionalization reaction of Michael acceptor 3 with mixed copper/zinc reagents allows the totally diastereoselective formation of 3,4-disubstituted-3-carbomethoxypyrrolidines in a three-component one-pot sequence. ( Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002).

Full text of DOI:10.1002/1099-0690(200211)2002:21<3536::AID-EJOC3536>3.0.CO;2-L

FULL PAPER
Stereoselective Synthesis of Substituted Pyrrolidines by a Domino Michael
Addition/Carbocyclization Reaction
Fabrice Denes,[a] Fabrice Chemla,*[a] and Jean F. Normant[a]
Dedicated to Marc Julia on the occasion of his 80th birthday
Keywords: Michael addition / Cyclization / Copper / Zinc / Domino reactions / Nitrogen heterocycles
The domino 1,4-addition/carbocyclization/functionalization
( Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany,
reaction of Michael acceptor 3 with mixed copper/zinc re- 2002)
agents allows the totally diastereoselective formation of 3,4-
disubstituted-3-carbomethoxypyrrolidines in a three-com-
ponent one-pot sequence.
Introduction
prepare these Reformatsky reagents by 1,4-addition of or-
ganometallic reagents onto the appropriate Michael ac-
ceptor 3 (Scheme 2).
We have recently shown[1] that zinc enolates derived from
substituted β-(N-allyl)-amino esters 1 undergo a smooth
carbocyclization reaction to give 3,4-disubstituted-3-car-
bomethoxypyrrolidines 2 with excellent stereochemical con-
trol (Scheme 1).
Results and Discussion
Preparation of Starting Materials
The Michael acceptor 3 was prepared by reaction of com-
mercially available methyl 2-(bromomethyl)acrylate with N-
allyl-N-benzylamine (Scheme 3). Compound 5 was pre-
pared from the corresponding β-amino ester 4 by the three-
step procedure depicted in Scheme 3 in 40% overall yield.
Scheme 1
These zinc enolates were prepared by deprotonation of
the corresponding esters with LDA and subsequent trans-
metalation with zinc salts. However, in some cases we ob-
served a β-elimination side reaction due presumably to the
instability of the lithium enolate in the presence of zinc
salts. In order to avoid this side reaction, we decided to
Scheme 3
Scheme 2
Reaction of 3 and 4 with Triorganozincates and
Organocopper Reagents
Triorganozincate reagents[2] are known to undergo a 1,4-
addition with enones,[3Ϫ10] although to the best of our
knowledge, few examples concern the reaction with α,β-un-
[a]
Laboratoire de Chimie Organique, Bte 183, UMR 7611,
´
Universite Pierre et Marie Curie,
4 place Jussieu, 75252 Paris cedex 05, France
Fax: (internat.) ϩ33-1/4427-5571
E-mail: fchemla@ccr.jussieu.fr
3536
 2002 WILEY-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim 1434Ϫ193X/02/1121Ϫ3536 $ 20.00ϩ.50/0 Eur. J. Org. Chem. 2002, 3536Ϫ3542

Stereoselective Synthesis of Substituted Pyrrolidines
FULL PAPER
saturated esters.[11,12] The reaction of lithium tri-n-butyl-
zincate with compound 3 at 0 °C in diethyl ether gives, after
hydrolysis, the 1,4-addition product 6 in 75% yield accom-
panied by 25% of N-allyl-N-benzylamine resulting from a
β-elimination reaction (Scheme 4). On the other hand, the
addition of zinc bromide after completion of the Michael
addition promotes the carbocyclization of the resulting en-
olate efficiently to give, after hydrolysis, the carbomethoxy-
pyrrolidine 7a in a 54% isolated yield and as a single dias-
tereomer. This diastereomer was found to be identical to
Scheme 5
[1]
the one obtained by deprotonation of the corresponding
substituted β-(N-allyl)amino ester (Scheme 4).
52% isolated yield and as a single diastereomer (Scheme 5).
These encouraging results led us to examine other or-
ganometallic species in order to avoid any excess of car-
banionic ligand. As zinc salts are required for the carbocy-
clization reaction, we turned to mixed organocopper/zinc
reagents.[14]
Domino 1,4-Addition/Carbocyclization Reaction with Mixed
Organocopper/Zinc Reagents
To the best of our knowledge, the only examples of 1,4-
addition of these reagents to α,β-ethylenic esters reported in
the literature are conducted in polar solvents with TMSCl
activation.[15] However, we were pleased to see that the reac-
tion of nBuCu(CN)ZnBr/LiBr (prepared from nBuLi and a
mixture of ZnBr2 and CuCN in diethyl ether) gave the cy-
clized product 7 smoothly in good yield, albeit with a mod-
erate stereoselectivity (7a/7b ϭ 63:37, Scheme 6). No inter-
mediate product (namely 6 upon hydrolysis) could be de-
tected, nor could any elimination product. In order to im-
prove the stereoselectivity, we tried to modify the reaction
conditions (temperature, ZnBr2 or CuCN equivalents, ad-
ditives...). These results are reported in Table 1. In all cases,
crude 7 was obtained in 75Ϫ85% yield and the ratio of 7a
to 7b determined by GC analysis.
Scheme 4
The same domino 1,4-addition/carbocyclization reaction
was performed with the substituted enoate 5. In this case,
the carbomethoxypyrrolidine 8 was obtained as a mixture
of two diastereomers in an 85:15 ratio. The relative config-
urations for the major diastereomer, isolated in a 43% yield,
were determined on the basis of nuclear Overhauser ef-
fects (Scheme 4).
