Radical-polar crossover domino reactions involving organozinc and mixed organocopper/organozinc reagents

Article abstract of DOI:10.1002/chem.200600334

A domino process involving Michael addition and carbocyclization has been developed starting from β-N-allylamino enoates and various organometallic reagents (organozinc halides, diorganozinc reagents, and copper/zinc mixed species). In all cases the mechanism of this domino reaction has been evidenced to involve a radical-polar crossover mechanism.

Full text of DOI:10.1002/chem.200600334

DOI: 10.1002/chem.200600334
Radical-Polar Crossover Domino Reactions Involving Organozinc and Mixed
Organocopper/Organozinc Reagents
Fabrice Denes, Sabrina Cutri, Alejandro Perez-Luna, and Fabrice Chemla*[a]
Abstract: A domino process involving Michael addition and carbocyclization has
been developed starting from b-N-allylamino enoates and various organometallic
reagents (organozinc halides,diorganozinc reagents,and copper/zinc mixed spe-
cies). In all cases the mechanism of this domino reaction has been evidenced to in-
volve a radical-polar crossover mechanism.
Keywords: copper · domino reac-
tions · Michael addition · radical
reactions · zinc
Introduction
We have recently shown (Scheme 1) that zinc enolates de-
rived from b-N-allyl amino esters undergo smooth and dia-
stereoselective carbocyclization to trans 3-carboxymethyl-4-
methylzinc compounds 1,which can be further functional-
ized to substituted trans-pyrrolidines 2.[1] The diastereoselec-
tivity was explained[2] by a transition state involving C-cen-
Scheme 2. Domino reaction with b-N-allyl amino enoates.[4]
tered[3] zinc enolate 3.
process was observed with higher order cyanocuprates or
zincates. By contrast the reaction occurs by a direct pathway
with mixed organocopper/organozinc reagents,without any
detection of the enolate 5 formed by Michael addition. Dia-
stereoselectivity is excellent in both processes,again in
favour of the trans-disubstituted metallated pyrrolidine 6-
Metal,which can be further functionalized.
Furthermore,in a preliminary communication
[5]
we also
reported that the same domino process can be carried out
with diorganozinc species. However,in this case the diaster-
eoselectivity is reversed,since the cis-substituted metallated
pyrrolidine 7-ZnBu is formed as the major product
[Eq. (1)]. This behaviour was attributed to a radical-polar
crossover mechanism involving molecular oxygen as initia-
tor.[6,7]
Scheme 1. Carbocyclization of b-N-allyl amino esters via zinc enolates.[1,2]
We later showed[4] that the same substituted pyrrolidines
can be obtained from the starting N-allyl methyl enoate 4a
by a domino process (Scheme 2) involving a Michael addi-
tion followed by a carbocyclization reaction. A stepwise
[a] Dr. F. Denes,Dr. S. Cutri,Dr. A. Perez-Luna,Prof. F. Chemla
UniversitØ Pierre et Marie Curie - Paris 6
Laboratoire de chimie organique (UMR CNRS 7611)
Institut de chimie molØculaire (FR 2769)
case 183,4 place Jussieu,75252 Paris cedex 05 (France)
Fax : (+33)144-277-567
Hereafter we give a full account of our results concerning
the mechanism (polar versus radical-polar crossover) of this
domino reaction.
E-mail: fchemla@ccr.jussieu.fr
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FULL PAPER
Results and Discussion
Reaction of enoates 4a–e with di-n-butylzinc: Di-n-butylzinc
reacted smoothly with Michael acceptor 4a at room temper-
ature. Pyrrolidine 8a was isolated in 88% yield after hydrol-
ysis of the resulting organometallic species 7-ZnBu. More-
over, 7-ZnBu was functionalized with various electrophiles
to give substituted pyrrolidines 9–11 in good yields
(Scheme 3). In situ oxidation by molecular oxygen during
the domino reaction afforded the corresponding lactone
12a. Solvent polarity seems to have no impact on the stereo-
selectivity of the reaction,as a similar cis:trans ratio was ob-
served in pentane (cis:trans=75:25),diethyl ether (76:24),
THF (72:28),and DMF (77:23).
The domino reaction was also performed on Michael ac-
ceptors bearing a substituent a to the nitrogen atom. Di-n-
butylzinc reacted at room temperature with Michael accept-
or 4b to afford after hydrolysis the corresponding pyrroli-
Scheme 4. Domino reaction with enoate 4b.
Reaction of enoate 4a with al-
kylzinc halides: Organozinc
halides are known to perform
1,4-addition processes only
under Lewis acid activation.[8]
However,we found that n-bu-
tylzinc bromide undergoes a
smooth domino process with
enoate 4a to afford pyrrolidine
8a in good yield. The diaster-
eoselectivity of this domino
process was found to be re-
versed compared to the reac-
tion with di-n-butylzinc and
the same as with copper/zinc
mixed reagents,that is the
trans diastereomer was the
major one [Eq. (3)].
Scheme 3. Functionalization of 7-ZnBu.
dine 8b in moderate yield (Scheme 4). Of the four possible
diastereomers,only two were observed. The structure of
each diastereomer was determined by NOE experiments.
The diastereoselectivity of the domino process is also
good with a substituent at the allylic position. When per-
formed with starting enoates 4c–e (Scheme 5),the reaction
led to a major or unique diastereomer 8c–e in good yields.
The structure of the major (or unique) diastereomer was in-
ferred from NOE experiments on the corresponding bicyclic
lactone 12d or 12e obtained from the starting enoates 4d or
4e after domino reaction and oxidation with molecular
oxygen.
In the reaction with 4a temperature has a strong influence
on the diastereoselectivity,which is reversed by performing
the reaction at low temperature [Eq. (2)]. Surprisingly,this
temperature effect was not observed for 4d and 4e,as no
difference in diastereoselectivity was found.
