Chiral 3-aminopyrrolidines as a rigid diamino scaffold for organocatalysis and organometallic chemistry

Article abstract of DOI:10.1016/j.tetasy.2010.04.038

Over 20 new and easily prepared diamines were screened for the asymmetric Morita-Baylis-Hillman reaction. Chiral non-racemic 3-(N,N-dimethylamino)-1- methylpyrrolidine was found to promote efficiently the reaction of methyl vinyl ketone and substituted benzaldehydes. Enantiomeric excesses up to 73% were reached with electron-deficient benzaldehyde derivatives. After a simple deprotonation, one of these diamines was transformed into a chiral mixed aggregate for the enantioselective synthesis of (R)-1-o-tolylethanol with 76% ee.

Full text of DOI:10.1016/j.tetasy.2010.04.038

Tetrahedron: Asymmetry 21 (2010) 1511–1521
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Chiral 3-aminopyrrolidines as a rigid diamino scaffold for organocatalysis
and organometallic chemistry
Mickael Pouliquen a, Jérôme Blanchet a, Michaël De Paolis b, B. Rema Devi b, Jacques Rouden a,
,
*
Marie-Claire Lasne a, Jacques Maddaluno b,
*
a Laboratoire de Chimie Moléculaire et Thioorganique, CNRS UMR 6507 & FR 3038, ENSICAEN and Université de Caen-Basse Normandie, 6 Boulevard du Marechal Juin,
14050 Caen Cedex, France
b Institut de Recherche en Chimie Organique Fine, CNRS UMR 6014 & FR 3038, Université de Rouen and INSA de Rouen, 76821, Mont St Aignan Cedex, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Over 20 new and easily prepared diamines were screened for the asymmetric Morita–Baylis–Hillman
reaction. Chiral non-racemic 3-(N,N-dimethylamino)-1-methylpyrrolidine was found to promote effi-
ciently the reaction of methyl vinyl ketone and substituted benzaldehydes. Enantiomeric excesses up
to 73% were reached with electron-deficient benzaldehyde derivatives. After a simple deprotonation,
one of these diamines was transformed into a chiral mixed aggregate for the enantioselective synthesis
of (R)-1-o-tolylethanol with 76% ee.
Received 3 March 2010
Accepted 1 April 2010
Available online 11 June 2010
Dedicated to Professor Henri Kagan on the
occasion of his 80th birthday.
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
many research groups have developed intensive research programs
with the aim of widening the scope of the reaction. A considerable
The work of pioneer groups such as that of Henri Kagan in the
field of asymmetric synthesis has endowed the organic chemistry
community with a set of tools allowing the strict control of the
newly created stereogenic centers on a routine basis. In many
cases, the efforts dedicated to the understanding of the elementary
mechanisms through which the stereochemical information is
transferred have made these major progresses possible.1 Because
the selective formation of carbon–carbon bonds is of paramount
importance to organic synthesis, a plethora of strategies based on
the use of various transition metals in stoichiometric or catalytic
amount has emerged. The recent renaissance of organocatalysis
has come to complete this methodologic arsenal through the
introduction of important developments in the aldol, Mannich,
Friedel–Craft or Diels–Alder reactions.2 Herein, resultsare presented
suggesting that the relatively rigid diamino scaffold found in the
3-aminopyrrolidine derivatives can be successfully employed not
only in the organocatalytic version of the Morita–Baylis–Hillman
reaction but also, as demonstrated before,3 in the 1,2-enantioselec-
tive addition of methylithium on o-tolualdehyde.
attention has been drawn to improve the kinetics of the reaction5
or to control the absolute configuration of the stereogenic center
generated during the reaction. From the pioneering survey of Hira-
ma6 to Hatakeyama0s milestone work,7 many enantioselective ap-
proaches have been reported using chiral phosphines,8 Brønsted
acids,9 peptides,10 bicyclic amines,11 sulfide12 or alkaloids deriva-
tives.13 Recently, highly selective bifunctional catalysts combining
a Brønsted acid with a Lewis base have appeared in the literature.14
However, the control of the stereochemistry remains a chal-
lenge for simple acceptors such as methyl vinyl ketone. Chiral ter-
tiary amine 1a in the presence of L-proline have been shown to
catalyze the reaction between methyl vinyl ketone and 2-nitro-
benzaldehyde with enantiomeric excesses (ee0s) as high as 83%
(Fig. 1).15 Hayashi reported good yields and ees (up to 75%) for
the enantioselective coupling of methyl vinyl ketone with various
aryl aldehydes in the presence of 30 mol % of the bis-pyrrolidine
1b.16 Similarly, N,N,N0,N0-tetramethyl-propane-1,3-diamine 1c
was recently identified as an efficient promoter in the Morita–Bay-
lis–Hillman reaction of cycloalkenones known to be poor sub-
strates.17 The use of chiral diamines has been neglected in this
reaction despite their higher stabilities and availabilities compared
to alkylphosphines.
The Morita–Baylis–Hillman reaction provides probably the
mildest synthesis of b-hydroxy-a-methylene carbonyl compounds
and has been comprehensively reviewed.4 The attractive character
of such a methodology resides in the variety of functional groups
present in the adduct, allowing further easy modification for the
preparation of useful organic compounds. During the last decade,
In the course of our program on organocatalysis,18 we antici-
pated that chiral diamines such as sparteine 2, its enantiomer suro-
gate 319 derived from (ꢀ)-cytisine another lupin alkaloid or
permethylated 3-aminopyrrolidine 4 could be suitable candidates
to catalyze the Morita–Baylis–Hillman reaction (Fig. 1). Tertiary
diamines 2 or 3 are well-known compounds to induce asymmetry
in various reactions,20 enantiopure 3-aminopyrrolidine derivatives
* Corresponding authors. Tel.: +33 231 452 893 (J.R.); tel.: +33 235 532 446 (J.M.).
E-mail addresses: jacques.rouden@ensicaen.fr (J. Rouden), jmaddalu@crihan.fr
(J. Maddaluno).
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.04.038

1512
M. Pouliquen et al. / Tetrahedron: Asymmetry 21 (2010) 1511–1521
Under various conditions, we investigated the minimum
N
requirements to promote the reaction and to observe an asymmet-
ric induction. The Morita–Baylis–Hillman adduct was isolated by
column chromatography and its enantiomeric excess measured
by chiral HPLC. From this first set of experiments, the best results
are reported in Table 1.
N
N
N
N
Me
N
H
1a
1c
1b
H
N
N(Me)2
Me
H
N
N
N
H
N
N
Me
Table 1
2
3
Preliminary amine screening in the Morita–Baylis–Hillman reaction
4
Me
N
OH
O
O
N
CHO
Me
Me
Me
N
6
5
O2N
O2N
chiral amine
(S)
Figure 1. Known chiral amines 1a,b,c for the Morita–Baylis–Hillman reaction and
initial set of tested amines 2–6.
conditions
Entry Amine Amine
(mol %)
Solvent T (°C) Time (h) % Yielda (ee)b
were shown to be excellent chiral ligands in the addition of orga-
nolithium reagents to aldehydes.3 These amines including Troger’s
base 5 and bisproline derivative 6 could well stabilize the enolate
intermediate through an interaction between the generated
ammonium and the free amine function (Scheme 1).
1
2
3
4
5
6
7
2
3
4
4
5
6
6
20
20
16
16
20
20
20
DMSO
DMSO
EtOH
DMSO
DMSO
DMSO
EtOH
20
20
0
20
20
20
20
48
48
96
96
48
48
48
0 (—)
15 (0)
71 (31)
59 (10)
0 (—)
100 (7)
86 (0)
R1
R3
Reaction conditions: methyl vinyl ketone (1 equiv), 4-O2NC6H4CHO (1.5 equiv, 2–
0.5 mmol scale).
N
R2
N
R4
O
O
OH
Ar
a
Isolated yields.
Ar-CHO
+
b
Me
Determined by chiral HPLC.
Me
The data in Table 1 show that only aminopyrrolidine 4 and pro-
line derivative 6 were efficient in promoting the Morita–Baylis–
Hillman reaction (entries 3, 4, 6, 7). Sparteine 2, Troger’s base 5,
(ꢀ)-cytisine derivatives 3 did not allow the reaction to proceed.
A polar (protic or aprotic) solvent was necessary in order to achieve
a high conversion (data not shown for other types of solvent). The
steric hindrance around the amine functions appeared to play an
important role (entries 1, 2, 5). Diamines 4 and 6 displayed similar
reactivities in ethanol (entries 3 and 7) but only aminopyrrolidine
4 led to an asymmetric induction (ee 31%). This promising result
led us to further investigate the parameters of the reaction with
tertiary diamine 4.
The influence of the reaction conditions (solvent, catalyst load-
ing and temperature) on the Morita–Baylis–Hillman reaction of
methyl vinyl ketone with 4-nitrobenzaldehyde in the presence of
aminopyrrolidine 4 was explored. The results are summarized in
Table 2. Compared to other solvents which afforded sluggish re-
sults and low selectivity (data not shown), the reaction was clean
in alcohols and the Morita–Baylis–Hillman adduct was isolated in
Ar
O
N
Ar
O
O
O
Me
R2
R1
O
Me
Me
R2
R1
NH
Ar-CHO
R3
H
H
N
NH
R4
R1
N R4
R3
N
R4
R2
R3
Scheme 1. Intramolecular stabilization of enolate by diamines.
Moreover, this amine could assist the deprotonation step neces-
sary to release the catalyst. We describe herein our results on the
efficiency (yields and asymmetric induction) of various chiral dia-
mines in the Morita–Baylis–Hillman reaction.
2. Results and discussion
First, we chose to screen chiral amines 2–6 (Fig. 1) in a model
reaction for the Morita–Baylis–Hillman reaction using a reactive
electrophile (4-nitrobenzaldehyde) and
a Michael acceptor
Table 2
(methyl vinyl ketone). Amines 2–6 were either commercially avail-
able (sparteine 2 and Troger’s base 5) or easily prepared, 3 from
(ꢀ)-cytisine,22,17 6 from proline23,24 and 4 in high yield from (R)-
3-aminopyrrolidine 7 (Scheme 2). This straightforward four-step
synthesis furnished pure diamine 4 in 79% overall yield and could
be carried out on a multigram scale.