Reaction of 3 with nBuCu/LiI and the cyanocuprate re-
agent nBuCu(CN)Li, when conducted in diethyl ether, gave
only products from the β-elimination process. This elimina-
tion process has already been observed in some similar 1,4-
additions of organocopper reagents to 2-(methylamino)-
Scheme 6
The diastereoselectivity of this domino reaction is of
enones.[13] On the other hand, the reaction of the higher course determined in the second step, namely the carbocy-
order cyanocuprate nBu2Cu(CN)Li2 gave the 1,4-addition clization reaction. We can assume that the enolate obtained
product 6 in 75% isolated yield upon hydrolysis, accompan- after the Michael reaction is a copper/zinc mixed enolate.
ied by N-allyl-N-benzylamine (20%). Here again, the enol- The stereoselectivity of the carbocyclization reaction of zinc
ate resulting from the Michael addition underwent carbocy- enolates prepared by deprotonation and subsequent trans-
clization reaction only upon addition of zinc bromide, and metalation was interpreted in terms of the reaction of a
the resulting carbomethoxypyrrolidine 7a was obtained in a carbon-centered zinc enolate.[1] The stereoselectivity here
Eur. J. Org. Chem. 2002, 3536Ϫ3542
3537

F. Denes, F. Chemla, J. F. Normant
FULL PAPER
voured over cyclization through enolate 9b on the basis of
simple steric hindrance. Intermediate 9a should be even
more favoured in the presence of an excess of Lewis acid
such as MgBr2 or ZnBr2, as shown in Table 1 (entries 2,3
and 6). On the other hand, the influence of an excess of
lithium salts (Table 1, entry 5) as well as the influence of an
excess or a deficit of copper salt (entries 7 and 8) are more
difficult to interpret; however, in these cases, the nature of
the enolate could be changed. Finally, for as yet unknown
reasons, the diastereoselectivity is better when an excess of
mixed organocopper/zinc reagent is used (Table 1, entry 9),
and is not sensitive to temperature (Table 1, entry 10 versus
9). It should be noted that all reactions were complete
within two hours.
Table 1. Domino 1,4-addition/carbocyclization on
nBuCu(CN)ZnBr·LiBr
3 with
Entry CuCN ZnBr2 Additives
Temperature 7a/7b ratio[a]
1
2
3
4
5
6
7
8
9
1 equiv. 1 equiv. -
room temp. 63:37
room temp. 90:10
room temp. 93:7
room temp. 63:37
1
1
1
1
1
0.1
2
1
1
2
3
1
1
1
1
1
1
1
-
-
LiBr (1equiv.)
LiBr (2 equiv.) room temp. 47:53
MgBr2 (1 equiv.) room temp. 77:33[b]
-
-
-
-
room temp. 52:48
room temp. 43:57
room temp. 84:16[c]
10
Ϫ20 °C
80:20[c]
[a]
[b]
Determined by GC analysis.
Accompanied by 20% of N-
[c]
benzyl-N-allylamine (by GC). With two equivalents of nBuCu-
(CN)ZnBr/LiBr.
Domino Michael Addition/Carbocyclization Reaction with
Other Mixed Copper/Zinc Reagents
can also be interpreted with the intermediacy of carbon-
centred copper/zinc enolates 9a and 9b, which should show
the same reactivity and stereoselectivity trends, as depicted
in Scheme 7. The substituted enolate derived from the 1,4-
addition to 5 should cyclize through the carbon-centered
copper/zinc enolate 9c, which has the methyl group in a
pseudoequatorial position, to give compound 8 as a major
product.
We examined our domino reaction with various other
copper/zinc species. We were very pleased to see that the
diastereoselectivity was totally controlled by using aryl or
vinylic organometallic reagents as can be seen in Scheme 8.
Surprisingly, these species, when made from ‘‘salt-free’’ or
‘‘non salt-free’’ organolithium reagents, gave the same excel-
lent diastereoselectivity, as only one diastereomer for 10, 11
and 12 was evidenced by 1H NMR spectroscopy. This is the
reverse to what was observed in the case of alkyllithium
reagents (see Table 1, entries 1,4 and 5). Here again, the
nature of the intermediate enolate could be different, de-
pending on the nature of the substituent introduced during
the 1,4-addition reaction.
