Novel guanidinyl pyrrolidine salt-based bifunctional organocatalysts: application in asymmetric conjugate addition of malonates to enones

Article abstract of DOI:10.1016/j.tetlet.2009.05.011

Novel guanidinyl pyrrolidine salts are useful bifunctional organocatalysts for the asymmetric addition of malonates to enones. These organocatalysts are effective under a wide range of reaction conditions and afford products in high yield and enantioselec

Full text of DOI:10.1016/j.tetlet.2009.05.011

Tetrahedron Letters 50 (2009) 4283–4285
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Novel guanidinyl pyrrolidine salt-based bifunctional organocatalysts:
application in asymmetric conjugate addition of malonates to enones
*
Emmanuel Riguet
Université de Reims Champagne-Ardenne, Institut de Chimie Moléculaire de Reims, CNRS UMR 6229, UFR Sciences Exactes et Naturelles, BP 1039, 51687, REIMS Cedex 2, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Novel guanidinyl pyrrolidine salts are useful bifunctional organocatalysts for the asymmetric addition of
malonates to enones. These organocatalysts are effective under a wide range of reaction conditions and
afford products in high yield and enantioselectivity.
Received 8 April 2009
Revised 5 May 2009
Accepted 6 May 2009
Available online 10 May 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Asymmetric organocatalysis
Chiral guanidine
Conjugate addition
Nowadays, asymmetric organocatalysis is recognised as a valu-
able addition and/or as an alternative methodology to more estab-
lished metal-based procedures.1 Since the two seminal reports by
List, Lerner and Barbas2 and MacMillan and co-workers,3 two
modes of aminocatalysis, namely enamine activation4 and imini-
um activation,5 have been extensively exploited in asymmetric
organocatalysis. The iminium activation strategy has been used
in a wide range of organocatalytic processes including cycloaddi-
tion,5 transfer hydrogenation6 and 1,4-addition.7 In the latter case,
the conjugate addition of malonates to enones has attracted spe-
cific attention in synthetic organic chemistry. Pioneering work,
introduced proline rubidium salts to catalyse the addition of di-
iso-propyl and di-tert-butyl malonates to both acyclic and cyclic
enones. Products were obtained with low to good enantioselectiv-
ities (35–88% ee).8,9 Ten years later, a highly efficient methodology
was reported using an imidazolidine catalyst. High yields (up to
99%) and good to excellent enantioselectivities (84–99% ee) were
obtained.10 However, when the more synthetically useful dimeth-
ylmalonate was used ee’s were moderate. Long reaction times as
well as a large excess of malonate were required. Recently Ley
and co-workers introduced a new methodology based on the use
of proline tetrazole catalyst and a stoichiometric amount of base.
In this case only 1.5 equiv of malonate was used and the reaction
time was reduced to 3 days. Moreover, good to high enantioselec-
tivities were obtained when both dimethylmalonate and diethyl-
malonate were used.11,12 Only very recently, Zhao and Yang
reported a highly efficient strategy using primary–secondary dia-
mine catalysts.13 Indeed the use of 20 mol % of catalyst gave the de-
sired products in a relatively short reaction time (24 h) in excellent
yields (up to 99%) and enantioselectivities (up to 99% ee) for a wide
range of acyclic enones. When cyclohexenone was used, reaction
times increased considerably (150 h) and products were obtained
in moderate yield but still with good enantioselectivity (90% ee).
It is noteworthy, that strategies based on other activation modes
have recently led to efficient organocatalytic enantioselective mal-
onate addition to enones,14,15albeit sometimes less efficient with
cyclic enones.14
The results reported herein concern the application of new
organocatalysts I containing a pyrrolidine ring and an acyclic gua-
nidine moiety (Fig. 1).
The initial hypothesis was that the pKa of guanidine would be
well suited for deprotonation of the malonate. Moreover, the pre-
sumed ability of guanidinium ion to efficiently complex a malonate
by both electrostatic interaction and two-directional hydrogen
bonds would be suitable for the efficient orientation of nucleo-
philic attack of malonate. Consequently, the attack of the nucleo-
phile could occur syn with respect to the pyrrolidine substituent,
H
N
H
N
Ar
N
H
I
N
H
Ar =
I a
I c
I b
* Tel.: +33 (0) 26 9131 96; fax: +33 (0) 26 9131 66.
E-mail address: emmanuel.riguet@univ-reims.fr
Figure 1. Organocatalysts with pyrrolidine guanidine scaffold.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.05.011