Ees and efficiency of 4 as a function of the reaction conditions
Entry
Solvent
4 (mol %)
T (°C)
Yielda (ee)b
%
1
2
3
MeOH
EtOH
i-PrOH
BuOH
8
16
16
8
0
0
0
65 (37)
71 (31)
87 (54)
81 (46)
80 (46)
95 (34)
81 (50)
100 (20)
91 (61)
98 (37)
100 (26)
92 (27)
4
0
5
6
7
8
s-BuOH
t-BuOH
sAmylOH
Dioxane/i-PrOH 1:1
i-PrOH
i-PrOH
i-PrOH
i-PrOH
8
16
8
16
60
8
0
20
0
Me
Me
NH2
N
N
Me
Me
c
a
0
9
ꢀ15
N
Bn
N
R
N
R
10
11
12
0
8
16
20
20
8 R = Bn
9.HCl R = H
10 R = CO2Et
4 R = Me
(R)-7
b
d
Reaction conditions: (R)-4 ꢁ mol %, methyl vinyl ketone (3 equiv, 0.5 mmol scale),
96 h.
a
Isolated yields.
Determined by chiral HPLC.
Scheme 2. Reagents and conditions: (a) HCHO, HCO2H, 80 °C, 95%; (b) Pd/C, H2, HCl
2.5 M, 92%; (c) ClCO2Et, Et3N, 100%; (d) LAH, Et2O, 90%.
b

M. Pouliquen et al. / Tetrahedron: Asymmetry 21 (2010) 1511–1521
1513
good to high yields. The selectivities observed in MeOH or EtOH
H
CF3
Ph
CF3
Ph
NH2
N
(Table 2, entries 1 and 2) led us to test other alcohols (entries 3–
12). Propan-2-ol afforded an acceptable selectivity (54% ee, entry
3), the highest ee (61%) being obtained when 60 mol % of catalyst
were used at ꢀ15 °C (entry 9). A combination of dioxane and pro-
pan-2-ol improved the solubility of reactants and preserved the
reactivity, but dramatically decreased the selectivity (entry 8).
The highest selectivity obtained in propan-2-ol (entries 3 and 9–
12) was the result of a compromise between the temperature
and the catalyst loading (0 °C and 16 mol %, entry 3).
Compared to other alcohols, methanol and ethanol afforded
lower yields (Table 2, entries 1 and 2) due to the formation of an
unstable side product (15–20% yield) identified as the mixed acetal
11 with methanol which has no precedent in the litterature.25,26
Compound 11 probably resulted from the conjugate addition of
the hemiacetal formed from methanol and nitrobenzaldehyde onto
methyl vinyl ketone. This reaction was completely suppressed
when a higher order alcohol was used as the solvent.
HN
a
b, c
N
Bn
N
Bn
N
Bn
(S)-7
21
(S,R)-20
dr = 15:1
Scheme 3. Reagents and conditions: (a) PhCOCF3, p-TsOH (5 mol %), PhMe, rfx,
36 h; (b) LiEt3BH (1 M in THF), Et2O, 0 °C, 16 h, dr = 3:1; (c) HBr (48% in H2O,
1 equiv), H2O, 0 °C then recrystallised at 90 °C, crystallization (2–3 runs), dr = 15:1
then CH2Cl2/NaHCO3 aq; 23% overall yield.
an overall yield of 23% from (S)-7 without chromatography purifi-
cation and with a dr of 15:1 (dr up to 22:1). Treatment of the
mother liquors delivered additional 13% of 20ꢂHBr with a lower
dr of 7:1. The (R) configuration of the second stereocenter of
20ꢂHBr was determined by single-crystal X-ray analysis (Fig. 3).
O
O
Me
OMe
O2N
11
In order to improve the enantioselectivity of the Morita–Baylis–
Hillman reaction and in an attempt to understand the role of both
nitrogens of the diamine, structural modifications of 3-aminopyr-
rolidine were achieved (Fig. 2). Compounds 8, 12–20 were pre-
pared using simple chemical steps (see the experimental part for
details). In order to modify the electronic properties of the nitrogen
(endo- or exocyclic) of the scaffold, hydrazine 19 and amine 20, fea-
Figure 3. One of the molecules from the asymmetric unit of 20ꢂHBr in thermal
ellipsoidal representation (50% probability).
turing a trifluoromethyl group in
a
position, were synthesized.
Amines 8, 12–20 were tested in the same model reaction as be-
fore and results are presented in Table 3. Compared to diamine 4,
pyrrolidine 12 afforded slightly lower enantioselective excess
(30–36%, Table 3, entries 1–5), but a similar reactivity. Racemic
piperidine 13, the six-membered ring analogue of 4, yielded the
Me
N
N
N(Me)2
Bn
N(Me)2
N
N
N
N
N
Table 3
Bn
Me
Me
Me
Me
Catalysts screening
Entry Amine Conditions
Cat. load
(mol %)
T
(°C)
Yielda (ee)b (%)
[Config.]
rac-13
15
(R)-8
(R)-12
(S)-14
Me
N
1
2
3
4
(R)-4
i-PrOH
16
16
16
16
0
0
20
0
87 (54) [S]
77 (36) [S]
81 (30) [S]
84 (30) [S]
CF3
Ph
N(Me)2
N(Me)2
HN
(R)-12 i-PrOH
(R)-12 i-PrOH
(R)-12 i-PrOH/
dioxane
(R)-12 s-AmylOH
rac-13 EtOH
(R)-8
(S)-14
15
(S)-16
(S)-16
(S)-17
(S)-17
(S)-18
(S)-18
Ar
N
N
N
Me
N
5
6
7
8
9
10
11
12
13
14
15
16
16
16
10
16
16
16
16
16
20
20
20
16
0
20
0
70 (33) [S]
23 (—)
59 (6) [S]
63 (3) [S]
0c (—)
41 (4) [S]
45 (5) [S]
72 (11) [S]
63 (3) [S]
59 (7) [S]
54 (5) [S]
30 (5) [S]
N(Me)2
Ar
Bn
(S)-16, Ar = 2-HOPh (S)-18, Ar = 2-HOPh (R)-19
(S)-17, Ar = 3-HOPh
(S,R)-20
i-PrOH
i-PrOH
i-PrOH
EtOH
MeCN
i-PrOH
MeCN
MeCN
DMSO
0
20
20d
20d
0
20
20
20
0e
Figure 2. Chiral amines tested in the Morita–Baylis–Hillman reaction.
The stereoselective synthesis of this new kind of electrodefi-
cient 3-aminopyrrolidine 20 is outlined in Scheme 3.27 Condensa-
tion of (S)-7 with trifluoroacetophenone afforded imine 21. The
difficult diastereoselective reduction of this imine required a
screening of possible sources of hydrides.28
Finally, unreactive imine 21 was reduced with super-hydride
(LiEt3BH, 1 M in THF) at 0 °C in Et2O to afford the best ratio of iso-
mers (dr = 3:1).29
Separation of these two products turned to be complicated
since 20 and its isomer were persistently coeluting. However,
treatment of the crude reaction with 1 equiv of HBr (48% in H2O)
allowed the isolation and enrichment of 20ꢂHBr after recrystalliza-
tions. Thus, 20ꢂHBr can be prepared efficiently on large scale with
(R)-19 i-PrOH/
dioxane
i-PrOH
17
(S,R)-
20
16
20d
0 (—)
Reaction conditions: Amine 16 mol %, methyl vinyl ketone (3 equiv, 0.5 mmol
scale), 96 h.
a
Isolated yields.
Determined by chiral HPLC.
Mixture of unidentified compounds.
168 h reaction time.
b
c
d
e
240 h reaction time.

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M. Pouliquen et al. / Tetrahedron: Asymmetry 21 (2010) 1511–1521
Table 4
Morita–Baylis–Hillman adduct in only 23% after four days of reac-
tion (entry 6). Aminopyrrolidines 8 and 14 bearing a benzyl substi-
tuent either on the endo- or on the exocyclic nitrogen behave
similarly. While affording moderate efficiencies, their enantiodis-
criminations were low (entries 7 and 8). All these data showed that
the 3-aminopyrrolidine structure is essential for the reactivity and
that both nitrogens appeared equally involved in the reaction. The
substitution of a methyl by a benzyl group was detrimental to the
enantioselectivity.
Hydrogen bonding being crucial for the high enantioselectivity
observed recently in Morita–Baylis–Hillman reactions,7 we synthe-
sized then tested aminopyrrolidines 16–18 bearing a phenol
appendage. Disappointingly, introduction of such hydrogen donor
groups failed to improve the enantioselectivity (11–3%) and the
rate of the reaction (Table 3, entries 10–15). The results, similar
to those obtained with diamines 8 or 14 bearing no hydroxyl func-
tion, confirmed the previous observation on the role of the benzyl
group.
Morita–Baylis–Hillman reaction of methyl vinyl ketone with aldehydes catalyzed by
diamine 4
Entry
Aldehyde
Concn (M)
Yielda (%)
eeb
1
2
3
4
5
6
7
8
9
2-O2N–C6H4CHO
2-F3C–C6H4CHO
2,4-Cl–C6H3CHO
4-F3C–C6H4CHO
4-MeO2C–C6H4CHO
4-NC–C6H4CHO
2-F3C–C6H4CHO
2-F3C–C6H4CHO
2-F3C–C6H4CHO
2-F3C–C6H4CHO
2-F3C–C6H4CHO
2
2
2
2
2
75
77
99
94
94
81
60
73
49
31
0
36
73
56
8
30
29
65
63
61
49
—
2
Neat
4
1
0.5
0.25
10
11
Reaction conditions: Amine 4 (16 mol %), methyl vinyl ketone (3 equiv) iPrOH, rt,
96 h.
a
Isolated yields.
b
Determined by chiral HPLC (S enantiomer is the major product in all entries).
To the best of our knowledge few examples of catalyst improve-
ment based on an ‘alpha effect’ have been reported.30,31 In our
model Morita–Baylis–Hillman reaction, hydrazine 19 afforded an
adduct nearly racemic in 30% yield after 240 h (Table 3, entry 16)
suggesting that the nucleophilic character of the amine and the
distance between both nucleophilic centers are essential for the
induction of chirality.
Alternatively, the electronic properties of the exocyclic amino
group were altered on the amine 20 thanks to the trifluoromethyl
group in the alpha position. The inductive effect generated by CF3
was expected to lower the nucleophilic character of the nitrogen
while acidifying the proton connected on. As a consequence, stron-
ger hydrogen bondings to the electrophiles could take place during
the course of the reaction. Additionally, it was a good opportunity
to explore the advantage on the selectivity of a second stereocenter
on the catalyst. Unfortunately, amine 20 did not promote the reac-
tion between methyl vinyl ketone and 4-O2NAC6H4CHO despite
long reaction time (Table 3, entry 17). A screening of Michael
acceptors such a acrylonitrile, methyl acrylate or the more reactive
1-naphthyl acrylate did not change the outcome of the Morita–
Baylis–Hillman reaction with diamine 20 (data not shown).32 De-
spite sharing a common scaffold with 4, amine 20 was inefficient
in promoting Morita–Baylis–Hillman reaction.
conditions afforded comparable enantioselectivities (entries 7
and 8). A similar behavior was observed with 4-nitrobenzaldehyde
(not shown).