Scheme 5. Domino reactions with enoates 4c–e.
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F. Chemla et al.
polar nature of the 1,4-addition process, we performed our
domino reaction with enoate 4a and various n-butyl metals
in the presence of iPrI (Scheme 6).
Scheme 6. Scrambling experiments.
Interestingly,the diastereoselectivity is highly dependent
on the presence and amount of Li or Zn salts,as shown in
Table 1. For example,the diastereoselectivity is better with
At first,we reasoned that if the 14, -addition follows a rad-
ical mechanism,the initially formed nBu radical should
react rapidly with iPrI in an iodine-exchange reaction to
afford the more stable iPr radical,and the major product
should be 13 after addition of the iPr moiety. Our results
are reported in Table 2.
Table 1. Domino reaction of n-butylzinc bromide with Michael acceptor
4a [Eq. (3)].
[a]
Entry
X
BuZnX
(equiv)
ZnX2
(equiv)
Formed LiX
(equiv)
cis:trans
ratio[b]
1
2
3
4
5
6
7
Br
Br
Br
Br
Cl
2
2
2
1
1
0
1
0
2
2
2
41:59[c]
17:83[d]
27:73[c]
15:85[d]
33:67[c]
24:76[c]
21:79[c]
Table 2. Scrambling experiments with various nBuM and iPrI
(Scheme 6).
0[e]
1
Entry nBuM
iPrI
(equiv) ratio
8a/13[a] d.r.[a] 8a
d.r.[a] 13
(cis:trans)
2
1
1.2
3
1[f]
1.5
(cis:trans)
Br 1.2
Br
3
1
2
3
4
nBuZnBr
nBuZnBr
nBu2Zn
nBuCu(CN)ZnBr
1
5
5
5
60:40
26:74
19:81
30:70
20:80
14:86
74:26
10:90
13:87
11:89
64:36
11:89
[a] nBuZnBr was formed by mixing equimolar amounts of nBuLi and
ZnBr2 before reaction with 4a. [b] cis:trans ratios were determined by
GC. [c] 12 h were necessary to reach completion. [d] 24 h were necessary
to reach completion. [e] nBuZnBr formed by mixing equimolar amounts
of nBu2Zn and ZnBr2 before reaction with 4a. [f] Enoate 4a was precom-
plexed with ZnBr2 before addition of nBuZnBr.
1
[a] Determined by H NMR spectroscopy on the crude material.
In all cases iPr incorporation is competitive with the
nBuM reaction,or even the major pathway when iPrI is
used in excess. These results seem to indicate a radical
nature of the 1,4-addition step. However, we have no data
concerning the relative reaction rates of nBuM versus iPrM
in these 1,4-additions. These scrambling experiments make
sense only if there is no (or negligible) equilibrium between
nBuM and iPrM.[9] Equilibrium between dialkylzincs (or al-
kylzinc iodides) and alkyl iodides has been reported only
under irradiation[10] or at high temperature in the presence
of CuCN or CuI,[11] albeit in both cases with experimental
conditions very different to ours. We thus examined possible
exchange between various nBuM and dodecyl iodide under
our conditions [Eq. (5),Table 3].
salt-free nBuZnBr (formed by mixing equimolar amounts of
nBu2Zn and ZnBr2,Table 1,entry 3) than with
nBuZnBr
containing lithium salts (formed by a transmetallation of
nBuLi and ZnX2,Table 1,entries 1 and 5). The best compro-
mise (in terms of diastereoselectivity and reaction time) is
obtained by using an excess of nBuZnBr (prepared from
nBuLi and ZnBr2) with an excess of ZnBr2 (Table 1,
entry 7). Under these conditions,the use of ZnCl instead of
2
ZnBr2 is detrimental (compare Table 1,entries 4 and 5),and
the precomplexation of the starting material with ZnII salt
has no effect on the stereoselectivity (Table 1,entry 6).
The reaction is also efficient when the organozinc species
is prepared from a Grignard reagent. Starting from iPrMgCl
we obtained a good yield and a similar selectivity [Eq. (4)].
The results show that in our reaction media little ex-
change between alkylzinc bromide or dialkylzinc and alkyl
iodide is expected,but this exchange is accelerated in the
presence of CuI salts. Thus,at least in the case of copper/
zinc mixed reagents,the possibility of exchange prior to 14, -
Mechanism of the domino reaction with organozinc reagents
and copper/zinc mixed reagents: To establish the radical or
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Radical-Polar Crossover Domino Reactions
FULL PAPER
Table 3. Exchange between various nBuM and n-C12H25I [Eq. (5)]
reaction is observed for 14 shows that the cyclization step
also follows a radical mechanism,and that the radical
formed by 1,4-addition is not reduced to metal enolate 5.
Indeed,in the case of 14,the radical resulting from 14, -addi-
tion is not trapped by an unsaturated group,and thus the
radical chain is broken. By contrast,in the case of 4a,radi-
cal 15 adds to the unsaturated group in an easy 5-exo-trig
process to give new radical 16,which is then reduced to or-
ganometallic species 6 or 7,depending on the nature of the
metal.
Entry
nBuM
n-C12H25I/n-C12H25M ratio[a]
1
2
3
4
n-BuZnBr[b]
93:7
93:7
76:24
60:40
nBu2Zn
nBuCu(CN)ZnBr[c]
nBuCu(CN)ZnBr[c,d]
[a] Determined by measuring (GC with internal standard) the ratio n-
C12H25I:n-C12H26 after hydrolysis. [b] Prepared from nBuLi and ZnBr2 in
diethyl ether [c] Prepared by adding nBuLi to a CuCN/ZnBr2 mixture in
diethyl ether. [d] After a reaction time of 24 h.