Scheme 7
In such an interpretation, and with the highly probable
hypothesis of a high configurational instability of enolates
9a and 9b,[16] cyclization through enolate 9a should be fa- Scheme 8
3538
Eur. J. Org. Chem. 2002, 3536Ϫ3542

Stereoselective Synthesis of Substituted Pyrrolidines
FULL PAPER
Reaction of the Resulting Pyrrolidinylmethylzinc Reagent
with Electrophiles
compound, and not a mixed copper-zinc reagent, as these
reagents are known to undergo a smooth coupling reaction
with iodoalkynes.[17]
We have already shown in our previous work that pyrroli-
dinylmethylzinc reagents derived from the carbocyclization
of zinc enolates can be functionalized with various elec-
trophiles. In some cases, CuCN addition was necessary to
enhance the reactivity of the zinc reagent. In the present
case, however, a copper salt is already present in the reac-
tion mixture, and we wanted to verify that, as in the previ-
ous example, the resulting organometallic reagent could be
widely functionalized. The formation of the pyrrolidinylme-
thylzinc, or -copper/zinc, reagent resulting from the domino
1,4-addition/carbocyclization reaction with PhCu(CN)-
ZnBr·3LiBr was confirmed by its reactions with various
electrophiles, as depicted in Scheme 9. In each case, the di-
astereoselectivity was excellent, as only one diastereomer
Conclusion
We have disclosed a domino 1,4-addition/carbocycliz-
ation reaction with electrophiles that allows the totally ster-
eoselective construction of various 3,4-disubstituted-3-car-
bomethoxypyrrolidines, with the concomitant formation of
two or three carbon-carbon bonds in a two- or three-step
one-pot procedure. The organometallic reagents involved in
this domino reaction can either be zincates, higher order
cyanocuprates or mixed copper/zinc compounds. This inter-
esting methodology leads with a great versatility to substi-
tuted β-proline-type heterocycles, compounds with a great
synthetic potential and biological interest.[18]
1
was seen by H NMR spectroscopy. The yields reported in
Scheme 9 are isolated yields after purification.
Experimental Section
General Remarks: Experiments involving organometallic reagents
were carried out in dry glassware under a positive pressure of dry
nitrogen. Liquid nitrogen was used as a cryoscopic fluid. A four-
necked round-bottomed flask equipped with an internal thermo-
meter, a septum cap, a nitrogen inlet and a mechanical stirrer was
used. THF was freshly distilled from sodium/benzophenone ketyl
prior to use. Zinc bromide (98%) was purchased from Aldrich. It
was melted under dry nitrogen and, immediately after cooling
down to room temperature, was dissolved in anhydrous THF. All
other reagents and solvents were of commercial quality and were
used without purification. Flash column chromatographic separa-
tions were carried out over Merck silica gel 60 (0.015Ϫ0.040 mm).
1H and 13C NMR spectra were recorded on Bruker ARX 400 or
AC 200 spectrometers. Chemical shifts are reported relative to an
internal standard of residual chloroform (δ ϭ 7.27 ppm for 1H and
δ ϭ 77.1 ppm for 13C) unless otherwise noted. IR spectra were
recorded with a PerkinϪElmer 1420 spectrophotometer. Mass
´
spectra were performed by the Service de Spectrometrie de Masse
´
de l’Universite Pierre et Marie Curie. Elemental analyses were per-
´
formed by the Service de Microanalyses de l’Universite Pierre et
Marie Curie.
Methyl 2-[(N-Allyl-N-benzylamino)methyl]acrylate (3): K2CO3
(6.90 g, 50 mmol) and NaI (0.75 g, 5 mmol) were added to a stirred
solution of N-allyl-N-benzylamine (7.35 g, 50 mmol) in DMF
(50 mL). The mixture was cooled to Ϫ10 °C and a solution of
methyl (bromomethyl)acrylate (8.95 g, 50 mmol) in DMF (50 mL)
was added dropwise. The reaction mixture was allowed to warm to
Scheme 9
Reaction of the pyrrolidinylmethyl organometallic re-
agent with deuterium oxide gave the deuterated pyrrolidine
13 in 57% yield as a single diastereomer. Coupling with allyl room temperature and stirred for 12 h. The reaction was quenched
with brine (100 mL), Et2O (50 mL) was added and the layers were
separated, the aqueous one being extracted three times with Et2O.
The combined organic layers were washed six times with brine,
dried over MgSO4, the solvents evaporated under reduced pressure
and the residue purified by chromatography with cyclohexane/
EtOAc (80:20) as eluent to give 3 (10.79 g, 88%) as a yellow oil. IR
(neat): ν˜ ϭ 3063, 2949, 2926, 2799, 1721, 1636, 1494, 1438, 1386,
bromide gave the pyrrolidine 14 in 57% yield, and reaction
with iodine gave the iodopyrrolidine 15 in 55% isolated
yield. It should be noted that in this type of functionaliz-
ation, three carbon-carbon bonds are formed in a one-pot
procedure. Surprisingly, the reaction with iodoalkyne 16
gave only the iodopyrrolidine 15 in 32% yield and not the
expected coupled pyrrolidinylalkyne. This non-classical be-
haviour is still unexplained; however, it could be a sign that
the organometallic reagent resulting from the domino 1,4-
1307, 1262, 1195, 1154, 1119, 983, 921, 818, 740, 699 cmϪ1 1H
.
NMR (400 MHz, CDCl3): δ ϭ 3.10 (d, J ϭ 6.11 Hz, 2 H), 3.33 (s,
2 H), 3.63 (s, 2 H), 3.75 (s, 3 H), 5.17 (dd, J ϭ 10.2, 1.5 Hz, 1 H),
addition/carbocyclization reaction is a true organozinc 5.23 (dd, J ϭ 17.3, 1.5 Hz, 1 H), 5.90 (ddt, J ϭ 17.3, 10.2, 6.6 Hz,
Eur. J. Org. Chem. 2002, 3536Ϫ3542 3539

F. Denes, F. Chemla, J. F. Normant
FULL PAPER
1 H,), 5.95 (d, J ϭ 1.5 Hz, 1 H), 6.30 (d, J ϭ 1.5 Hz, 1 H), aqueous solution of NH4Cl/NH3. The layers were separated, the
7.23Ϫ7.36 (m, 5 H) ppm. 13C NMR (100 MHz, CDCl3): δ ϭ 51.68, aqueous one being extracted three times with CH2Cl2. The com-
53.85, 56.60, 58.03, 117.32, 125.95, 126.90, 128.24 (2C), 128.62
(2C), 135.74, 138.39, 139.48, 167.47 ppm. C15H19NO2 (245.3206):
calcd. C 73.44; H 7.81; N 5.71; found C 73.35; H 7.96; N 5.71.
bined organic layers were washed with brine, dried over MgSO4
and the solvents were evaporated under reduced pressure.