Racemization during the course of the reaction is documented
for the phosphine-catalyzed aza-Morita–Baylis–Hillman in the
presence of protic additives.33 In order to check the configurational
stability of the Morita–Baylis–Hillman adduct under the reaction
conditions, the ee of the adduct of methyl vinyl ketone with 2-tri-
fluoromethylbenzaldehyde was measured after various reaction
times. Figure 4 suggests that no racemization took place, even after
120 h, despite the strong basic character of the catalyst 4 since an
average ee of 59% is measured all along.
100
90
80
70
60
50
40
30
20
10
0
Control experiments involving 1-methylpyrrolidine 15 as cata-
lyst afforded trace amounts of Morita–Baylis–Hillman adduct
(Table 3, entries 9 and 17). These results underscored the impor-
tance of the structural and electronic environment of the exocyclic
nitrogen of the catalyst. All these data established the need for
both nitrogens to bear small methyl substituents to catalyze effi-
ciently the reaction and to afford significant enantioselectivities.
The scope of the reaction of methyl vinyl ketone with a variety
of ortho and para substituted electron-deficient aldehydes was
next examined (Table 4). The best substrates for a satisfactory
enantioselectivity were those bearing a strong electronegative
group NO2 or CF3 in para or ortho position respectively (compari-
sons of entries 1,2 and 4). As expected the yields were lower in
the case of ortho substituted benzaldehydes. Switching the nitro
group at the para position to a less electron withdrawing group
preserved the reactivity but led to an important erosion of the
selectivity (entries 4–6, Table 4 compared to entry 3, Table 2). Un-
der our standard reaction conditions, benzaldehyde was found to
be unreactive.
9h
23h
31h
47h
55h
76h
120h
Figure 4. Reaction conditions: Amine
methyl vinyl ketone (3 equiv), iPrOH, 0 °C. The ees were determined by chiral HPLC.
4
(16 mol %), 2-F3C–C6H4CHO (1 equiv),
Chiral organocatalysts that have been designed originally as po-
tential ligands for Lewis acidic metals are numerous.34 Transform-
ing
a chiral organocatalyst into a promoter for asymmetric
organometallic reactions—the reverse journey—can also be a good
way of discovering new systems for enantioselective synthesis.
Thus, and within the frame of our works on lithium amides of
3-aminopyrrolidines (3-APLi) as chiral ligands for 1,2-addition of
alkyl-21,35 vinyl-36 and aryllithiums37 on aldehydes, we decided
to evaluate the potential of the secondary amine 20 in this type
of organometallic chemistry. The formation of non-covalent mixed
aggregates between the 3-APLi and the organolithium reagent has
been well documented in several cases and these species have
been proposed as being at the origin of good to high level of asym-
metric induction in the 1,2-addition on aldehydes.38 The model
reaction we have been working on consists in the addition of an
alkyllithium, complexed by a chiral 3-APLi, on o-tolualdehyde.
The formation of 1:1 mixed aggregates 3-APLi/RLi in donor solvent
such as THF has been evidenced in several cases by 6Li–1H NOESY,
COSY and HOESY experiments. The resulting complex displays
N–Li–C–Li quadrilateral aggregate directly connected to the
The influence of the concentration was also studied using 2-tri-
fluoromethylbenzaldehyde. Decreasing the concentration under
1 M led to a dramatic loss of reactivity and selectivity (comparison
of entries 2, 7–9 and 10–11). The best compromise to achieve both
good yield and ee’s requires a concentration of the aldehyde higher
than 2 M (ee 65%, entries 2). Higher concentration or solventless

M. Pouliquen et al. / Tetrahedron: Asymmetry 21 (2010) 1511–1521
1515
stereogenic centers of the amide. Therefore, the transformation of
amine 20 into chiral lithium amides by a simple deprotonation in
the presence of 2 equiv of MeLi should lead to a similar mixed
aggregate featuring a lithium amide stabilized by inductive effect
(Scheme 4). The Lewis acidity of the lithium cation of amide
20ꢂLi is supposed to be increased because of the inductive effect
of the vicinal CF3 group. As a consequence, the shape and the
lengths of the bonds (N–Li–C–Li) of 20ꢂLi and the aggregate 20ꢂLi/
MeLi are expected to be slightly affected allowing a possible
improvement of enantioselectivity during the reaction of hydrox-
yalkylation. The influence of fluorine or fluorinated groups on the
chemical and stereochemical properties of lithium amides is not
well known, but interesting results were obtained with fluorinated
lithium amides, in particular by Koga.39
reaction. Compared to the previously proline derived diamine 1b16
and N,N,N0,N0-tetramethylpropane-1,3-diamine 1c17 which were
used in large amounts (30 mol % or 1 equiv), 8 mol % of pyrrolidine
4 are sufficient for high conversion and chiral induction. Addition-
ally, thesynthesisof a new class of 3-aminopyrrolidinebearing a chi-
ral 2,2,2-trifluoroethyl group has been designed. If synthetic
applications of this substrate are still to be found, amine 20 may con-
stitute a scaffold with interesting biological activities.40 Further
investigations concerning the mechanism and optimization of all
these catalysts will be reported in due course. Finally, this study
highlights the potential of the aminopyrrolidine skeleton, compared
to piperidines, in organocatalytic reactions.
4. Experimental
CF3
Ph
CF3
Ph
H
H
4.1. General method
Li
Ph
MeLi
HN
N
H
(1 equiv.)
N
Proton NMR spectra were recorded on Bruker Avance DPX 250,
300 and 400 spectrometers. Default solvent for NMR spectra
recording was CDCl3. 1H chemical shifts are reported in parts per
million (d) relative to internal tetramethylsilane (TMS, 0.0 ppm),
or with the solvent reference. 13C NMR spectra were recorded on
Bruker 400 (100 MHz), 300 (125 MHz) or 250 (62 MHz) spectrom-
eters with complete proton decoupling. Carbon chemical shifts are
reported in parts per million (d) relative to TMS with the respective
solvent resonance as the internal standard (CDCl3, 77.0 ppm). Thin
layer chromatography was performed on Silica Gel 60 F-254 plates
(0.1 mm, Merck). Detection was accomplished by irradiation with a
UV lamp or staining with KMnO4 or ninhydrin solutions. Chro-
matographic separations were achieved on silica gel columns (Kie-
CF3
N
Li
N
N
Bn
Bn
20
Bn
20.Li
MeLi
CLA
organocatalyst
(1 equiv.)
OH
Li
N
o-TolCHO
N
CH3
Li
Bn
Ph
selgel 60, 40–63 lm, Merck). Analytical high performance liquid
F3C
H
chromatography (HPLC) was carried out with a Waters instrument
[detector M996 (200–400 nm) and pump 600], respectively. Mass
and high resolution mass spectra (HRMS) were obtained on a
Waters-Micromass Q-Tof micro instrument. IR spectra were re-
corded on a Perkin–Elmer 16 PC FTIR spectrometer. Optical rota-
tions were measured, at room temperature, on a Perkin–Elmer
22
20.Li/MeLi
Scheme 4. Structure and model reaction of 3APLi 20ꢂLi mixed aggregates.
The enantioselective hydroxyalkylation of o-tolualdehyde with
MeLi in the presence of a stoechiometric amount of the chiral lith-
ium amide was investigated. Following our previously published
procedure,3 we added 2 equiv of MeLi on 20 at ꢀ78 °C in THF.
The reaction was next warmed up to ꢀ20 °C then cooled back to
ꢀ78 °C before addition of o-tolualdehyde. This protocol afforded
alcohol 22 with a good enantioselectivity (76% ee, 90% yield) but
without obvious improvement over our previous results with elec-
tron rich 3-aminopyrrolidines (up to 85% ee).
Therefore, altering the electronic properties of the lithium
amide through inductive effect does not seem to play a significant
role in the model reaction. Nevertheless, we are currently pursuing
this strategy of dual use of these amines 4–20 for both organocatal-
ysis and the promotion of enantioselective transformations
involving organometallic reagents. In particular, the efficiency of
the di-tertiary diamines 4, 8, 12–19 in the enantioselective hydrox-
yalkylation illustrated in Scheme 4 is currently being evaluated.
241 LC polarimeter in a 10 cm cell. Specific rotation {[a]D} values
are given in units of 10ꢀ1 deg cm2 gꢀ1. Melting points were deter-
mined on a Gallenkamp apparatus and are uncorrected. Solvents
(THF, CH2Cl2, MeCN, Et2O) were dried and purified from Pure-
Solv™ 400 Solvent Purification System. All aldehydes and methyl
vinyl ketone were used as received. (ꢀ)-Sparteine 2, (+)-Troger’s
base 5, (R) or (S)-1-benzyl-3-aminopyrrolidine 7 are commercially
available. Piperazine 641,42 and alcohol 22 [42070-90-6] are known
compounds.
4.2. Synthesis of catalysts
4.2.1. Dimethyl-((R)-1-methylpyrrolidin-3-yl)amine 4 and ((R)-
1-benzylpyrrolidin-3-yl)dimethylamine 8
To (R)-1-benzyl-3-aminopyrrolidine 7 (1.0 g, 5.7 mmol) was
added a mixture of formaldehyde (8.0 mL, 37 w/v%, 100 mmol)
and formic acid (7.3 mL, 194 mmol). The solution was refluxed
for 4 h. After cooling, aqueous ammonia (28%) was added until
pH >10. The aqueous layer was extracted with Et2O and the organic
layers were combined and dried over Na2SO4. The volatile com-
pounds were evaporated and (R)-1-benzyl-N,N-dimethylpyrrol-
idine 8 was obtained as a colorless oil which did not require any
3. Conclusions
With the aim of finding simple and stable organocatalysts for the
Morita–Baylis–Hillman reaction, monocyclic and bicyclic diamines
derived from (+)- and (ꢀ)-3-aminopyrrolidine and from (ꢀ)-cytisine
were synthesized and tested in the reaction of methyl vinyl ketone
and aromatic aldehydes. The most efficient catalyst was found to
be dimethyl-((R)-1-methylpyrrolidin-3-yl)amine 4. This organocat-
alyst presents the majoradvantages ofbeing easily preparedon mul-
tigram scale and to be simply removed from the reaction mixture
due to its volatility. The results presented above suggest that both
nucleophilic nitrogens of the aminopyrrolidines are involved in the
purification (1.1 g, 95%). ½a D20
ꢃ
¼ þ2:8 (c 0.5, CHCl3). 1H NMR d
1.64–1.77 (m, 1H), 1.87–2.07 (m, 2H), 2.19 (s, 6H), 2.29 (dd,
J = 8.4 Hz, J = 6.8 Hz, 1H), 2.48 (dt, J = 8.9 Hz, J = 6.8 Hz, 1H), 2.69–
2.88 (m, 2H), 3.53 and 3.62 (AB, J = 12.8 Hz, 2H), 7.24–7.35 (m,
5H). 13C NMR d 29.0, 43.7, 53.2, 58.4, 60.4, 65.3, 126.7, 128.0,
128.5, 138.9. IR (neat,
m
cmꢀ1) 2948, 2862, 2778, 1660, 1494,
1454, 1152, 1042, 910, 698 cmꢀ1. MS (EI) m/z = 204 (M+Å, 3), 159

1516
M. Pouliquen et al. / Tetrahedron: Asymmetry 21 (2010) 1511–1521
(42), 132 (60), 113 (62), 91 (72), 84 (42), 65 (31), 42 (100). HRMS
(MH+) Calcd for C13H21N2: 205.1705. Found: 205.1700.