This radical domino pathway is followed in the case of al-
kylzinc bromide,dialkylzinc,and,more surprisingly,in the
case of mixed organocopper/zinc reagents.
Diastereoselectivity: The diastereoselectivity of the carbo-
cyclization step via zinc enolates has been explained by tran-
sition state 3 (Scheme 9) involving a C-centred zinc enolate.
addition,and therefore a polar addition step,cannot be ex-
cluded. Besides,whatever the nature of the addition process
is (radical or polar),the scrambling experiments give no in-
formation regarding the nature (radical or polar) of the car-
bocyclization step.
To try to solve the problem,we thus examined the reac-
tivity of Michael acceptor 14 with various organometallic
species. We observed that no 1,4-addition occurred between
14 and nBu2Zn or nBuZnBr. More surprisingly,no reaction
was
observed
with
either
nBuCu(CN)ZnBr
or
PhCu(CN)ZnBr (Scheme 7). By contrast,rapid reaction of
14 occurs in the presence of nBu3ZnLi,although we were
unable to isolate any product (presumably due to b elimina-
tion and polymerization).
These results show unequivocally that the first step of our
domino reaction,that is,the 14,-addition process,follows a
radical mechanism (Scheme 8). Moreover,the fact that no
Scheme 9. Possible equilibration between 6 and 7.
The diastereoselectivity of the
radical-polar crossover reac-
tion involving nBu2Zn can be
explained through cyclization
of radical 15.
Considering the diastereodi-
vergency of our domino radi-
cal-polar crossover reaction,it
was interesting to verify that
the diastereoselectivity was not
the result of thermodynamic
control. Indeed an equilibrium
between 6 and 7 (Scheme 9)
Scheme 7. Reaction with enoate 14.
could be envisioned,and
a
thermodynamic preference
could favor one of these orga-
nometallic species depending
on the nature of the metal
À
À
ligand ( ZnBu versus ZnBr).
To check this,we prepared in-
dependently each organome-
tallic species 7-Bu and 6-Br
(Scheme 10) and transformed
them into their 7-Br and 6-Bu
counterparts through Schlenk
Scheme 8. Mechanism of the radical-polar crossover domino reaction.
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F. Chemla et al.
mediate could also be involved
in the case of nBu2Zn at low
temperature,although it is still
unclear why the reversal of
stereoselectivity is observed
only in the case where no sub-
stituent is present on the ring.
Conclusion
We have shown that the
domino Michael addition/car-
bocyclization reaction of orga-
Scheme 10. Impact of the nature of the metal ligand of the cyclized organometallic species.
equilibrium displacement or addition of nBuLi. No change
in stereoselectivity after hydrolysis was observed,that is,no
equilibrium exists between 7-Bu and 6-Bu,or between 7-Br
and 6-Br. Thus,the diastereoselectivity of the domino reac-
tion results only from the radical cyclization step.
nozinc halides,diorganozinc compounds and organocopper/
zinc mixed species with enoates 4a–e follows a pure radical-
polar crossover mechanism.[14] The radical 1,4-addition[15] is
followed by a 5-exo-trig radical cyclization and subsequent
reduction of the radical to an organometallic species. By this
process 3,4-disubstituted 3-carbomethoxyl pyrrolidines have
been prepared in good yields and good to excellent diaster-
eoselectivity. This diastereoselectivity is highly dependent
on the nature of the starting organometallic species. To the
best of our knowledge,the fact that organozinc halides and
copper/zinc mixed species can behave as radical precursors
is unprecedented[16] and these results could be linked to the
latest developments in enantioselective 1,4-addition of orga-
nozinc compounds catalyzed bu CuI complexes.[17]
The diastereoselectivity of the nBu2Zn domino reaction
can be explained (Scheme 11) by radical intermediate 17
Experimental Section
General remarks: Experiments involving organometallics were carried
out in dried glassware under a positive pressure of dry nitrogen. Liquid
nitrogen was used as a cryoscopic fluid. A three-necked round-bottom
flask equipped with an internal thermometer,a septum cap,a nitrogen or
argon inlet and a magnetic stirrer was used. Et2O was freshly distilled
from sodium benzophenone ketyl prior to use. Zinc bromide (98%) was
purchased from Aldrich. It was melted under dry nitrogen and,immedi-
ately after cooling to room temperature,was dissolved in anhydrous
Et2O. Commercial nBuLi was titrated with a 1m solution of sBuOH in
toluene in the presence of 2,2’-biquinoline. All other reagents and sol-
vents were of commercial quality and were used without purification.
Flash column chromatographic separations were carried out over Merck
silica gel 60 (0.015–0.040 mm). 1H NMR and 13C NMR spectra were re-
corded on a Bruker AVANCE 400 spectrometer. Chemical shifts are re-
ported in ppm relative to an internal standard of residual chloroform
(d=7.27 ppm for 1H NMR and d=77.1 ppm for 13C NMR). IR spectra
were recorded with a ATRD Bruker Tensor 27 spectrophotometer. MS
and HRMS were performed at the Service de SpectromØtrie de Masse de
l’Ecole Normale SupØrieure,24 rue Lhomond,75231 Paris Cedex 05. Ele-
mental analyses were performed at the Service de Microanalyses de
l’UniversitØ Pierre et Marie Curie,Bat F,case 55-4 place Jussieu,75252
Paris Cedex 05.
Scheme 11. Origin of diastereoselectivity in the radical-polar crossover
domino process.
following the Beckwith–Houk model.[12] For A1,3 strain[13]
minimization,the carbomethoxyl moiety should adopt a
pseudoequatorial position. The minor diasteromer could be
formed through cyclization of conformer 18. Again on the
basis of A1,3 strain minimization,this less favoured conform-
er should be further disfavoured when a sterically demand-
ing group R1 is present,and this explains the enhanced dia-
stereoselectivity observed for 4b–e.