The crude material was diluted with CH2Cl2 (100 mL) and DBU
(13.7 g, 90 mmol) was added at room temperature. The reaction
mixture was stirred at room temperature for 4 days. The solvents
were evaporated under reduced pressure and the residue diluted in
Et2O (50 mL). A saturated aqueous solution of NaHCO3 (50 mL)
was added and the layers were separated, the aqueous one being
extracted three times with Et2O. The combined organic layers were
washed with brine, dried over MgSO4 and the solvents were evapor-
ated under reduced pressure. The residue was purified by chroma-
tography using cyclohexane as eluent to give 5 (3.22 g, 40%) as a
yellow oil. IR (neat): ν˜ ϭ 3063, 3027, 2973, 2927, 2804, 1723, 1642,
Methyl 3-(N-Allyl-N-benzylamino)butyrate (4): Methyl crotonate
(40 g, 400 mmol) was added at room temperature to a stirred solu-
tion of benzylamine (21.6 g, 200 mmol) in MeOH. After stirring at
room temperature for 72 h, the solvent and the excess of methyl
crotonate were removed under reduced pressure. Crude methyl 3-
(N-benzylamino)butyrate (40.62 g, 98%) was used for further trans-
formation without purification. IR (neat): ν˜ ϭ 3600Ϫ3200, 3027,
2950, 2933, 2862, 1736, 1661, 1494, 1453, 1437, 1376, 1295, 1254,
1195, 1175, 1028, 1009, 737, 699 cmϪ1 1H NMR (400 MHz,
.
CDCl3): δ ϭ 1.16 (d, J ϭ 6.6 Hz, 3 H), 1.60Ϫ1.92 (1 H), 2.39 (dd,
J ϭ 15.3, 5.6 Hz, 1 H), 2.50 (dd, J ϭ 15.3, 6.6 Hz, 1 H), 3.16 (sext,
J ϭ 6.6 Hz, 1 H), 3.67 (s, 3 H), 3.76 (d, J ϭ 13.2 Hz, 1 H), 3.83 (d,
J ϭ 13.2 Hz, 1 H), 7.22Ϫ7.34 (m, 5 H) ppm. 13C NMR (100 MHz,
CDCl3): δ ϭ 20.58, 41.53, 49.76, 51.30, 51.64, 127.05, 128.22 (2C),
128.54 (2C), 140.45, 172.91.
1494, 1436, 1374, 1276, 1155, 1062, 994, 919, 740, 699 cmϪ1 1H
.
NMR (400 MHz, CDCl3): δ ϭ 1.16 (d, J ϭ 6.6 Hz, 3 H), 2.96 (dd,
J ϭ 14.2, 7.6 Hz, 1 H), 3.15 (ddt, J ϭ 14.2, 5.1, 1.5 Hz, 1 H), 3.35
(d, J ϭ 14.2 Hz, 1 H), 3.70 (d, J ϭ 14.2 Hz, 1 H), 3.74 (s, 3 H),
4.00 (q, J ϭ 6.6 Hz, 1 H), 5.07Ϫ5.09 (m, 1 H), 5.14 (dq, J ϭ 17.3,
1.5 Hz, 1 H), 5.58 (s, 1 H), 5.83 (m, 1 H), 6.07 (s, 1 H), 7.16Ϫ7.32
(m, 5 H) ppm. 13C NMR (100 MHz, CDCl3): δ ϭ 11.22, 51.68,
52.85, 53.08, 53.48, 116.61, 122.56, 126.72, 128.12 (2C), 128.62
(2C), 137.01, 140.31, 144.38, 168.70 ppm. C16H21NO2 (259.34):
calcd. C 74.10, H 8.16, N 5.40; found C 73.94, H 8.24, N 5.27.