bined organic extracts were dried over Na2SO4 and evaporated un-
der reduced pressure. The crude product was purified by flash
chromatography (CH2Cl2/MeOH, 98:2) to afford the diamine 23
Pyrrolidine
8 (1.0 g, 4.9 mmol) and Pd–C (10%, 260 mg,
0.25 mmol) were added to a solution of methanol and 2.5 M aque-
ous HCl (16:4, 20 mL). The mixture was stirred at 40 °C under a
atmosphere of hydrogen (40 bars) for 24 h. The solids were filtered
over Celite and washed with MeOH (50 mL). The filtrate was evap-
orated under reduced pressure to give the crude dihydrochloride
10 as a pale yellow oil which was used directly in the next step
(843 mg, 92%). 1H NMR (D2O) d 1.80 (dq, J = 12.6 Hz, J = 8.3 Hz,
1H), 1.98–2.11 (m, 1H), 2.26 (s, 6H), 2.79 (quint, J = 7.3 Hz, 1H),
2.94 (dd, J = 11.1 Hz, J = 7.7 Hz, 1H), 3.08–3.20 (m, 1H), 3.20–3.32
(m, 2H). 13C NMR (D2O) d 29.0, 44.4, 44.9, 48.3, 64.9.
as a colorless oil (500 mg, 54%). ½a D20
ꢃ
¼ þ2:3 (c 0.5, CHCl3). 1H
NMR d 1.70–1.86 (m, 5H), 1.96–2.11 (m, 1H), 2.33 (dd, J = 7.9 Hz,
J = 6.9 Hz, 1H), 2.42–2.58 (m, 5H), 2.72–2.93 (m, 3H), 3.59 and
3.62 (AB, J = 12.9 Hz, 2H), 7.20–7.36 (m, 5H). 13C NMR d 23.3,
30.2, 53.1, 53.3, 59.6, 60.7, 64.1, 127.0, 128.3, 128.9, 139.1. IR (neat,
m
cmꢀ1) 2960, 2785, 1603, 1585, 1495, 1454, 1380, 1256, 1205,
1136. GC/MS (m/z) 231 (100, MH+), 160 (32), 139 (83), 132 (41),
120 (43), 110 (60), 96 (36), 91 (70), 65 (25), 42 (53). HRMS
(MH+) Calcd for C15H23N2: 231.1861. Found: 231.1862.
The diamine 23 (500 mg, 2.17 mmol) and Pd/C (166 mg, 10% Pd,
0.16 mmol) was added to a solution of methanol and 2.5 M aque-
ous HCl (4:1, 20 mL). The mixture was stirred at 40 °C under an
hydrogen atmosphere (P = 40 bars) for 24 h. The solids were fil-
tered over Celite and washed with MeOH (50 mL). The filtrate
was evaporated under reduced pressure to give the crude dihydro-
To the bis-hydrochloride 9 (187 mg, 1 mmol) in CH2Cl2 (20 mL)
were added triethylamine (2.24 mL, 16 mmol) and ethyl chlorofor-
mate (1.6 mL, 1.6 mmol). The mixture was stirred at room temper-
ature for 24 h. The solvent was removed and the residue treated
with an aqueous solution of ammonia (10 mL). The aqueous layer
was extracted with CH2Cl2. The combined organic extracts were
dried (MgSO4) and evaporated under reduced pressure. The crude
product was purified by column chromatography (CH2Cl2/MeOH,
chloride 24 as a colorless solid (462 mg, 100%). ½a D20
¼ þ1:2 (c 0.3,
ꢃ
H2O). 1H NMR (D2O) d 1.80–2.00 (m, 2H), 2.00–2.24 (m, 3H), 2.46–
2.61 (m, 1H), 3.02–3.19 (m, 2H), 3.26–3.73 (m, 5H), 3.78 (dd,
J = 13.0 Hz, J = 8.2 Hz, 1H), 4.05 (quint, J = 7.9 Hz, 1H). 13C NMR
93:7) to give 10 as a colorless oil (186 mg, 100%). ½a D20
¼ ꢀ11:4 (c
ꢃ
0.25, CHCl3). 1H NMR d 1.25 (t, J = 7.1 Hz, 3H), 1.70–1.89 (m, 1H),
2.02–2.18 (m, 1H), 2.27 (s, 6H), 2.57–2.75 (m, 1H), 3.05–3.21 (m,
1H), 3.25–3.42 (m, 1H), 3.50–3.76 (m, 2H), 4.13 (q, J = 7.1 Hz,
2H). 13C NMR d (2 conformers) 14.9, 29.8 30.7, 44.3, 44.9 45.2,
(D2O) d 22.6, 27.5, 44.5, 45.9, 54.0, 61.9. IR (NaCl, m
cmꢀ1) 3371,
2965, 2479, 1635, 1449, 1040.
Boc2O (710 mg, 3.26 mmol) was added to a stirred solution of
the crude dihydrochloride 24 (460 mg, 2.17 mmol) and K2CO3
(1.05 g, 7.6 mmol) in THF/H2O (1:1, 70 mL). The mixture was stir-
red at room temperature for 12 h and the aqueous layer was ex-
tracted with EtOAc (3 ꢁ 15 mL). The combined organic extracts
were dried over MgSO4 and evaporated under reduced pressure.
The crude product was purified by flash chromatography
(CH2Cl2/MeOH, 98:2) to afford the aminocarbamate 25 as a color-
50.2 50.5, 60.9 61.0, 64.9 65.7, 155.1. IR (neat,
m
cmꢀ1) 1698,
1426, 1381, 1275, 1210, 1124. MS (EI) (m/z) 186 (83), 171 (25),
157 (52), 141 (20), 113 (70), 99 (10), 84 (100), 70 (65). HRMS
(MH+) Calcd for C9H19N2O2: 187.1447. Found: 187.1460.
To the carbamate 10 (145 mg, 0.78 mmol) in Et2O (20 mL) at
0 °C under argon was added LiAlH4 (140 mg, 3.47 mmol) in one
portion. The suspension was heated under reflux for 24 h. After
cooling at 0 °C, the grey suspension was treated successively with
less oil (290 mg, 56%). ½a D20
ꢃ
¼ þ11:2 (c 0.2, CHCl3). 1H NMR d 1.45
(s, 9H), 1.72–1.89 (m, 5H), 1.99–2.11 (m, 1H), 2.44–2.61 (m, 4H),
2.69 (sext, J = 7.5 Hz, 1H), 3.13 (q, J = 9.3 Hz, 1H), 3.21–3.34 (m,
1H), 3.42–3.69 (m, 2H). 13C NMR d (2 conformers) 23.4, 28.6,
30.9 31.7, 44.6 44.9, 50.6 51.1, 53.2, 63.6 64.2, 79.2, 154.6. IR (NaCl,
water (140 lL), aqueous NaOH (15%, 140 lL) and water (420 lL).
The solids were filtered over Celite and washed with Et2O
(100 mL). The filtrate was evaporated under reduced pressure to
give the title compound 4 as a pale yellow and volatile oil
m
cmꢀ1) 2970, 2875, 2788, 1694, 1479, 1455, 1400, 1364, 1249,
(90 mg, 90%) which required no purification. [
a
]
D = ꢀ0.4 (c 0.8,
1166, 1148, 1120. GC/MS (m/z) 241 (22, MH+), 185 (100), 141 (4).
HRMS (MH+) Calcd for C13H25N2O2: 241.1907. Found: 241.1916.
To the aminocarbamate 25 (290 mg, 1.21 mmol) in Et2O (20 mL)
at 0 °C under an atmosphere of argon was added LiAlH4 (180 mg,
4.82 mmol) in one portion. The suspension was heated under re-
CHCl3). 1H NMR d 1.67–1.80 (m, 1H), 1.89–2.09 (m, 1H), 2.22 (s,
6H), 2.29 (dd, J = 8.0 Hz, J = 6.5 Hz, 1H), 2.34 (s, 3H), 2.45 (dt,
J = 9.0 Hz, J = 6.8 Hz, 1H), 2.69–2.88 (m, 3H). 13C NMR d 29.7,
42.4, 43.9, 55.6, 60.9, 66.0. IR (NaCl,
m
cmꢀ1) 2967, 2783, 1452,
1362, 1347, 1270, 1238, 1202, 1154, 1021. GC/MS (m/z) 129 (7),
113 (2), 97 (2), 83 (58), 70 (23), 57 (79), 42 (100). HRMS (MH+)
Calcd for C7H17N2: 129.1392. Found: 129.1387.
flux for 24 h. After cooling to 0 °C, water (180
l
L) and aqueous
L). The
NaOH (15%, 180 L) were added followed by water (540
l
l
solids were filtered over Celite and washed with Et2O (50 mL).
The filtrate was evaporated under reduced pressure to give the vol-
atile crude diamine (R)-12 as a colorless oil (170 mg, 91%) which
4.2.2. (R)-10-Methyl-[1,30]bipyrrolidine 12
required no purification. ½a D20
ꢃ
¼ ꢀ6:5 (c 1.2, CHCl3). 1H NMR d
1.71–1.86 (m, 5H), 1.95–2.12 (m, 1H), 2.14–2.30 (m, 1H), 2.33 (s,
3H), 2.38–2.57 (m, 5H), 2.69–2.79 (m, 3H). 13C NMR d 23.3, 30.8,
42.3, 53.9, 55.5, 62.0, 64.6. IR (NaCl,
m
cmꢀ1) 2963, 2778, 1477,
N
N
N
a
b
c
(R)-7
1448, 1377, 1346, 1312, 1239, 1140, 1029. GC/MS (m/z) 155
(100, MH+), 127 (81), 112 (5), 96 (16), 84 (79). HRMS (MH+) Calcd
for C9H19N2: 155.1535. Found: 155.1524.
N
Bn
N
H
N
Boc
(HCl)2
25 R = Boc
23
24
d
4.2.3. Dimethyl-(1-methylpiperidin-3-yl)amine 13
(R)-12 R = Me
Reagents and conditions: (a) dibromobutane, K2CO3, EtOH, 54%;
(b) Pd/C, MeOH, aq HCl, 100%; (c) Boc2O, K2CO3, THF/H2O, 56%; (d)
Et2O, reflux, 91%.