By contrast,with organometallic species containing stron-
ger Lewis acids such as organozinc and mixed copper/zinc
species,the cyclization reaction should occur through radical
intermediate 19 (similar to organometallic species 3 in-
volved in the carbocyclization of zinc enolates),in which
chelation between the nitrogen atom,the oxygen atom of
General procedure 1: preparation of enoates 4a–e: Enoates 4a,b were
prepared as previously reported.[4] Substituted enoates 4c–e were pre-
pared from the corresponding substituted N-benzyl-N-allyl amines[18] by
the following general procedure: K2CO3 (6.90 g,50 mmol) and NaI
(0.75 g,5 mmol) were added to a stirred solution of amine (52 mmol) in
DMF (50 mL). The mixture was cooled to À108C and a solution of bro-
momethyl acrylic acid methyl ester (50 mmol) in DMF (50 mL) was
added dropwise. The reaction mixture was allowed to warm to room tem-
II
the carboxyl group,and a metal salt (Zn or CuI) would
counterbalance A1,3 strain minimization. This radical inter-
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Radical-Polar Crossover Domino Reactions
FULL PAPER
perature and stirred for 12–24 h. The reaction was quenched with brine
(100 mL). Et2O (50 mL) was added,the layers were separated and the
aqueous layer was extracted three times with Et2O. The combined organ-
ic layers were washed six times with brine and dried over MgSO4,and
the solvents were evaporated under reduced pressure to yield crude
enoates 4c–e.
3.66 (s,2H),3.68 (s,3H),7.21–7.35 ppm (m,5H);
CDCl3): d=14.09,15.16,22.54,25.61,32.39,38.48,43.69,51.32,56.75,
60.19,60.31,61.23,126.90,128.30 (2C),128.68 (2C),139.66,175.74 ppm;
elemental analysis (%) calcd for C19H29NO2: C 75.21,H 9.63,N 4.62;
found: C 75.04,H 9.64,N 4.62; further elution gave trans-8a[4] (132 mg,
22%).
13C NMR (100 MHz,
Methyl 2-[{N-benzyl-N-(1-methylallyl)amino}methyl]acrylate (4c): Pre-
pared according to general procedure 1 from N-benzyl-N-(1-methylallyl)-
amine (8.05 g,50 mmol). The residue was purified by chromatography
with cyclohexane/AcOEt (90/10) as eluent to give the title compound
(12.32 g,95%) as a yellow oil. IR (neat): n˜ =3063,3027,2970,2950,2931,
Methyl
(2S*,3R*,4S*)-1-benzyl-2,4-dimethyl-3-pentylpyrrolidine-3-car-
boxylate (8b): Prepared according to general procedure 2 from enoate
4b (520 mg,2 mmol) to yield the corresponding pyrrolidine as a mixture
of two diastereoisomers in a ratio of 87/13 (determined by GC). The resi-
due was purified by chromatography with cyclohexane/AcOEt (90/10) as
eluent to give the title compound (major diastereomer,311 mg,49%) as
2831,1721,1635,1494,1437,1371,1263,1195,1133,1073,1028,998,955,
À1
921,739,699 cm
;
1H NMR (400 MHz,CDCl 3): d=1.14 (d,3H, J=
a yellow oil. IR (neat): n˜ =3027,2933,2872,2795,1728,1495,1454,1379,
1329,1230,1197,1140,1096,1028,740,699 cm
;
1H NMR (400 MHz,
À1
6.6 Hz),3.22–3.38 (m,3H),3.56 (d,1H,
J=14.2 Hz),3.63 (d,1H, J=
14.2 Hz),3.72 (s,3H),5.06–5.16 (m,2H),5.84–5.93 (m,1H),5.96 (s,
1H),6.23 (s,1H),7.20–7.34 ppm (m,5H);
d=15.08,49.96,51.78,54.17,56.01,115.76,125.61,126.84,128.30 (2C),
128.50 (2C),139.18,139.70,140.43,167.75 ppm; elemental analysis (%)
calcd for C16H21NO2: C 74.10,H 8.16,N 5.40; found: C 74.29,H 8.24,N
5.24.
CDCl3): d=0.88 (t, J=6.9 Hz,3H),0.90 (d, J=7.1 Hz,3H),1.06 (d, J=
6.6 Hz,3H),1.21–1.39 (m,6H),1.55–1.67 (m,2H),1.93 (t, J=9.4 Hz,
1H),2.10 (dquint, J=10.2,6.6 Hz,1H),2.95 (dd, J=8.7,6.6 Hz,1H),
3.17 (q, J=6.6 Hz,1H),3.32 (d, J=12.7 Hz,1H),3.69 (s,3H),3.99 (d,
J=12.7 Hz,1H),7.21–7.34 ppm (m,5H);
13C NMR (100 MHz,CDCl 3):
d=14.23,15.18,16.25,22.68,25.37,33.00,33.75,40.78,51.22,58.56,58.72,
60.40,64.62,126.82,128.26 (2C),128.95 (2C),140.35,176.06 ppm; ele-
mental analysis (%) calcd for C20H31NO2: C 75.67,H 9.84,N 4.41; found:
C 75.70,H 9.94,N 4.42. Further elution gave methyl (2 S*,3R*,4R*)-1-
benzyl-2,4-dimethyl-3-pentylpyrrolidine-3-carboxylate.