K2CO3 (120 mmol) and a solution of allyl bromide (9.6 mL,
110 mmol) in DMF (40 mL) at 0 °C were added to a stirred solu-
tion of methyl 3-(N-benzylamino)butyrate (20.8 g, 100 mmol) in
DMF (100 mL). The cold bath was removed and the solution was
allowed to warm to room temperature. The reaction mixture was
stirred at room temperature for 12 h and hydrolysed with an aque-
ous saturated solution of NaHCO3 (200 mL). Et2O (100 mL) was
added and the layers separated, the aqueous one being extracted
three times with Et2O. The combined organic layers were washed
ten times with brine, dried over MgSO4 and the solvent evaporated
under reduced pressure. The residue was purified by chromato-
graphy with cyclohexane/ethyl acetate (90:10) as eluent to give 4
(22.7 g, 92%) as a yellow oil. IR (neat): ν˜ ϭ 3064, 3026, 2950, 2933,
2878, 2806, 1739, 1494, 1453, 1436, 1372, 1297, 1257, 1198, 1156,
1073, 1028, 996, 918, 740, 699 cmϪ1. 1H NMR (400 MHz, CDCl3):
δ ϭ 1.06 (d, J ϭ 6.8 Hz, 3 H), 2.29 (dd, J ϭ 14.1, 7.1 Hz, 1 H),
2.60 (dd, J ϭ 14.1, 7.8 Hz, 1 H), 2.97 (dd, J ϭ 14.2, 7.2 Hz, 1 H),
3.14 (dd, J ϭ 14.2, 5.2 Hz, 1 H), 3.36Ϫ3.47 (m, 1 H), 3.44 (d, J ϭ
13.9 Hz, 1 H), 3.65 (s, 3 H), 3.69 (d, J ϭ 13.9 Hz, 1 H), 5.07Ϫ5.12
(m, 1 H), 5.15Ϫ5.22 (m, 1 H), 5.75Ϫ5.86 (m, 1 H), 7.21Ϫ7.34 (m,
5 H) ppm. 13C NMR (100 MHz, CDCl3): δ ϭ 13.90, 39.09, 51.22,
51.31, 52.48, 52.99, 116.43, 126.65, 127.99 (2C), 128.46 (2C),
137.08, 140.03, 172.56.
General Procedure A: Cyclisation with Zincates: nBuLi (3.6 mL, 2.5
in hexanes, 9 mmol) was added dropwise to a solution of zinc
bromide (3 mL, 1  in Et2O, 3 mmol) at Ϫ80 °C diluted with 10 mL
Et2O. The cold bath was removed and the temperature was allowed
to reach 0 °C. After 15 min at 0 °C, the mixture was cooled to Ϫ78
°C and a solution of ester 3 or 5 (2 mmol) in Et2O (5 mL) was
added dropwise. The mixture was stirred at Ϫ78 °C for 1 hour and
then allowed to warm to 0 °C. A solution of zinc bromide (9 mL,
1  in Et2O, 9 mmol) was added at 0 °C and the cold bath removed.
After being stirred for 30 min at room temperature, the reaction
was hydrolysed with an aqueous solution of NH4Cl/NH4OH (2:1).
The layers were separated, the aqueous one being extracted three
times with ethyl acetate. The combined organic layers were washed
with brine, dried over MgSO4 and the solvent evaporated under
reduced pressure.
General Procedure B: Conjugate Addition/Cyclization of Zinc/Cop-
per Reagents: An ethereal solution of zinc bromide (4 mL, 1  in
Et2O, 4 mmol) and a solution of RLi (4 mmol in Et2O) were added
dropwise consecutively to a suspension of copper cyanide (360 mg,
4 mmol) in Et2O (7 mL) at Ϫ10 °C. The reaction mixture was
stirred at 0 °C for 1 h and a solution of 3 (2 mmol) in Et2O was
added dropwise at 0 °C. The cold bath was removed and the bi-
phasic mixture was stirred at room temperature for 2 h. The reac-
tion was hydrolysed with an aqueous solution of NH4Cl/NH4OH
(2:1). The layers were separated, the aqueous one being extracted
three times with ethyl acetate. The combined organic layers were
washed with brine, dried over MgSO4 and the solvents evaporated
under reduced pressure.
Methyl 2-[1-(N-Allyl-N-benzylamino)ethyl]acrylate (5): nBuLi
(24.8 mL, 2.5 in hexanes, 62 mmol) was added to a stirred solution
of diisopropylamine (8.8 mL, 62.6 mmol) in THF (30 mL) at Ϫ70
°C. After stirring at Ϫ70 °C for 30 min and then at 0 °C for an
additional 30 min, the solution was cooled to Ϫ78 °C and a solu-
tion of 4 (7.67 g, 31 mmol) in THF (50 mL) was added dropwise
at Ϫ78 °C. This mixture was stirred at Ϫ78 °C for 1 h. Paraformal-
dehyde (2.7 g, 90 mmol) was then added in one portion at Ϫ78 °C,
the cold bath removed and the reaction mixture stirred at room
temperature for 30 min. The solution was hydrolysed with a satur-
ated aqueous solution of NaHCO3. Et2O (30 mL) was added and Methyl
(3S*,4S*)-1-Benzyl-4-methyl-3-pentylpyrrolidine-3-carb-
the layers were separated, the aqueous one being extracted three
times with Et2O. The combined organic layers were washed with
brine, dried over MgSO4 and the solvents were evaporated under
reduced pressure.
The crude material was diluted with CH2Cl2 (120 mL) under argon
atmosphere. Pyridine (2.8 mL, 34 mmol) and Ac2O (3.5 mL,
37 mmol) were added at room temperature. The mixture was stirred
oxylate (7a): Prepared according to procedure A from 3 (490 mg,
2 mmol). The residue was chromatographed with cyclohexane/
EtOAc (80:20) as eluent to give 7a (267 mg, 54%) as a yellow oil.