N
N
N
a
b
Dibromobutane (864 mg, 4.0 mmol) was added to N-benzyl-3-
aminopyrrolidine 7 (704 mg, 4.0 mmol), K2CO3 (552 mg, 4.0 mmol)
and EtOH (20 mL). The mixture was heated at 60 °C for 24 h. After
cooling at room temperature, water was added (20 mL) and the
aqueous layer was extracted with EtOAc (3 ꢁ 15 mL). The com-
N
CO2Et
(HCl)2
26
N
N
H
13
27
Reagents and conditions: (a) ClCO2Et, Et3N, CH2Cl2, 63%; (b)
LiAlH4, THF, 58%.

M. Pouliquen et al. / Tetrahedron: Asymmetry 21 (2010) 1511–1521
1517
Commercially available 3-dimethylaminopiperidine dihydro-
chloride 26 (400 mg, 2.0 mmol) was dissolved in CH2Cl2 (50 mL).
Triethylamine (3.8 mL, 27.1 mmol) and ethyl chloroformate
(3.2 mL, 32.0 mmol) were added and the mixture was stirred at
room temperature for 24 h. The solvent was removed and aqueous
ammonia was added. The aqueous layer was extracted with
CH2Cl2. The combined organic extracts were dried (MgSO4) and
evaporated under reduced pressure. The crude product was puri-
fied by column chromatography (CH2Cl2/MeOH, 98:2) to afford
27 as a yellow pale oil (250 mg, 63%). 1H NMR d 1.28 (t,
J = 7.1 Hz, 3H), 1.34–1.52 (m, 2H), 1.72–1.80 (m, 1H), 1.96–2.04
(m, 1H), 2.15–2.24 (m, 1H), 2.35 (s, 6H), 2.65–2.80 (m, 2H), 3.91–
4.10 (m, 1H), 4.15 (q, J = 7.1 Hz, 2H), 4.17–4.32 (m, 1H). 13C NMR
d (2 conformers) 14.8 14.9, 24.4, 28.8, 42.4, 44.3, 46.8 47.1, 60.9
(155 mg, 4.08 mmol). The suspension was heated under reflux for
24 h. After cooling to 0 °C, water (155 L) was added followed by
aqueous NaOH (15%, 155 L) and by water (465 L). The solids
l
l
l
were filtered over Celite and washed with Et2O (50 mL). The filtrate
was evaporated under reduced pressure to give the volatile crude
diamine 30 as a colorless oil (70 mg, 90%) which required no puri-
fication. ½a 2D0
ꢃ
¼ ꢀ0:8 (c 1.0, CHCl3). 1H NMR d 1.50–1.64 (m, 2H),
2.04–2.25 (m, 2H), 2.33 (s, 3H), 2.38 (s, 3H), 2.35–2.49 (m, 1H),
2.63 (dt, J = 9.3 Hz, J = 6.5 Hz, 2H), 3.14–3.25 (m, 1H). 13C NMR d
32.5, 34.7, 42.2, 55.3, 59.6, 69.2. IR (NaCl,
m
cmꢀ1) 3297, 2923,
2853, 2796, 1452, 1365, 1239, 1172, 1147. GC/MS (EI) (m/z) 115
(11, MH+), 99 (4), 83 (53), 82 (23), 70 (22), 58 (28), 57 (88), 42
(100). HRMS (MH+) Calcd for C6H15N2: 115.1235. Found: 115.1239.
To a solution of benzaldehyde (71 lL, 0.7 mmol) and the pyrrol-
61.0, 61.4, 155.7. IR (NaCl,
m
cmꢀ1) 1698, 1434, 1276, 1260, 1159.
idine 30 (50 mg, 0.44 mmol) in THF (5 mL) was added sodium tri-
acetoxyborohydride (279 mg, 1.32 mmol). The mixture was stirred
at room temperature under an atmosphere of argon for 24 h and
then treated with aqueous ammonia. The aqueous layer was ex-
tracted with CH2Cl2 and the organic layers were combined and
dried over Na2SO4. The solvent was removed under vacuum and
the crude product was purified by flash chromatography (CH2Cl2/
MeOH/NH4OH, 92:8:1) to afford the diamine (S)-14 as a colorless
GC/MS (m/z) 200 (15), 155 (3), 127 (3), 98 (5), 84 (100), 71 (8),
56 (9), 42 (22). HRMS (MH+) Calcd for C10H21N2O2: 201.1603.
Found: 201.1604.
To the piperidine 27 (220 mg, 1.1 mmol) in Et2O (30 mL) at 0 °C
under Ar was added LiAlH4 (200 mg, 4.79 mmol) in one portion.
The suspension was heated under reflux for 24 h. After cooling to
0 °C, water (200
l
L) and aqueous NaOH (15%, 200
lL) were added
followed by water (600
l
L).The solids were removed by filtration
oil (65 mg, 72%). ½a D20
ꢃ
¼ þ5:5 (c 1.0, CHCl3). 1H NMR d 1.81–1.90
through Celite and the filter cake was washed with Et2O
(100 mL). The filtrate was evaporated under reduced pressure to
give 13 as a pale yellow oil (90 mg, 58%). 1H NMR d 1.15 (dq,
J = 12.0 Hz, J = 4.1 Hz, 1H), 1.51–1.70 (tt, J = 13.1 Hz, J = 3.8 Hz,
1H), 1.73–1.95 (m, 4H), 2.29 (s, 3H), 2.31 (s, 6H), 2.32–2.44 (m,
1H), 2.75 (br d, 1H), 2.97 (br dt, 1H). 13C NMR d 24.6, 26.6, 42.2,
(m, 1H), 2.00–2.09 (m, 1H), 2.12 (s, 3H), 2.36 (s, 3H), 2.47 (dd,
J = 9.2 Hz, J = 6.9 Hz, 1H), 2.53 (dt, J = 8.8 Hz, J = 6.2 Hz, 1H), 2.64–
2.71 (m, 1H), 2.80 (dd, J = 9.2 Hz, J = 7.4 Hz, 1H), 3.16 (dq,
J = 8.8 Hz, J = 6.9 Hz, 1H), 3.43 and 3.54 (AB, J = 13.1 Hz, 2H),
7.20–7.32 (m, 5H). 13C NMR d 29.1, 39.6, 42.5, 55.7, 60.0, 60.3,
64.4, 126.9, 128.2, 129.1, 139.1. IR (NaCl,
m
cmꢀ1) 2964, 2939,
46.7, 55.9, 58.7, 61.5. IR (NaCl,
m
cmꢀ1) 1449, 1371, 1253, 1160,
2837, 2777, 1532, 1495, 1479, 1452, 1364, 1245, 1169. GC/MS
(EI) (m/z) 205 (92, MH+), 177 (37), 146 (15), 134 (93), 120 (15),
113 (38), 91 (100). HRMS (MH+) Calcd for C13H21N2: 205.1705.
Found: 205.1695.
1017. GC/MS (m/z) 142 (26), 97 (22), 84 (100), 71 (20), 58 (72),
42 (58). HRMS (MH+) Calcd for C8H19N2: 143.1548. Found:
143.1538.
4.2.5. 2-[(S)-3-Dimethylaminopyrrolydin-1-ylmethyl]phenol 16
4.2.4. (S)-N-Benzyl-N-methyl-N-(1-methylpyrrolidin-3-yl)amine 14
Me
Me
NHBoc
NHBoc
NHMe
N
Me
NHBoc
N
b
c
b
c
N
N
R
N
N
Me
N
R
N
Me
OH
OH
28 R = H
30
(S)-14
a
31 R = Bn
28 R = H
29 R = Boc
2-OH 32
3-OH 33
2-OH (S)-16
3-OH (S)-17
a
Reagents and conditions: (a) Boc2O, THF/H2O, K2CO3, 77%; (b)
LiAlH4, Et2O, reflux, 90%; (c) PhCHO, NaBH(OAc)3, THF, 72%.
Boc2O (262 mg, 1.2 mmol) was added to pyrrolidine 28
(185 mg, 1 mmol), K2CO3 (166 mg, 1.2 mmol) and THF/H2O (1:1,
8 mL). The mixture was stirred at room temperature for 12 h, then
water (10 mL) was added and the aqueous layer was extracted
with Et2O (3 ꢁ 10 mL). The combined organic extracts were dried
over MgSO4 and evaporated under reduced pressure. The crude
product was purified by flash chromatography (CH2Cl2/MeOH,
Reagents and conditions: (a) Pd/C, H2, MeOH, 100%; (b) salicyl-
aldehyde, NaBH(OAc)3, THF, 100% for 32; 3-hydroxybenzaldehyde,
NaBH(OAc)3, THF, 89% for 33; (c) HCHO, HCO2H, reflux, 79% for (S)-
16, 71% for (S)-17.
A solution of the known (S)-Boc pyrrolidine 3143 (430 mg,
1.56 mmol) and Pd/C (170 mg, 10% Pd, 0.16 mmol) in degassed
MeOH (10 mL) was stirred at room temperature under an atmo-
sphere of hydrogen (balloon) for 24 h. The solids were removed
by filtration through Celite and the filter cake was washed with
MeOH (50 mL). The filtrate was evaporated under reduced pres-
sure to give 2844 as a colorless solid (285 mg, 100%) which was di-
rectly used for the next step. Mp 74 °C. 1H NMR d 1.45 (s, 9H), 1.65–
1.72 (m, 1H), 2.10–2.20 (m, 1H), 2.79–3.15 (m, 5H), 4.11 (br s, 1H),
4.95 (br s, 1H). 13C NMR d 28.6, 33.4, 45.6, 51.7, 53.8, 79.7, 155.8.
99:1) to afford 29 as a colorless oil (220 mg, 77%). ½a D20
¼ þ6:8 (c
ꢃ
2.0, CHCl3). 1H NMR d 1.44 (s, 9H), 1.45 (s, 9H), 1.75–1.90 (m,
1H), 2.05–2.16 (m, 1H), 3.16 (br dd, 1H), 3.32–3.47 (m, 2H), 3.58
(dd, J = 11.3 Hz, J = 6.2 Hz, 1H), 4.17 (br s, 1H), 4.60 (br s, 1H). 13C
NMR d (2 conformers) 28.4, 28.5, 31.2 32.1, 43.7 44.0, 49.9 50.6,
51.4 51.9, 79.5, 79.7, 154.5, 155.3. IR (NaCl,
m
cmꢀ1) 3326, 2977,
1675, 1526, 1478, 1455, 1406, 1365, 1250, 1161, 1130. GC/MS
(ESI) (m/z) 309 (55, M+Na+), 253 (62), 209 (100), 197 (31), 109
(77). HRMS (M+Na+) Calcd for C14H26N2O4Na: 309.1790. Found:
309.1780.