13C NMR (100 MHz,CDCl 3):
Methyl 2-[{N-benzyl-N-(1-phenylallyl)amino}methyl]acrylate (4d): Pre-
pared according to general procedure 1 from N-benzyl-N-(1-phenylallyl)-
amine (2.23 g,10 mmol). The residue was purified by chromatography
with cyclohexane/AcOEt (95/5) as eluent to give the title compound
(2.83 g,88%) as a yellow oil. IR (neat): n˜ =3083,3062,2949,2931,2836,
Methyl (2S*,3R*,4R*)-1-benzyl-2,4-dimethyl-3-pentylpyrrolidine-3-car-
1721,1634,1601,1494,1449,1437,1384,1370,1303,1263,1195,1154,
boxylate: (minor diastereomer,45 mg,7%) : IR (neat): n˜ =3063,3027,
À1
;
1H NMR (400 MHz,CDCl 3): d=
À1
1116,1072,1029,929,747,699 cm
3.34 (s,2H),3.57 (d,1H
2955,2931,2871,2794,1731,1605,1454,1378,1232,1196,1127,698 cm
1H NMR (400 MHz,CDCl 3): d=0.84 (t, J=6.9 Hz,3H),0.98 (d,
7.1 Hz,3H),1.05 (d, J=6.6 Hz,3H),1.17–1.28 (m,6H),1.49–1.63 (m,
;
J=14.0 Hz),3.69 (d,1H, J=14.0 Hz),3.70 (s,
J=
3H),4.28 (d,1H, J=8.6 Hz),5.19 (d,1H, J=17.0 Hz),5.42 (dd,1H, J=
10.1,1.8 Hz),6.00–6.07 (m,1H),6.08 (s,1H),6.28 (s,1H),7.21–7.44 ppm
(m,10H); 13C NMR (100 MHz,CDCl 3): d=50.14,51.78,54.45,66.16,
119.58,125.79,126.98,127.12,128.08 (2C),128.30 (2C),128.40 (2C),
128.56 (2C),135.54,138.66,139.72,141.26,167.57 ppm; elemental analy-
sis (%) calcd for C21H23NO2: C 78.47,H 7.21,N 4.36; found: C 78.42,H
7.22,N 4.26.
2H),2.44 (dd, J=9.2,4.6 Hz,1H),2.52 (dd,
2.66 (m,1H),3.09 (q, J=6.6 Hz,1H),3.30 (d, J=13.3 Hz,1H),3.63 (s,
3H),3.87 (d, J=13.3 Hz,1H),7.16–7.27 ppm (m,5H);
13C NMR
J=9.2,7.6 Hz,1H),2.58–
(100 MHz,CDCl 3): d=14.19,14.51,15.89,22.62,25.80,29.50,32.84,
37.30,51.80,57.77,58.09,59.00,64.26,126.76,128.24 (2C),128.58 (2C),
140.29,177.70 ppm.
Methyl 2-[{N-Benzyl-N-(1-isopropylallyl)amino}methyl]acrylate (4e):
Prepared according to general procedure 1 from N-benzyl-N-(1-isopropy-
lallyl)amine (1.89 g,10 mmol). The residue was purified by chromatogra-
phy with cyclohexane/AcOEt (90/10) as eluent to give the title compound
(2.21 g,77%) as a yellow oil. IR (neat): n˜ =3066,3027,2953,2871,2834,
Methyl (3R*,4S*,5R*)-1-benzyl-4,5-dimethyl-3-pentylpyrrolidine-3-car-
boxylate (8c): Prepared according to general procedure 2 from enoate 4c
(519 mg,2 mmol). The residue was purified by chromatography with cy-
clohexane/AcOEt (90/10) as eluent to give 8c (406 mg,64%) as a yellow
oil. IR (neat): n˜ =3027,2932,2861,2795,1729,1495,1454,1375,1323,
À1
1227,1194,1143,1029,739,699 cm
;
1H NMR (400 MHz,CDCl 3): d=
1722,1634,1494,1437,1383,1369,1304,1264,1195,1155,1137,1092,
À1
1071,1028,1000,922,742,699 cm
;
1H NMR (400 MHz,CDCl 3): d=
0.83 (t, J=6.9 Hz,3H),0.88 (d, J=7.1 Hz,3H),1.05–1.14 (m,2H),1.12
(d, J=5.6 Hz,3H),1.15–1.28 (m,4H),1.42–1.49 (m,1H),1.57–1.65 (m,
0.75 (d, J=6.6 Hz,3H),0.99 (d, J=6.6 Hz,3H),1.78 (m,1H),2.47 (dd,
J=10.2,9.7 Hz,1H),3.07 (d, J=15.8 Hz,1H),3.30 (d, J=14.0 Hz,1H),
1H),1.78–1.85 (m,1H),2.23 (dq,
10.2 Hz,1H),2.82 (d, J=10.2 Hz,1H),3.29 (d, J=13.2 Hz,1H),3.65 (s,
3H),4.01 (d, J=13.2 Hz,1H),7.21–7.35 ppm (m,5H);
13C NMR
J=8.7,5.6 Hz,1H),2.78 (d,
J=
3.49 (dd, J=15.8,2.0 Hz,1H),3.73 (s,3H),3.82 (d,
J=14.0 Hz,1H),
4.93 (dd, J=17.3,2.0 Hz,1H),5.30 (dd, J=10.2,2.5 Hz,1H),5.63 (dt,
J=17.3,9.7 Hz,1H),5.97 (m,1H),6.23 (m,1H),7.21–7.35 ppm (m,
5H); 13C NMR (100 MHz,CDCl 3): d=20.52,20.88,29.34,50.19,51.78,
54.47,69.19,119.18,125.75,126.84,128.26 (2C),128.91 (2C),135.19,
139.04,140.17,167.89 ppm.