IR (neat): ν˜ ϭ 3027, 2953, 2932, 2861, 2788, 1732, 1495, 1454,
1378, 1290, 1256, 1196, 1138, 1072, 1029, 738, 699 cmϪ1. 1H NMR
(400 MHz, CDCl3): δ ϭ 0.83 (t, J ϭ 7.1 Hz, 3 H), 0.93Ϫ1.13 (m,
2 H), 0.99 (d, J ϭ 7.1 Hz, 3 H), 1.16Ϫ1.27 (m, 4 H), 1.31Ϫ1.39
at room temperature for 12 hours and hydrolysed with a saturated (m, 1 H), 1.62Ϫ1.71 (m, 1 H), 1.98 (t, J ϭ 8.64 Hz, 1 H), 2.08 (d,
3540 Eur. J. Org. Chem. 2002, 3536Ϫ3542

Stereoselective Synthesis of Substituted Pyrrolidines
FULL PAPER
J ϭ 9.7 Hz, 1 H), 2.41Ϫ2.51 (m, 1 H), 2.91Ϫ2.97 (m, 1 H), 3.44 ane/EtOAc (80:20) as eluent to give 12 (345 mg, 60%) as a yellow
(d, J ϭ 9.7 Hz, 1 H), 3.51 (d, J ϭ 13.7 Hz, 1 H), 3.62 (d, J ϭ oil. IR (neat): ν˜ ϭ 3063, 3027, 2933, 2862, 2792, 1731, 1647, 1495,
13.7 Hz, 1 H), 3.65 (s, 3 H), 7.18Ϫ7.31 (m, 5 H) ppm. 13C NMR 1453, 1435, 1376, 1356, 1301, 1199, 1136, 1100, 1076, 1028, 893,
(400 MHz, CDCl3): δ ϭ 13.91, 14.07, 22.54, 25.28, 32.44, 33.10, 740, 699 cmϪ1 1H NMR (400 MHz, CDCl3): δ ϭ 1.07 (d, J ϭ
39.80, 51.84, 54.53, 60.28, 61.55, 61.70, 126.87, 128.25 (2C), 128.61 7.3 Hz, 3 H), 1.64 (s, 3 H), 2.13 (t, J ϭ 8.8 Hz, 1 H), 2.19 (d, J ϭ
.
(2C), 139.31, 177.39 ppm. C19H29NO2 (303.4958): calcd. C 75.21,
H 9.63, N 4.62; found C 75.04, H 9.64, N 4.49.
14.5 Hz, 1 H), 2.36 (d, J ϭ 9.8 Hz, 1 H), 2.47Ϫ2.54 (m, 1 H), 2.58
(d, J ϭ 14.5 Hz, 1 H), 2.95 (dd, J ϭ 8.8, 7.3 Hz, 1 H), 3.47 (d, J ϭ
9.8 Hz, 1 H), 3.60 (d, J ϭ 13.2 Hz, 1 H), 3.66 (d, J ϭ 13.2 Hz, 1
H), 3.69 (s, 3 H), 4.64 (s, 1 H), 4.76 (s, 1 H), 7.22Ϫ7.25 (m, 1 H),
7.30Ϫ7.35 (m, 4 H) ppm. 13C NMR (100 MHz, CDCl3): δ ϭ 13.68,
23.41, 40.58, 41.03, 51.83, 53.29, 60.17, 60.91, 60.96, 113.31,
126.83, 128.20 (2C), 128.58 (2C), 139.20, 142.41, 177.05 ppm.
C18H25NO2 (287.401): calcd. C 75.22, H 8.77, N 4.87; found C
75.10, H 8.89, N 4.78.
Methyl (2S*,3S*,4S*)-1-Benzyl-2,4-dimethyl-3-pentylpyrrolidine-3-
carboxylate (8): Prepared according to Procedure A from 5
(634 mg, 1 mmol) to yield the corresponding pyrrolidine as a mix-
ture of diastereoisomers in an 85:15 ratio (determined by GC). The
residue was chromatographed with cyclohexane/EtOAc (80:20) as
eluent to give 8 (368 mg, 58%) as a yellow oil. IR (neat): ν˜ ϭ 3027,
2932, 2871, 1730, 1453, 1228, 1196, 1139, 698 cmϪ1 1H NMR
.
Methyl (3S*,4S*)-4-Deuteromethyl-1,3-dibenzylpyrrolidine-3-carb-
oxylate (13): Prepared according to procedure B from 3 (491 mg,
2 mmol). The reaction was hydrolysed with D2O (2 mL) after 24
hours at room temperature. After work up, the residue was chroma-
tographed with cyclohexane/EtOAc (80:20) as eluent to give 13
(344 mg, 53%) as a yellow oil. IR (neat): ν˜ ϭ 3062, 3027, 2933,
(400 MHz, CDCl3): δ ϭ 0.88 (t, J ϭ 6.9 Hz, 3 H), 0.89 (d, J ϭ
7.2 Hz, 3 H), 1.09 (d, J ϭ 6.3 Hz, 3 H), 1.13Ϫ1.37 (m, 6 H),
1.44Ϫ1.61 (m, 2 H), 1.96 (dd, J ϭ 9.2, 7.6 Hz, 1 H), 2.61 (q, J ϭ
6.3 Hz, 1 H), 2.74 (sext, J ϭ 7.2 Hz, 1 H), 3.11 (dd, J ϭ 9.2, 7.6 Hz,
1 H), 3.28 (d, J ϭ 13.2 Hz, 1 H), 3.69 (s, 3 H), 3.93 (d, J ϭ 13.2 Hz,
1 H), 7.20Ϫ7.35 (m, 5 H) ppm. 13C NMR (100 MHz, CDCl3): δ ϭ
14.23, 15.22, 15.87, 22.64, 25.21, 32.69, 32.90, 36.39, 51.32, 57.73,
58.37, 59.83, 66.20, 126.84, 128.24 (2C), 128.83 (2C), 139.58,
175.80 ppm. C20H31NO2 (317.47): calcd. C 75.67, H 9.84, N 4.41;
found C 75.70, H 9.94, N 4.42.