To a solution of pyrrolidine 29 (195 mg, 0.68 mmol) in Et2O
(15 mL) at 0 °C under an atmosphere of argon was added LiAlH4
To salicylaldehyde (140 lL, 1.35 mmol) and aminocarbamate
28 (279 mg, 1.5 mmol) in THF (10 mL) was added sodium triacet-
oxyborohydride (475 mg, 2.25 mmol). The mixture was stirred at
room temperature under an atmosphere of argon for 12 h and then
treated with aqueous NaOH (3 N). The aqueous layer was extracted
with Et2O and the organic layers were combined and dried over

1518
M. Pouliquen et al. / Tetrahedron: Asymmetry 21 (2010) 1511–1521
Na2SO4. Solvent was removed under vacuum and the crude prod-
uct was purified on silica gel chromatography (CH2Cl2/MeOH,
97:3) to afford amine 32 as a colorless oil (370 mg, 100%).
53.3, 58.2, 60.5, 65.4, 114.8, 116.4, 120.5, 129.5, 140.0, 156.9. IR
(NaCl,
m
cmꢀ1) 2957, 2786, 1586, 1484, 1456, 1379, 1280, 1234,
1155, 1038. GC/MS (m/z) 221 (100, MH+), 193 (59), 176 (100),
½
a 2D0
ꢃ
¼ þ18:1 (c 1.1, CHCl3). 1H NMR d 1.43 (s, 9H), 1.45–1.50 (m,
136 (22), 107 (95).
1H), 1.62–1.72 (m, 1H), 2.25–2.36 (m, 1H), 2.41–2.50 (m, 1H),
2.63–2.70 (m, 1H), 2.72–2.81 (m, 1H), 2.83–2.93 (m, 1H), 3.79
(AB, J = 19.5 Hz, 2H), 4.22 (br s, 1H), 4.90 (br s, 1H), 6.78 (t,
J = 7.4 Hz, 1H), 6.82 (d, J = 8.1 Hz, 1H), 6.97 (d, J = 7.4 Hz, 1H),
7.16 (t, J = 7.7 Hz, 1H). 13C NMR d 28.3, 32.3, 49.7, 52.3, 58.7,
60.3, 79.5, 115.9, 119.1, 121.9, 128.0, 128.7, 155.3, 157.5. IR (neat,
4.2.7. 2-{[Methyl-((S)-1-methylpyrrolidin-3-
yl)amino)]methyl}phenol 18
R
N
R1
N
NH2
m
cmꢀ1) 3334, 2976, 2817, 1689, 1591, 1490, 1471, 1365, 1250,
a
c
OH
OH
1165. GC/MS (m/z) 293 (15, MH+), 238 (5), 237 (100), 131 (17),
107 (2). HRMS (MH+) Calcd for C16H25N2O3: 293.1865. Found:
293.1855.
N
Bn
N
N
Bn
34 R = H
35 R = Boc
R2
To an aqueous solution of formol (1.84 mL, 37% w/v, 22 mmol)
was added formic acid (1.76 mL, 45.1 mmol) and the amine 32
(320 mg, 1.1 mmol). The mixture was heated under reflux for 4 h.
After cooling, the solution was treated with aqueous ammonia
and the aqueous layer was extracted with Et2O. The combined or-
ganic extracts were dried over Na2SO4 and evaporated under re-
duced pressure. The crude product was purified by flash
chromatography (CH2Cl2/MeOH, 96:4) to afford diamine (S)-16 as
36 R1 = Boc, R2 = H
(S)-7
b
d
(S)-18 R1 = R2 = Me
Reagents and conditions: (a) salicylaldehyde, NaBH(OAc)3, THF,
64%; (b) Boc2O, CH2Cl2, 67%; (c) Pd/C, H2, MeOH, 97%; (d) HCHO,
HCO2H, reflux, 81%.
To a solution of salicylaldehyde (380 lL, 3.6 mmol) and N-ben-
a colorless oil (190 mg, 79%). ½a D20
ꢃ
¼ þ16:6 (c 2.5, CHCl3). 1H NMR
zyl-3-aminopyrrolidine (S)-7 (708 mg, 4 mmol) in THF (20 mL) was
added sodium triacetoxyborohydride (1.27 mg, 6 mmol). The mix-
ture was stirred at room temperature under an atmosphere of ar-
gon for 12 h and then quenched with an aqueous solution of
NaOH (3 N). The aqueous layer was extracted with Et2O. The organ-
ic layers were combined and dried over Na2SO4. The solvent was
removed under vacuum and the crude product was purified by
flash chromatography (CH2Cl2/MeOH, 98:2) to afford diamine 34
d 1.75–1.87 (m, 1H), 1.98–2.14 (m, 1H), 2.22 (s, 6H), 2.43–2.50
(m, 1H), 2.63 (dt, J = 9.2 Hz, J = 6.1 Hz, 1H), 2.75–2.95 (m, 3H),
3.79 and 3.80 (AB, J = 14 Hz, 2H), 6.77 (t, J = 7.5 Hz, 1H), 6.82 (d,
J = 8.1 Hz, 1H), 6.98 (d, J = 7.0 Hz, 1H), 7.17 (dt, J = 7.7 Hz,
J = 1.4 Hz, 1H). 13C NMR d 29.2, 43.8, 52.9, 57.8, 59.2, 65.3, 116.0,
119.1, 122.2, 128.1, 128.8, 157.9. IR (neat,
m
cmꢀ1) 2950, 2866,
2817, 1614, 1591, 1468, 1404, 1254, 1135, 1035. GC/MS (ESI) (m/
z) 221 (25, MH+), 193 (9), 176 (16), 136 (5), 115 (88), 107 (100).
HRMS (MH+) Calcd for C18H23N2O: 221.1630. Found: 221.1640.
as a colorless oil (720 mg, 64%). ½a D20
ꢃ
¼ þ8:9 (c 0.75, CHCl3). 1H
NMR d 1.60–1.74 (m, 1H), 2.07–2.22 (m, 1H), 2.38 (dt, J = 8.7 Hz,
J = 6.8 Hz, 1H), 2.58 (d, J = 5.0 Hz, 2H), 2.74 (dt, J = 8.7 Hz,
J = 5.0 Hz, 1H), 3.31 (sext, J = 4.5 Hz, 1H), 3.60 (s, 2H), 3.92 (s,
2H), 6.75 (dt, J = 7.3 Hz, J = 0.8 Hz, 1H), 6.82 (d, J = 8.1 Hz, 1H),
6.95 (d, J = 7.3 Hz, 1H), 7.15 (dt, J = 7.7 Hz, J = 1.4 Hz, 1H), 7.21–
7.33 (m, 5H). 13C NMR d 31.5, 50.8, 52.7, 56.1, 59.7, 60.2, 116.5,
4.2.6. 3-[(S)-3-Dimethylaminopyrrolydin-1-ylmethyl]phenol 17
To a solution of 3-hydroxybenzaldehyde (122 mg, 1 mmol) and
aminocarbamate 28 (185 mg, 1 mmol) in dichloromethane (10 mL)
was added sodium triacetoxyborohydride (300 mg, 1.4 mmol). The
mixture was stirred at room temperature under an atmosphere of
argon for 24 h and then treated with NaHCO3. The aqueous layer
was extracted with Et2O and the organic layers were combined
and dried over Na2SO4. The solvent was removed under vacuum
and the crude product was purified on silica gel chromatography
119.0, 122.5, 127.1, 128.3, 128.4, 128.8, 138.9, 158.4. IR (neat,
m
cmꢀ1) 3291, 1589, 1492, 1474, 1454, 1409, 1378, 1348, 1255,
1185, 1149, 1104, 907. MS (ESI) (m/z) 283 (100, MH+), 177 (95).
HRMS (MH+) Calcd for C18H23N2O: 283.1810. Found: 283.1799.
Boc2O (636 mg, 2.92 mmol) was added to a solution of diamine
34 (690 mg, 2.43 mmol) in CH2Cl2 (40 mL). The mixture was stirred
at room temperature for 36 h and quenched with water. The aque-
ous layer was extracted with EtOAc (3 ꢁ 15 mL). The combined or-
ganic extracts were dried over MgSO4 and evaporated. The crude
product was purified by flash chromatography (CH2Cl2/MeOH,
98:2) to afford the aminocarbamate 35 as a colorless oil (620 mg,
(CH2Cl2/MeOH, 98:2) to afford amine 33 as
a colorless oil
(260 mg, 89%). ½a D20
ꢃ
¼ ꢀ4:8 (c 0.5, CHCl3). 1H NMR d 1.42 (s, 9H),
1.52–1.70 (m, 1H), 2.20–2.40 (m, 2H), 2.62 (d, J = 4.8 Hz, 2H),
2.80–2.95 (m, 1H), 3.55 (s, 2H), 4.21 (br s, 1H), 5.16 (br d, 1H),
6.72–6.82 (m, 3H), 7.11–7.20 (m, 1H). 13C NMR d 28.5, 32.5, 52.9,
53.5, 60.0, 60.9, 79.5, 115.1, 116.4, 121.1, 129.6, 139.2, 155.7,
156.4. IR (NaCl,
m
cmꢀ1) 3325, 2976, 2807, 1678, 1589, 1486,
67%). ½a 2D0
ꢃ
¼ þ4:6 (c 1.05, CHCl3). 1H NMR d 1.50 (s, 9H), 1.72–
1455, 1392, 1366, 1249, 1160, 1078. GC/MS (m/z) 293 (40, MH+),
237 (100). HRMS (MH+) Calcd for C16H25N2O3: 293.1865. Found:
293.1875.