(100 MHz,CDCl 3): d=13.79,14.09,18.20,22.48,25.52,32.41,38.25,
51.22,51.26,55.20,57.90,59.32,66.10,126.72,128.24 (2C),128.66 (2C),
140.27,176.00 ppm; elemental analysis (%) calcd for C 20H31NO2: C 75.67,
H 9.84,N 4.41; found: C 75.75,H 9.71,N 4.31.
General procedure 2: domino reactions with di-n-butylzinc: nBu2Zn
(2 mL,ca. 2 n in heptane,4 mmol) was added to a stirred solution of
acrylic ester (2 mmol) in Et2O (10 mL) at room temperature. The reac-
tion mixture was stirred at room temperature for 12 h. The reaction mix-
ture was hydrolyzed with an aqueous solution of NH4Cl/NH4OH (2/1).
The layers were separated,and the aqueous layer was extracted three
times with ethyl acetate. The combined organic layers were washed with
Methyl (3R*,4S*,5R*)-1-benzyl-4-methyl-3-pentyl-5-phenylpyrrolidine-3-
carboxylate (8d): Prepared according to general procedure 2 from
enoate 4d (683 mg,2 mmol). The residue was purified by chromatogra-
phy with cyclohexane/AcOEt (90/10) as eluent to give 8d (486 mg,64%)
as a yellow oil. 1H NMR (400 MHz,CDCl 3): d=0.73 (d, J=7.1 Hz,3H),
0.76 (t, J=6.9 Hz,3H),1.04–1.25 (m,6H),1.48–1.56 (m,1H),1.73–1.84
(m,2H),2.81 (d, J=10.2 Hz,1H),2.92 (d, J=10.2 Hz,1H),3.10 (d, J=
brine,dried over MgSO and the solvents evaporated under reduced
4
10.2 Hz,1H),3.11 (d, J=13.2 Hz,1H),3.61 (s,3H),3.69 (d,
J=13.2 Hz,
1H),7.10–7.38 ppm (m,10H);
13C NMR (100 MHz,CDCl 3): d=13.26,
pressure.
14.13,22.54,25.56,32.47,38.32,51.42,53.04,55.60,57.75,58.90,76.41,
126.74,127.53,128.06 (2C),128.24 (2C),128.46 (2C),128.56 (2C),
140.11,142.33,175.98 ppm; elemental analysis (%) calcd for C 25H33NO2:
C 79.11,H 8.76,N 3.69; found: C 79.07,H 8.94,N 3.59. Further elution
Methyl
(3R*,4S*)-1-benzyl-4-methyl-3-pentylpyrrolidine-3-carboxylate
(cis-8a): Prepared according to general procedure 2 from enoate 4a
(490 mg,2 mmol). The residue was purified by chromatography with cy-
clohexane/AcOEt (80/20) as eluent to give cis-8a (400 mg,66%) : IR
(neat): n˜ =3027,2954,2931,2859,2790,1731,1495,1454,1377,1346,
1253,1231,1197,1142,1070,1029,985,739,699 cm
gave (2aR*,5S*,5aS*)-4-benzyl-2a-pentyl-5-phenylhexahydropyrrolo
c]furan-2-one (12d).
A
À1
;
1H NMR
(400 MHz,CDCl 3): d=0.86 (t, J=7.1 Hz,3H),0.91 (d, J=6.6 Hz,3H),
1.11–1.31 (m,6H),1.47–1.54 (m,1H),1.82–1.90 (m,1H),2.07–2.16 (m,
(2aR*,5S*,5aS*)-4-Benzyl-2a-pentyl-5-phenylhexahydropyrrolo[3,4-
C
2H),2.76 (d, J=9.8 Hz,1H),2.92–3.00 (m,1H),2.99 (d,
J=9.8 Hz,1H),
Chem. Eur. J. 2006, 12,6506 – 6513
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA,Weinheim
www.chemeurj.org
6511

F. Chemla et al.
(d, J=10.2 Hz,1H),2.67 (m,1H),2.99 (d,
10.2 Hz,1H),3.32 (d, J=9.2 Hz,1H),3.76 (d, J=13.2 Hz,1H),4.19–4.27
(m,2H),7.21–7.51 ppm (m,10H);
13C NMR (100 MHz,CDCl 3): d=
14.05,22.52,24.77,31.99,36.60,52.77,54.45,56.96,61.97,68.89,76.11,
127.17,127.75,128.38 (4C),128.58 (2C),129.13 (2C),138.43,140.15,
181.78 ppm; HRMS calcd for C24H30NO2 [MÀH]+: m/z 364.2277; found:
364.2281.
J=13.2 Hz,1H),3.11 (d, J=
solvents were evaporated under reduced pressure. The residue was puri-
fied by chromatography with cyclohexane/AcOEt (80/20) as eluent to
give 83 (412 mg,48%) as an inseparable mixture of two diastereoisomers.
Major diastereoisomer: 1H NMR (400 MHz,CDCl 3): d=0.86 (t, J=
6.9 Hz,3H),1.04–1.30 (m,6H),1.57–1.65 (m,1H),1.84–1.91 (m,1H),
2.38 (t, J=8.7 Hz,1H),2.44–2.52 (m,1H),2.75 (d,
J=9.7 Hz,1H),3.01
(dd, J=11.7,9.2 Hz,1H),3.07 (d, J=9.7 Hz,1H),6.19 (m,1H),3.37
(dd, J=9.7,3.6 Hz,1H),3.63–3.73 (m,2H),3.70 (s,3H),7.23–7.35 ppm
Methyl
(3R*,4S*,5R*)-1-benzyl-5-isopropyl-4-methyl-3-pentylpyrroli-
(m,5H); 13C NMR (100 MHz,CDCl ): d=6.39,14.05,22.46,25.19,32.15,
3
dine-3-carboxylate (8e): The product was prepared according to general
procedure 2 from enoate 4e (575 mg,2 mmol). The residue was purified
by chromatography with cyclohexane/AcOEt (90/10) as eluent to give
the title compound (387 mg,56%) as a yellow oil. IR (neat): n˜ =3027,
38.94,51.34,51.85,57.20,59.81,60.86,61.08,127.09,128.40 (2C),128.56
(2C),139.02,174.44 ppm; elemental analysis (%) calcd for C 19H28INO2:
C 53.15,H 6.57,N 3.26; found: C 53.26,H 6.58,N 3.31.