4284
E. Riguet / Tetrahedron Letters 50 (2009) 4283–4285
which is in contrast to the steric hindrance (compare Refs. 10,12).
During the final course of this work, the report of Pansare and Lin-
gampally16 based on a similar working hypothesis17 was published
and it prompted us to report our preliminary results. It should be
noted that the use of acyclic guanidine catalysts is rare compared
to that of their cyclic or bicyclic counterparts.18 It was decided to
evaluate type I catalysts that contain aromatic ring moiety on
the guanidine (Fig. 1). The appropriate choice of substituents on
this ring could efficiently modulate the pKa, steric and electronic
properties of guanidine. In this work we describe the catalytic
activities of compounds Ia, Ib and Ic which essentially differ in
the steric hindrance of the guanidine moiety.
more basic counteranion were investigated. Pleasingly, pivalic acid
salts Ia(tBuCO2H)2, Ib(tBuCO2H)2 and Ic(tBuCO2H)2 efficiently cata-
lysed the asymmetric addition of malonates 2a, 2b and 2c to cyclo-
hexenone 1 using 10 mol % of catalyst and 1.5 equiv of malonate.22
As shown in Table 1, after a reaction time of 24 h high isolated
yield and good enantioselectivity (73–82%) were observed with
all three malonates. The S configuration of products is in agree-
ment with nucleophile attack occurring syn with respect to the
pyrrolidine substituent. Comparable isolated yields (85–95%) were
obtained in all reactions whatever catalysts or malonates were
used.
Enantioselectivity varied however according to the catalysts
and malonates. Slightly better enantioselectivity was observed
for more hindered substituents on the guanidine moiety. This
trend was clearer when dimethylmalonate was used, 73%, 76%
and 82% ee’s were obtained when catalysts Ia(tBuCO2H)2, Ib(tBu-
CO2H)2 and Ic(tBuCO2H)2 were used, respectively, (entries 4–6).
Moreover, in contrast with most of the previous reports, the same
or better enantioselectivities were obtained when dimethylmalo-
nate was used. This is particularly interesting with regard to its
higher reactivity for further synthetic applications.
It was next demonstrated that enantioselectivity could be im-
proved when the reaction was performed in various solvents (Ta-
ble 2). Using dimethylmalonate and catalyst Ic(tBuCO2H)2 the
enantioselectivity was maintained (84% ee) or slightly decreased
(78% ee) when toluene or isopropanol was used (entries 2 and 8),
but enantioselectivity increased significantly with both acetonitrile
and chloroform (93% ee and 91% ee) (entries 4 and 6). Nevertheless,
yields were moderate with these last two solvents (51% after 48 h).
Fortunately, good yields can be obtained (80%) at higher concentra-
tions without affecting enantioselectivity (entries 5 and 7).
The effect of temperature was next investigated. In spite of the
high catalyst loading and long reaction times which are often re-
quired in organocatalysis to achieve good conversion, attempts to
carry out reactions at higher temperatures are rarely reported. This
could be explained by the assumption that heating has a negative
impact on enantioselectivity. Nevertheless some examples with
an opposite trend have been reported.24 In asymmetric organoca-
talysis, Kappe and co-workers clearly demonstrated that heating
can significantly enhance the reaction rate without affecting
Compounds Ia, Ib and Ic were efficiently synthesised in three
steps according to slightly modified literature procedure starting
from (S)-N-Boc-aminomethylpyrrolidine (see ESI for Supplemen-
tary data).19
The investigation was started by evaluating the catalysts ability
to promote conjugate addition of malonates to cyclohexenone 1
under neat conditions at room temperature. As shown in Table 1
the use of 10 mol % of free base catalysts Ia, Ib and Ic and dimeth-
ylmalonate as the nucleophile led to a total conversion but affor-
ded a racemic product. These results probably reflect a simple
base catalysis20 and the absence of iminium formation. At this
point it seemed clear that the use of free base catalysts was not
appropriate to allow concomitant iminium formation and guani-
dine activation.21 Consequently, the use of carboxylic acid salts of
the catalysts was explored with the idea that faster iminium for-
mation would occur. A subsequent dual activation by the guanidi-
nium carboxylate ion pair could then take place (carboxylate
assisted deprotonation of malonate and complexation of the
resulting specie by guanidinium). First, it was observed that triflu-
oroacetic acid salts Ia(CF3CO2H)2, Ib(CF3CO2H)2 and Ic(CF3CO2H)2
were completely inert. No formation of the expected product was
observed by TLC analysis even after a prolonged reaction time. This
can be explained by the experimental conditions which are favour-
able for the formation of the iminium ion but unfavourable for the
deprotonation of the malonate. Consequently, catalyst salts with a
Table 1
Addition of malonates to cyclohexenonea
O
O
Table 2
10 mol% catalyst
neat, RT, 24h
a
Optimisation studies with catalyst Ic(tBuCO2H)2
RO2C
CO2R
CO2R
CO2R
O
O
2a R= Me
2b R= Et
2c R= Bn
3a R= Me
3b R= Et
3c R= Bn
1
10 mol%
Ic(tBuCO2H)2
solvent, RT, 48h
MeO2C
CO2Me
CO2Me
CO2Me
Entry
Catalyst
Malonate
Product
Yieldb (%)
eec,d (%)
1
2a
3a
1
2
3
4
5
6
7
8
9
Ia
Ib
Ic
2a
2a
2a
2a
2a
2a
2b
2b
2b
2c
2c
2c
3a
3a
3a
3a
3a
3a
3b
3b
3b
3c
3c
3c
nde
nde
nde
90
87
91
81
85
88
95
97
94
racf
racf
racf
73
76
82
69
73
75
77
Entry
Solvent
None
Yieldb (%)
ee (%)
1
2
3
4
5
6
7
8
9
91
68
82
51
76
51
80
76
89
89
82c
Ia (tBuCO2H)2
Ib (tBuCO2H)2
Ic (tBuCO2H)2
Ia (tBuCO2H)2
Ib (tBuCO2H)2
Ic (tBuCO2H)2
Ia (tBuCO2H)2
Ib (tBuCO2H)2
Ic (tBuCO2H)2
iPrOH (1 mL)
78c
iPrOH (0.5 mL)
CH3CN (1 mL)
CH3CN (0.5 mL)
CHCl3 (1 mL)
CHCl3 (0.5 mL)
Toluene (1 mL)
Toluene (0.5 mL)
CHCl3 (0.5 mL)e
79c,d
93c
91c,d
91c
92c,d
84c
10
11
12
78
81
84c,d
90d
10
a
Reaction conditions: 2-cyclohexenone 1 (0.5 mmol), malonates 2 (0.75 mmol),
catalyst I (10 mol %), 24 h, rt.
a
Reaction conditions: 2-cyclohexenone 1 (0.5 mmol), malonates 2 (0.75 mmol),
catalyst Ic(tBuCO2H)2 (10 mol %), solvents (1 mL or 0.5 mL), 48 h, rt.
b
Isolated yield.
b
c
Isolated yield.
Determined by chiral HPLC analysis (Chiralpak IC), average of two runs.
Absolute configuration determined from Refs. 12,23.
nd: not determined.
rac: racemic.
c
d
Determined by chiral HPLC analysis (Chiralpak IC).
13C NMR of ketal with (2R,3R)-2,3-butanediol.
d
e
e
f
Reflux, reaction time 12 h.