1.83 (m, 1H), 2.11–2.20 (m, 1H), 2.29 (q, J = 8.4 Hz, 1H), 2.45 (dd,
J = 10.3 Hz, J = 8.3 Hz, 1H), 2.90 (dd, J = 10.4 Hz, J = 3.4 Hz, 1H),
2.91–3.00 (m, 1H), 3.51 (d, J = 12.5 Hz, 1H), 3.78 (d, J = 12.2 Hz,
1H), 4.40 (d, J = 15.2 Hz, 1H), 4.55 (d, J = 15.3 Hz, 1H), 4.66 (br s,
1H), 6.72 (t, J = 7.4 Hz, 1H), 6.91 (dd, J = 8.1 Hz, J = 1.1 Hz, 1H),
7.18 (dt, J = 7.7 Hz, J = 1.6 Hz, 1H), 7.23–7.43 (m, 6H). 13C NMR d
28.6, 30.1, 44.4, 53.5, 55.6, 57.2, 60.3, 81.5, 117.7, 119.6, 125.1,
To a solution of formol (37% w/v in water) (1.37 mL, 16.4 mmol)
and formic acid (1.32 mL, 33.6 mmol) was added the amine 33
(240 mg, 0.82 mmol). The mixture was heated under reflux for
4 h. After cooling, the solution was treated with aqueous ammonia
and the aqueous layer was extracted with Et2O. The combined or-
ganic extracts were dried over Na2SO4 and evaporated under re-
duced pressure. The crude product was purified by flash
chromatography (CH2Cl2/MeOH, 93:7) to afford the diamine (S)-
127.5, 128.5, 129.2, 129.5, 131.4, 137.9, 156.2, 157.4. IR (neat,
m
cmꢀ1) 3281, 3064, 1759, 1652, 1605, 1486, 1454, 1419, 1367,
1345, 1241, 1120, 909. GC/MS (ESI) (m/z) 383 (9, MH+), 327
(100), 283 (26), 177 (11). HRMS (MH+) Calcd for C23H31N2O3:
383.2335. Found: 383.2327.
17 as a colorless oil (120 mg, 71%). ½a D20
ꢃ
¼ þ1:2 (c 0.9, CHCl3). 1H
NMR d 1.72–1.81 (m, 1H), 1.94–2.03 (m, 1H), 2.23 (s, 6H), 2.34–
2.41 (m, 1H), 2.52 (dt, J = 9.0 Hz, J = 6.7 Hz, 1H), 2.73 (m, 1H),
2.80–2.89 (m, 2H), 3.52 and 3.57 (AB, J = 12.8 Hz, 2H), 6.68 (ddd,
J = 7.8 Hz, J = 2.4 Hz, J = 0.8 Hz, 1H), 6.71–6.74 (m, 1H), 6.77–6.81
(d, J = 7.6 Hz, 1H), 7.13 (t, J = 7.8 Hz, 1H). 13C NMR d 28.7, 43.7,
A suspension of aminocarbamate 35 (220 mg, 0.58 mmol) and
Pd/C (31 mg, 10% Pd, 0.029 mmol) in degassed MeOH (10 mL)
was stirred at room temperature under an atmosphere of hydrogen
(balloon) for 24 h. The solids were filtered through Celite and
washed with MeOH (50 mL). The filtrate was evaporated under

M. Pouliquen et al. / Tetrahedron: Asymmetry 21 (2010) 1511–1521
1519
reduced pressure to give the crude 36 as a colorless solid (165 mg,
This nitrosopyrrolidine 37 (200 mg, 0.93 mmol) was diluted in
water (6 mL). NH4OAc (4 M, 12 mL) and TiCl3 (15% w/v in 10%
aqueous HCl, 6 mL), were added and the mixture was stirred for
1 h. Aqueous solution of ammonia was added and the aqueous
layer was extracted with CH2Cl2. The combined organic extracts
were dried (MgSO4) before evaporation under reduced pressure
to give the aminopyrrolidine 38 which did not require any purifi-
97%). Mp 82 °C. ½a D20
ꢃ
¼ ꢀ4:4 (c 1.5, CHCl3). 1H NMR d 1.48 (s, 9H),
2.02–2.12 (m, 1H), 2.13–2.25 (m, 1H), 3.11 (q, J = 8.8 Hz, 1H),
3.20–3.33 (m, 2H), 3.38–3.48 (m, 2H), 4.36 and 4.44 (AB,
J = 15.4 Hz, 2H), 6.69 (br s, 2H), 6.80 (t, J = 7.4 Hz, 1H), 6.99 (d,
J = 8.0 Hz, 1H), 7.12 (t, J = 7.6 Hz, 1H), 7.17 (d, J = 7.4 Hz, 1H). 13C
NMR d 28.5, 28.7, 45.5, 47.4, 50.6, 57.1, 81.9, 116.7, 119.8, 124.2,
129.2, 130.3, 155.2, 156.2. IR (neat,
m
cmꢀ1) 3186, 1674, 1598,
cation (151 mg, 81%). ½a D20
ꢃ
¼ ꢀ13:2 (c 0.4, CHCl3). 1H NMR d 1.45
1456, 1419, 1367, 1239, 1160, 1124, 908. GC/MS (m/z) 293 (11,
MH+), 237 (100), 193 (44). HRMS (MH+) Calcd for C16H25N2O3:
293.1865. Found: 293.1856.
(s, 9H), 1.55–1.65 (m, 1H), 2.20–2.41 (m, 2H), 2.66–2.72 (m, 1H),
2.74–2.90 (m, 2H), 3.00–3.11 (m, 2H), 4.15 (br s, 1H), 4.95 (br s,
1H). 13C NMR d 28.5, 32.0, 53.5, 58.6, 61.9, 79.4, 155.4. IR (NaCl,
A solution of formol (0.92 mL, 37% in water, 11.28 mmol) and
formic acid (0.88 mL, 22.75 mmol) was added to the amine 36
(165 mg, 0.56 mmol). The mixture was heated under reflux for
4 h. After cooling, the solution was treated with aqueous ammonia
and the aqueous layer was extracted with Et2O. The combined or-
ganic extracts were dried over Na2SO4 and evaporated under re-
duced pressure. The crude product was purified by flash
chromatography (CH2Cl2/MeOH, 96:4) to afford the diamine (S)-
m
cmꢀ1) 3322, 2976, 2932, 1688, 1513, 1456, 1391, 1365, 1246,
1162, 1047. MS (ESI) (m/z) 202 (30, MH+), 146 (100), 102 (7). HRMS
(MH+) Calcd for C9H19N3O2: 202.1556. Found: 202.1552.
Boc2O (518 mg, 2.38 mmol) was added to a stirred solution of
the aforementioned aminopyrrolidine 38 (95 mg, 0.475 mmol) in
CH2Cl2 (20 mL). The mixture was stirred at room temperature for
24 h, and then evaporated under reduced pressure. The residue
was purified by flash chromatography (pentane/EtOAc, 70:30) to
afford bis-Boc-aminopyrrolidine 39 as a colorless oil (100 mg,
18 as a colorless oil (100 mg, 81%). ½a D20
ꢃ
¼ ꢀ9:5 (c 1.0, CHCl3). 1H
NMR d 1.83–1.98 (m, 1H), 2.00–2.16 (m, 1H), 2.25 (s, 3H), 2.36 (s,
3H), 2.51–2.69 (m, 3H), 2.79 (t, J = 8.4 Hz, 1H), 3.26 (dq,
J = 8.8 Hz, J = 6.8 Hz, 1H), 3.66 (d, J = 14.0 Hz, 1H), 3.78 (d,
J = 14 Hz, 1H), 6.77 (dt, J = 7.5 Hz, J = 0.9 Hz, 1H), 6.81 (d,
J = 8.1 Hz, 1H), 6.95 (d, J = 6.5 Hz, 1H), 7.16 (dt, J = 7.7 Hz,
J = 1.5 Hz, 1H). 13C NMR d 28.3, 38.9, 42.4, 55.5, 58.9, 59.6, 63.7,
70%). ½a 2D0
ꢃ
¼ þ9:6 (c 0.45, CHCl3). 1H NMR d 1.43 (s, 9H), 1.45 (s,
9H), 1.65–1.75 (m, 1H), 2.11–2.19 (m, 1H), 2.68–2.80 (m, 1H),
2.88–2.97 (m, 1H), 2.98–3.08 (m, 1H), 3.15–3.25 (m, 1H), 4.15 (br
s, 1H), 5.21 (br s, 1H), 5.58 (br s, 1H). 13C NMR d 28.1, 28.2, 31.2,
48.5, 52.6, 60.3, 78.9, 79.9, 154.7, 155.2. IR (NaCl,
m
cmꢀ1) 3290,
2977, 2933, 1685, 1514, 1456, 1391, 1365, 1248, 1157, 1076. MS
(ESI) (m/z) 324 (51, MNa+), 268 (100), 224 (45), 212 (18), 168 (6),
124 (5). HRMS (MNa+) Calcd for C14H27N3O4Na: 324.1899. Found:
324.1883.
116.2, 119.1, 121.7, 128.5, 128.7, 158.0. IR (neat,
m
cmꢀ1) 3362,
1589, 1475, 1455, 1423, 1347, 1254, 1150, 1017. GC/MS (ESI) (m/
z) 221 (26, MH+), 193 (4), 115 (100), 107 (2). HRMS (MH+) Calcd
for C13H21N2O: 221.1638. Found: 221.1630.
To the carbamate 39 (265 mg, 0.88 mmol), in THF (10 mL), were
added NaH (60% in oil, 345 mg, 8.8 mmol) and MeI (560 lL,
8.8 mmol). The mixture was stirred at room temperature for
24 h. Water was added and the aqueous layer was extracted with
CH2Cl2. The combined organic extracts were dried (MgSO4) and
then evaporated under reduced pressure. The residue was purified
by flash chromatography (pentane/EtOAc, 80:20) to afford the
4.2.8. (R)-N2,N2,N3,N3-Tetramethylpyrrolidine-1,3-diamine 19
NHBoc
NHBoc
NH2
NHBoc
a
b
c
compound 40 as a colorless oil (220 mg, 76%). ½a D20
¼ þ3:2 (c 0.5,
ꢃ
N
H
N
NO
N
NH2
N
CHCl3). 1H NMR d 1.45 (s, 9H), 1.47 (s, 9H), 1.61–1.66 (m, 1H),
1.74–1.84 (m, 1H), 2.03–2.12 (m, 1H), 2.85 (s, 3H), 2.92 (s, 3H),
2.93–3.20 (m, 3H), 4.16–4.36 (m, 1H). 13C NMR d 27.4, 28.5, 28.6,
NHBoc
38
39
28
37
28.9, 29.8, 48.4, 51.2, 52.0, 79.6, 80.1, 155.8. IR (NaCl,
m )
cmꢀ1
N
2974, 2931, 2873, 1689, 1479, 1455, 1405, 1390, 1365, 1339,
1251, 1139. GC/MS (ESI) (m/z) 330 (41, MH+), 274 (100), 218
(50), 174 (10). HRMS (MH+) Calcd for C16H33N3O4: 330.2393.
Found: 330.2411.