2862, 2795, 1729, 1495, 1453, 1194, 1094, 700 cmϪ1 1H NMR
.
(400 MHz, CDCl3): δ ϭ 1.16 (d, J ϭ 7.1 Hz, 2 H), 2.33 (t, J ϭ
8.7 Hz, 1 H), 2.47 (d, J ϭ 9.7 Hz, 1 H), 2.55 (quint., J ϭ 7.6 Hz,
1 H), 2.77 (d, J ϭ 13.2 Hz, 1 H), 2.91 (t, J ϭ 8.7 Hz, 1 H), 3.09
(d, J ϭ 9.7 Hz, 1 H), 3.16 (d, J ϭ 13.2 Hz, 1 H), 3.61Ϫ3.70 (m, 2
H), 3.65 (s, 3 H), 7.04Ϫ7.35 (m, 10 H) ppm. 13C NMR (100 MHz,
CDCl3): δ ϭ 13.71 (t, J ϭ 19.3 Hz, 1 C), 37.93, 40.72, 51.68, 55.50,
59.83, 60.15, 60.76, 126.46, 126.92, 128.24 (4 C), 128.66 (2 C),
129.57 (2 C), 138.27, 139.16, 176.34 ppm. C21H24DNO2 (324.43):
calcd. C 77.74, H 8.08, N 4.32; found C 78.05, H 7.80, N 4.27.
Methyl (3R*,4S*)-1,3-Dibenzyl-4-methylpyrrolidine-3-carboxylate
(10): Prepared according to procedure B from 3 (490 mg, 2 mmol)
and PhLi·LiBr (3.2 mL, 1.27  in Et2O, 4 mmol). The residue was
chromatographed with cyclohexane/EtOAc (80:20) as eluent to give
10 (356 mg, 55%) as a yellow oil. IR (neat): ν˜ ϭ 3062, 3028, 2959,
2795, 1728, 1604, 1495, 1473, 1454, 1436, 1377, 1357, 1314, 1271,
1196, 1133, 1097, 1070, 1029, 910, 735, 701 cmϪ1 1H NMR
.
Methyl
(3S*,4S*)-1,3-Dibenzyl-4-but-3-enylpyrrolidine-3-carb-
oxylate (14): Prepared according to procedure B from 3 (491 mg,
2 mmol). After 24 hours at room temperature, a solution of allyl
bromide (350 µL, 4 mmol) in degassed THF was added at room
temperature and the mixture stirred for 24 hours. After work up,
the residue was chromatographed with cyclohexane/EtOAc (80:20)
as eluent to give 14 (385 mg, 57%) as a yellow oil. IR (neat): ν˜ ϭ
3029, 2932, 2852, 2793, 2660, 1732, 1449, 1257, 1212, 904, 862,
(400 MHz, CDCl3): δ ϭ 1.28 (d, J ϭ 7.1 Hz, 3 H), 2.44 (t, J ϭ
8.6 Hz, 1 H), 2.60 (d, J ϭ 9.9 Hz, 1 H), 2.68 (m, 1 H), 2.86 (d, J ϭ
13.4 Hz, 1 H), 3.02 (t, J ϭ 8.6 Hz, 1 H), 3.24 (d, J ϭ 9.9 Hz, 1 H),
3.28 (d, J ϭ 13.4 Hz, 1 H), 3.72 (s, 3 H), 3.74 (s, 2 H), 7.15Ϫ7.46
(m, 10 H) ppm. 13C NMR (100 MHz, CDCl3): δ ϭ 14.06, 38.09,
40.88, 51.78, 55.58, 59.95, 60.27, 60.86, 126.59, 127.05, 128.35 (4C),
128.82 (2C), 129.66 (2C), 138.30, 139.13, 176.42 ppm. C21H25NO2
(323.434): calcd. C 77.98, H 7.79, N 4.33; found C 78.12, H 7.73,
N 4.26.
1
700 cmϪ1. H NMR (400 MHz, CDCl3): δ ϭ 1.46Ϫ1.56 (m, 1 H),
1.91Ϫ2.14 (m, 3 H), 2.35Ϫ2.45 (m, 2 H), 2.46 (d, J ϭ 9.6 Hz, 1
H), 2.80 (d, J ϭ 13.2 Hz, 1 H), 2.89Ϫ2.96 (m, 1 H), 3.03 (d, J ϭ
9.6 Hz, 1 H), 3.19 (d, J ϭ 13.2 Hz, 1 H), 3.58Ϫ3.68 (m, 2 H), 3.65
(s, 3 H), 4.96Ϫ4.99 (m, 1 H), 5.01Ϫ5.05 (m, 1 H), 5.82 (ddt, J ϭ
17.0, 10.0, 6.4 Hz, 1 H), 7.04Ϫ7.35 (m, 10 H) ppm. 13C NMR
(100 MHz, CDCl3): δ ϭ 28.75, 32.79, 37.79, 45.92, 51.70, 55.62,
58.98, 59.87, 60.17, 114.93, 126.48, 126.95, 128.22 (2C), 128.28
(2C), 128.64 (2C), 129.67 (2C), 138.25, 138.37, 139.20, 176.18 ppm.