(2aR*,5aS*)-4-Benzyl-2a-pentylhexahydropyrrolo[3,4-c]furan-2-one
A
2956,2931,2872,2789,1732,1495,1454,1384,1372,1289,1254,1223,
1197,1134,1029,1005,738,698 cm
0.84 (t, J=6.9 Hz,3H),0.90 (d, J=7.1 Hz,3H),0.96 (d, J=7.1 Hz,3H),
1.01 (d, J=7.1 Hz,3H),1.16–1.28 (m,6H),1.61–1.68 (m,1H),1.76–1.86
À1
;
1H NMR (400 MHz,CDCl 3): d=
(12a): nBu2Zn (2 mL,ca. 2 n in heptane,4 mmol) was added to a stirred
solution of 4a (491 mg,2 mmol) in THF (10 mL) in a flask topped by a
drying tube fitted with CaCl2 at room temperature. The reaction mixture
was stirred at room temperature for 12 h. Activated zinc (for reduction
of potential peroxo intermediates,120 mg) was added and the reaction
mixture stirred at room temperature for 1 h. The reaction mixture was
hydrolyzed with an aqueous solution of NH4Cl/NH4OH (2/1). The layers
were separated,and the aqueous layer was extracted three times with
ethyl acetate. The combined organic layers were washed with brine,dried
over MgSO4 and the solvents evaporated under reduced pressure. The
residue was purified by chromatography with cyclohexane/AcOEt (90/10)
to give 12a (115 mg,20%) as a yellow oil. 1H NMR (400 MHz,CDCl 3):
d=0.87 (t, J=6.6 Hz,3H),1.21–1.43 (m,6H),1.51–1.58 (m,1H),1.74–
(m,2H),2.03–2.05 (m,2H),2.53 (d,
10.2 Hz,1H),3.16 (d, J=13.7 Hz,1H),3.64 (s,3H),4.02 (d,
1H),7.19–7.34 ppm (m,5H);
J=10.2 Hz,1H),2.78 (d,
J=
J=13.7 Hz,
13C NMR (100 MHz,CDCl 3): d=14.11,
17.51,18.46,20.02,22.48,25.29,28.81,32.29,37.59,43.39,51.20,55.58,
57.06,58.56,76.70,126.68,128.28 (4C),140.76,175.72 ppm; elemental
analysis (%) calcd for C22H35NO2: C 76.47,H 10.21,N 4.05; found: C
76.56,H 10.29,N 3.96. Further elution gave (2a R*,5S*,5aS*)-4-benzyl-2a-
pentyl-5-isopropylhexahydropyrrolo[3,4-c]furan-2-one (12e).
R
(2aR*,5S*,5aS*)-4-Benzyl-2a-pentyl-5-isopropylhexahydropyrrolo[3,4-
A
c]furan-2-one (12e): (20 mg,3%). 1H NMR (400 MHz,CDCl 3): d=0.87
(t, J=6.9 Hz,3H),0.94 (d, J=6.6 Hz,3H),0.99 (d, J=7.1 Hz,3H),1.15–
1.39 (m,6H),1.61–1.77 (m,2H),2.12–2.20 (m,1H),2.44–2.46 (m,1H),
1.81 (dt, J=12.7,4.1 Hz,1H),2.17 (d,
6.6 Hz,1H),2.64–2.71 (m,1H),2.82 (d,
J=9.2 Hz,1H),2.47 (dd, J=9.2,
J=9.7 Hz,1H),3.27 (d, J=
9.2 Hz,1H),3.50 (d, J=13.2 Hz,1H),3.61 (d, J=13.2 Hz,1H),4.04 (dd,
2.45 (d, J=10.2 Hz,1H),2.60 (dt,
J=7.6,3.1 Hz,1H),2.87 (d,
J=
J=9.2,3.6 Hz,1H),4.39 (t,
J=9.2 Hz,1H),7.21–7.33 ppm (m,5H);
10.2 Hz,1H),3.05 (d, J=13.2 Hz,1H),3.99 (d, J=13.2 Hz,1H),4.13
(dd, J=9.7,3.6 Hz,1H),4.33 (dd, J=9.7,8.7 Hz,1H),7.21–7.34 ppm (m,
5H); 13C NMR (100 MHz,CDCl 3): d=14.07,15.57,20.22,22.48,24.73,
27.64,32.03,36.25,43.39,44.16,52.49,57.18,62.99,71.52,127.19,128.48
13C NMR (100 MHz,CDCl 3): d=14.07,22.50,25.17,32.09,34.63,42.58,
55.00,58.98,61.19,64.06,72.93,127.21,128.42 (2C),128.52 (2C),138.43,
181.78 ppm; HRMS calcd for C18H26NO2 [MÀH]+: m/z 288.1964; found:
288.1961.