To the biscarbamate 40 (220 mg, 0.67 mmol) in Et2O (15 mL) at
0 °C under an atmosphere of argon was added LiAlH4 (150 mg,
3.95 mmol). The suspension was heated under reflux for 24 h. After
NBoc
e
d
39
N
N
N
BocN
40
19
Reagents and conditions: (a) NaNO2, HCl, THF, 70% (b) TiCl3,
NH4OAc, 81%; (c) Boc2O, CH2Cl2, 70%; (d) NaH, MeI, THF, 76%; (e)
LAH, Et2O, 96%.
cooling to 0 °C, water (150
lL) and NaOH (15%, 150 lL) were added
followed by water (450 L). The solids were filtered over Celite and
l
To the pyrrolidine 28 (185 mg, 1 mmol), were added a solution
of THF (6 mL)/HCl (0.5 M, 2 mL, 5 mmol) and NaNO2 (89 mg,
1.3 mmol). The mixture was stirred at room temperature for
48 h. The aqueous layer was extracted with Et2O. The combined or-
ganic extracts were washed with a saturated aqueous solution of
NaCl and were dried (MgSO4) before evaporation under reduced
pressure. The crude product was purified by flash chromatography
(CH2Cl2/MeOH, 98:2) to afford the nitrosopyrrolidine 37 as a color-
washed with Et2O (30 mL). The filtrate was evaporated under re-
duced pressure to give pyrrolidine 19 as a colorless oil (100 mg,
96%) which did not require any purification. ½a D20
¼ þ7:1 (c 0.5,
ꢃ
CHCl3). 1H NMR d 1.55–1.70 (m, 1H), 1.80–2.02 (m, 1H), 2.22 (s,
6H), 2.40 (s, 6H), 2.48–2.69 (m, 2H), 2.76–2.86 (m, 2H), 2.97 (dd,
J = 7.5 Hz, J = 6.5 Hz, 1H) 13C NMR d 27.6, 40.3, 43.9, 45.3, 50.1,
63.4. IR (NaCl,
m
cmꢀ1) 2933, 2857, 1614, 1455, 1391, 1366,
1348, 1251, 1143. MS (EI) (m/z) 157 (12), 113 (78), 84 (100), 70
(14), 58 (8), 42 (54). HRMS (MH+) Calcd for C8H20N3: 158.1657.
Found: 158.1662.
less solid (150 mg, 70%). Mp 103 °C. ½a D20
ꢃ
¼ þ6:6 (c 0.4, CHCl3). 1H
NMR d (2 conformers) 1.41 (s, 4.5H) 1.42 (s, 4.5H), 1.87–2.10 (m,
1H), 2.19–2.38 (m, 1H), 3.43 (m, 0.5 H), 3.51–3.74 (m, 1H), 3.80
(dd, J = 15.0 Hz, J = 7.0 Hz, 0.5 H), 4.16–4.55 (m, 3H), 5.0 (br s,
1H). 13C NMR d (2 conformers) 28.0, 30.5, 43.6, 47.9, 55.2, 80.2,
4.2.9. (S)-1-Benzylpyrrolidin-3-yl-((R)-2,2,2-trifluoro-1-
phenylethyl)amine 20
To a solution of (S)-7 (7.65 g, 0.043 mmol) in freshly distilled
PhMe (50 mL) were added 2,2,2-trifluoroacetophenone (6.07 mL,
0.043 mmol) and APTS (150 mg). The system is fitted with a Dean
155.2 155.3. IR (neat,
m
cmꢀ1) 3671, 3368, 2980, 1678, 1519,
1459, 1416, 1366, 1303, 1249, 1159. MS (ESI) (m/z) 216 (14,
MH+), 160 (100), 130 (10).

1520
M. Pouliquen et al. / Tetrahedron: Asymmetry 21 (2010) 1511–1521
Stark apparatus and heated to 140 °C for 36 h. The crude reaction
was diluted with Et2O and washed with a solution of NaHCO3
(10%), brine and dried on Na2SO4. The organic layer was concen-
trated under vacuum to deliver imine 21 as brown oil. To a solution
of 21 in freshly distillated Et2O (100 mL) cooled to 0 °C was slowly
added LiEt3BH (1.1 equiv, 1 M in THF). The mixture was stirred
16 h at this temperature before quenching with a solution of aque-
ous NaHCO3 (10%) and extractions with Et2O. The organic layers
were pooled, washed with brine and dried with Na2SO4. After con-
centration by rotary evaporation, the ratio of isomers of diamine 20
was estimated by 1H NMR spectroscopy of the crude reaction
(dr = 3:1). The crude was taken up in MeOH (20 mL) and 1 equiv
of HBr (48% in H2O) was added at 0 °C. The resulting mixture
was concentrated to dryness and 200 mL of demineralized water
was added, the heterogenous system was heated to 90 °C and fil-
trated while still hot. The brown pale filtrate was separated from
oily solids remaining. The filtrate was once more heated and the
hot solution obtained was poured into a beaker to let the system
cool to rt. The crystallization is rapidly occurring and the crystals
were let growing during 1 h. The solids were then filtrated and
sucked to dryness. The crystals were taken into water -the mini-
mum amount- and heated to 90 °C. Additional water was added
to ensure the full solubility at this temperature and the operation
of recrystallisation was repeated as described above until high dr
of 20 was obtained (4.17 g, 23%, dr = 15:1, according to 1H and
19F NMR of the amine). This operation was usually repeated 2–3
times before obtaining this ratio of isomers. Aqueous filtrates were
pooled and concentrated until half of the volume of water is re-
moved. The operations of crystallization were repeated on this
material to yield a second batch of additional 20ꢂHBr (2.70 g,
13%, dr = 7:1). The ratio of isomers can be increased to 22:1 from
15:1 by further recrystallisation. Suitable crystals for X-ray charac-
terization were obtained by slow evaporation of a solution of
20ꢂHBr in CH2Cl2. Dissolving the salt 20ꢂHBr in CH2Cl2 and treating
this with a NaHCO3 saturated aqueous solution delivered 20 as
(0.5 mL) and methyl vinyl ketone (120 lL, 1.5 mmol, 3 equiv).
The mixture was stirred for four days at 0 °C. The solvent was evap-
orated under reduced pressure and the residue purified via flash
chromatography (pentane/EtOAc, 80:20) to afford 3-(hydroxy(4-
nitrophenyl)methyl)but-3-en-2-one. Enantiomeric excess was
determined using a Daicel Chiralpak AD-H column [1 mL minꢀ1
n-heptane (95%), MeOH/EtOH (v:v: 1:1, 5%, 20 °C, room tempera-
ture (R: 60 min; S: 90 min)]. Absolute configurations were deter-
mined by comparison with the signs of the optical rotations of
previously reported compounds: X-Ar-CH(OH)C(@CH2)COMe:
X = 4-NO2 (column AD-H, 20 °C, 1 mL minꢀ1, 95% heptane—5%
(50% MeOH + 50% EtOH): t1 = 58.5 min, t2 = 87.6 min),48 X = 2-NO2
(AD-H, 20 °C, 1 mL minꢀ1
, 95% heptane—5% iPrOH: t1 = 50.0,
t2 = 55.2.),10 X = 2-CF3 (AD-H, 20 °C, 1 mL minꢀ1, 95% heptane—5%
iPrOH: t1 = 11.9, t2 = 14.7).49 The S configurations of the major
enantiomers of the Morita–Baylis–Hillman adducts with X = CN
(AD-H, 20 °C, 1 mL minꢀ1, 95% heptane—5% (50% MeOH + 50%
EtOH): t1 = 51.7 min, t2 = 98.9 min), 2,4-Cl2 (OD-H, 20 °C,
0.8 mL minꢀ1, 90% heptane—10% iPrOH: t1 = 8.2, t2 = 12.2), 4-CF3
(AD-H, 20 °C, 1 mL minꢀ1, 95% heptane—5% (50% MeOH + 50%
EtOH): t1 = 25.0, t2 = 26.6),50 4-CO2Me (AD-H, 20 °C, 1 mL minꢀ1
,
90% heptane—10% iPrOH: t1 = 15.6 min, t2 = 17.2 min) were as-
signed by comparing their retention times with those of the closest
known structures.
4.5. Typical procedure for hydroxyalkylations of o-tolualdehyde
Under an argon atmosphere, MeLi (1 equiv, 1.6 M solution in
Et2O) was added to a solution of 20 (1 equiv) in anhydrous THF
(C = 0.2 M) at ꢀ20 °C. After stirring 20 min, a second portion of
MeLi (1.2 equiv, 1.6 M solution in Et2O) was added dropwise to
the preformed solution of lithium amide (20ꢂLi) and the resulting
mixture was stirred for 30 min at ꢀ20 °C. Then, the mixture was
cooled to ꢀ78 °C and aged 30 min at this temperature. A solution
of o-tolualdehyde (1 equiv) in THF (2 mL) was added at ꢀ78 °C
over a 5-min period and the mixture was stirred at ꢀ78 °C for
90 min. The medium was quenched at ꢀ78 °C with a 3 M aqueous
HCl solution and was extracted with Et2O (3 ꢁ 10 mL). The com-
bined organic layers were washed with NaHCO3 (10 mL) and brine
(10 mL), dried (MgSO4) and concentrated under reduce pressure.
Purification of the residue by column chromatography (AcOEt/
cyclohexane 30:70) gave 22. The enantiomeric excess was mea-
sured by GC with a chiral permethylated b-cyclodextrin column
(R-isomer 6.80 min and S-isomer 8.15 min).
pale yellow oil after removal of the solvent. ½a D20
¼ ꢀ67 (c 7.0,
ꢃ
CH2Cl2); 1H NMR (300 MHz, CDCl3) d 7.98–7.09 (m, 10H), 4.30–
4.12 (m, 1H), 3.72 (q, J = 13.0 Hz, 2H), 3.35 (s, 1H), 2.84–2.76 (m,
1H), 2.67–2.61 (m, 2H), 2.49 (m, 1H), 2.18 (m, 1H), 1.71–1.64 (m,
1H); 13C NMR (75 MHz, CDCl3) d 139.1, 134.7, 134.7, 129.1,
128.8, 128.8, 128.7, 128.4, 127.1, 125.6 (q, J = 281 Hz), 63.4 (q,
J = 28 Hz), 60.4, 59.8, 55.0, 52.8, 32.5; 19F NMR (282 MHz) d
ꢀ73.9. MS (EI, M+): 334 (50%), 314 (100%).
4.3. Crystallographic study of 20ꢂHBr
Acknowledgments
A
colorless prism monoclinic, space group P21 (No. 4),
a = 9.631(2) Å, b = 7.4178(17) Å, c = 27.787(6) Å, b = 94.044(4)°,
V = 1980.2(8) Å3, Z = 8, dcalcd = 1.393, = 2.106 mmꢀ1 was used
The Région Basse-Normandie and the PUNCh interregional net-
work are acknowledged for a fellowship to M.P, the Ministère de
l’Enseignement Supérieur et de la Recherche, CNRS and the Euro-
pean Union (FEDER funding) for financial supports. The authors
thank Dr. Morgane Sanselme for single-crystal X-ray analysis.
l
for data collection. Diffraction intensities were measured using a
Bruker SMART APEX diffractometer equipped with a CCD area Detec-
tor using Mo Kalpha radiation at ambient temperature. Unit cell
parameters and orientation matrix were determined by using the
SMART software.45 Intensities were integrated, corrected for Lorentz
polarization. Absorption and unit cell parameters were refined by
using SAINT plus and SADABS Softwares.46 The SHELX 97 Software pack-
age47 was used to solve and to refine the structural model. The final
cycle of full-matrix least-squares refinement was based on 3656
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