C24H29NO2 (363.22); calcd. C 79.30, H 8.04, N 3.85; found C
78.33, H 7.92, N 3.90.
Methyl (3S*,4S*)-1-Benzyl-3-(cyclohex-1Ј-enylmethyl)-4-methylpyr-
rolidine-3-carboxylate (11): Prepared according to procedure B
from 3 (490 mg, 2 mmol) and cyclohexenyllithium (2.26 mL, 1.77
 in Et2O, 4 mmol). The residue was purified by chromatography
with cyclohexane/EtOAc (80:20) as eluent to give 11 (341 mg, 52%)
as a pale yellow oil. IR (neat): ν˜ ϭ 3026, 2932, 2861, 2835, 2791,
1731, 1495, 1453, 1375, 1270, 1202, 1172, 1136, 1099, 1069, 1028,
741, 699 cmϪ1 1H NMR (400 MHz, CDCl3): δ ϭ 1.04 (d, J ϭ
.
7.1 Hz, 3 H), 1.43Ϫ1.56 (m, 4 H), 1.69Ϫ1.82 (m, 2 H), 1.82Ϫ1.93
(m, 2 H), 2.06 (d, J ϭ 13.7 Hz, 1 H), 2.09 (t, 1 H, J ϭ 9.2 Hz,
8.6 Hz), 2.31 (d, J ϭ 10.2 Hz, 1 H), 2.43Ϫ2.49 (m, 2 H), 2.91 (dd,
J ϭ 9.2, 7.6 Hz, 1 H), 3.41 (d, J ϭ 10.2 Hz, 1 H), 3.61 (s, 2 H),
3.66 (s, 3 H), 5.34 (s, 1 H), 7.21Ϫ7.37 (m, 5 H) ppm. 13C NMR
(100 MHz, CDCl3): δ ϭ 13.75, 22.24, 23.05, 25.45, 29.01, 40.94,
41.23, 51.74, 53.62, 60.21, 60.78, 61.02, 124.46, 126.80, 128.20 (2C),
128.58 (2C), 134.41, 139.34, 177.30 ppm. HR MS (CI, methane):
m/z ϭ C21H30NO2 [MHϩ]: calcd. 328.2277; found 328.2271.
Methyl
(3S*,4S*)-1,3-Dibenzyl-4-iodomethylpyrrolidine-3-carb-
oxylate (15): Prepared according to procedure B from 3 (491 mg,
2 mmol). After 24 hours at room temperature, a solution of iodine
(1 g, 4 mmol) in degassed THF (5 mL) was added at 0 °C. The
cold bath was removed and the reaction mixture stirred at room
temperature until completion. The reaction was hydrolysed with an
aqueous solution of NH4Cl/NH4OH (2:1). The layers were separ-
ated, the aqueous one being extracted three times with ethyl acet-
ate. The combined organic layers were washed with brine, dried
over MgSO4 and the solvents evaporated under reduced pressure.
Methyl (3S*,4S*)-1-Benzyl-4-methyl-3-(2-methylallyl)pyrrolidine-3-
carboxylate (12): Prepared according to procedure B from 3 The residue was chromatographed with cyclohexane/EtOAc (80:20)
(490 mg, 2 mmol) and isopropenyllithium·LiBr (3.3 mL, 1.22  in
as eluent to give 15 (512 mg, 58%) as a yellow oil. IR (neat): ν˜ ϭ
Et2O, 4 mmol). The residue was chromatographed with cyclohex-
3084, 3061, 3027, 2948, 2792, 1731, 1603, 1494, 1454, 1434, 1272,
Eur. J. Org. Chem. 2002, 3536Ϫ3542
3541

F. Denes, F. Chemla, J. F. Normant
FULL PAPER
[5]
[6]
[7]
[8]
[9]
1216, 744, 700 cmϪ1. 1H NMR (400 MHz, CDCl3): δ ϭ 2.63Ϫ3.70
(m, 1 H), 2.67 (d, J ϭ 9.7 Hz, 1 H), 2.87 (d, J ϭ 12.9 Hz, 1 H),
2.90Ϫ2.96 (m, 1 H), 2.99 (d, J ϭ 9.7 Hz, 1 H), 3.05Ϫ3.10 (m, 1
H), 3.09 (d, J ϭ 12.9 Hz, 1 H), 3.25 (dd, J ϭ 12.2, 9.2 Hz, 1 H),
3.64 (s, 2 H), 3.65 (s, 3 H), 3.72 (dd, J ϭ 9.2, 3.6 Hz, 1 H),
6.98Ϫ7.01 (m, 2 H), 7.16Ϫ7.34 (m, 8 H) ppm. 13C NMR
(100 MHz, CDCl3): δ ϭ 5.60, 37.00, 48.99, 52.00, 56.60, 59.77 (2C),
60.52, 126.84, 127.11, 128.36 (4C), 128.66 (2C), 129.61 (2C),
137.16, 138.92, 175.03 ppm. This compound is too unstable to give
satisfactory elemental analysis.
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[10]
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[12]
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[14]
[15]
Acknowledgments
Thanks are due to Monique Baudry for the preparation of starting
`
materials and to the Ministere de la Recherche et de lЈEnseigne-
´
ment Superieur for a grant (to F. D.)
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F. Denes, F. Chemla, J. F. Normant, Synlett 2002, 919Ϫ922.
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[O02356]
3542
Eur. J. Org. Chem. 2002, 3536Ϫ3542