(2C),128.58 (2C),138.96,181.38 ppm; HRMS calcd for C
21H32NO2
Methyl
1-benzyl-3-isobutyl-4-methylpyrrolidine-3-carboxylate
(13):
[MÀH]+: m/z 330.2433; found: 330.2434.
iPrMgCl (2.2m in Et2O,1.35 mL,3 mmol)was added to ZnBr
(1m in
2
Methyl (3R*,4S*)-1-benzyl-4-but-3-enyl-3-pentylpyrrolidine-3-carboxy-
late (10): nBu2Zn (2 mL,ca. 2 n in heptane,4 mmol) was added to a stir-
red solution of acrylic ester 4a (491 mg,2 mmol) in Et 2O (10 mL) at
room temperature. The reaction mixture was stirred at room temperature
for 12 h. CuCN (36 mg,0.4 mmol) was added at room temperature in one
portion. The reaction mixture was stirred for 30 min. Degassed THF
(10 mL) was added,followed by allyl bromide (0.7 mL,8 mmol). The re-
action mixture was stirred at room temperature for 15 h. After workup,
the residue was purified by chromatography with cyclohexane/AcOEt
(80/20) as eluent to give 10 (466 mg,68%) as a mixture of two diaster-
eoisomers in a 76:24 ratio (determined by GC). Purification by chroma-
tography afforded cis-10 (260 mg,38%) as a yellow oil. IR (neat): n˜ =
Et2O,4.5 mL,4.5 mmol) at À788C. The temperature was raised to 08C
and the mixture stirred for 25 min. A solution of enoate 4a (245 mg,
1 mmol) was added via canula and the cooling bath was removed. The
mixture was stirred at room temperature for 4 h and an aqueous solution
of NH4Cl/NH4OH (2:1) (8 mL) was added. The aqueous layer was ex-
tracted with EtOAc (3ꢁ20 mL). The combined organic layers were
washed with brine (20 mL),dried over MgSO ,filtered and concentrated.
4
Purification by flash chromatography (cyclohexane/ethyl acetate 60/40)
afforded the title compound (250 mg,87%) as a mixture of two diaster-
eoisomers (d.r.=87:13 by 1H NMR spectroscopy) as a colorless oil. IR
(CHCl3): n˜ =3027,2955,2872,2789,1731,1454,1138,739,699;
1H NMR
(CDCl3,400 MHz): d=0.80 (d, J=6.6 Hz,3H),0.90 (d, J=6.6 Hz,3H),
1.04 (d, J=7.1 Hz,3H),1.42 (dd, J=13.4,5.3 Hz,1H),1.52 (m,1H),
1.71 (dd, J=13.4,7.6 Hz,1H),2.03 (t, J=8.8 Hz,1H),2.19 (d, J=9.9 Hz,
3027,2931,2859,2790,1729,1641,1495,1454,1378,1345,1228,1198,
À1
1140,1072,1028,993,911,739,699 cm
;
1H NMR (400 MHz,CDCl 3):
d=0.86 (t, J=6.9 Hz,3H),1.10–1.32 (m,7H),1.46–1.61 (m,2H),1.84–
1.96 (m,2H),1.97–2.07 (m,2H),2.16 (t, J=8.9 Hz,1H),2.80 (d, J=
9.7 Hz,1H),2.95 (d, J=9.7 Hz,1H),3.04 (dd, J=8.7,6.1 Hz,1H),3.65
(d, J=13.2 Hz,1H),3.68 (s,3H),3.71 (d, J=13.2 Hz,1H),4.92–4.99 (m,
2H),5.75 (ddt, J=17.3,10.2,6.6 Hz,1H),7.22–7.35 ppm (m,5H);
13C NMR (100 MHz,CDCl 3): d=14.11,22.54,25.62,29.42,32.43,32.77,
38.44,48.79,51.44,56.45,59.24,60.36,60.48,114.91,127.01,128.36 (2C),
1H),2.47 (ddd, J=15.8,14.3,7.2 Hz,1H),2.98 (dd,
3.56 (d, J=2.8 Hz,1H),3.59 (d, J=6.6 Hz,1H),3.68 (d, J=6.6 Hz,1H),
3.70 (s,3H),7.22–7.40 ppm (m,5H);
13C NMR (CDCl3,100 MHz):
J=8.9,7.1 Hz,1H),
d
13.7,22.7,24.5,25.4,41.0,41.5,51.7,53.4,60.2,61.2 (2C),126.8,128.2
(2C),128.5 (2C),139.2,177.8 ppm; MS (CI NH 3): 290 ([MH]+); elemen-
tal analysis (%) calcd for C18H27NO2: C 74.70,H 9.40,N 4.84; found: C
74.34,H 9.21,N 4.45.
128.74 (2C),138.41,139.46,175.76 ppm; HRMS calcd for C
22H34NO2
[MÀH]+: m/z 344.2590; found: 344.2585.
Methyl (3R*,4S*)-1-benzyl-4-iodomethyl-3-pentylpyrrolidine-3-carboxy-
late (11): nBu2Zn (2 mL,ca. 2 n in heptane,4 mmol) was added to a stir-
red solution of acrylic ester 4a (491 mg,2 mmol) in Et 2O (10 mL) at
room temperature. The reaction mixture was stirred at room temperature
for 12 h. the reaction mixture was cooled to À408C and a solution of I2
(2.03 g,8 mmol) in degassed THF (10 mL) was added dropwise. After
30 min at À408C,the reaction mixture was hydrolyzed with an aqueous
solution of NH4Cl/NH4OH (2/1). The layers were separated,and the
aqueous layer was extracted three times with Et2O. The combined organ-
Acknowledgements
Thanks are due to Prof. Michꢂle Bertrand (Aix-Marseille III) for helpful
discussions.
ic layers were washed with brine and Na2SO3,dried over MgSO and the
[1] F. Denes,F. Chemla,J. F. Normant, Synlett 2002,919–922.
4
6512
www.chemeurj.org
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA,Weinheim
Chem. Eur. J. 2006, 12,6506 – 6513

Radical-Polar Crossover Domino Reactions
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Tetrahedron
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Received: March 9,2006
Published online: June 21,2006
Chem. Eur. J. 2006, 12,6506 – 6513
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6513