E. Riguet / Tetrahedron Letters 50 (2009) 4283–4285
4285
MeO2C
CO2Me
O
MeO2C
CO2Me
tive catalysts. Detailed mechanistic studies as well as the
application of type I catalysts to more challenging reactions are
currently under investigation.
2a
4
10 mol%
I (tBuCO2H)2
5
neat, RT, 5d
O
Acknowledgements
I a (tBuCO2H)2 yield= 86 % ee= 65 %
I c (tBuCO2H)2 yield= 94 % ee= 71 %
The author would like to thank Dr. Norbert Hoffmann for fruit-
ful scientific discussion, Dr. Karen Plé for helpful discussion and
Sylvie Lanthony and Agathe Martinez for their technical assistance
with HPLC and NMR.
Scheme 1.
H
H or Ar
N
H
H or Ar
N
N
H or Ar
H or Ar
Supplementary data
N
H
N
H
N
B
N
I
N
1
and
2
B
(tBuCO2H)2
H
Supplementary data (experimental details and characterisation
data for all new compounds) associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.2009.05.011.
O
Probably
Faster step
H
O
O
BH
RO
O
RO
OR
H
H
OR
B
References and notes
Scheme 2.
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A detailed mechanism for these reactions is difficult to be estab-
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formation of iminium intermediate can be postulated based on
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had only a slight effect on enantioselectivity obtained. When the
trifluoroacetate salt of the catalyst was used, formation of iminium
intermediate probably occurred, but the trifluoroacetate was not
basic enough to deprotonate the malonate. In contrast, when a piv-
alate salt was used, pivalate with its guanidinium counteranion
was probably basic enough for deprotonation. The guanidinium
then acts as a complexing agent and controls the approach of mal-
onate from the si face of the iminium double bond (attack syn with
respect to the pyrrolidine substituent).
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on guanidinyl pyrrolidine scaffold was developed. First investiga-
tions show that such compounds were able to catalyse conjugate
addition of malonate to enone in a relatively short reaction time
and in a wide range of experimental conditions including sol-
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enantioselectivities were obtained using only 1.5 equiv of dimeth-
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of the steric and electronic properties of guanidine as well as vary-
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yield is obtained after 24 h. Compound Ic(tBuCOOH)1 has a reactivity similar to
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enantioselectivity is lower (around 70%) and poorly reproducible, probably
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addition catalysed by the free base. The mixed salt Ic(tBuCOOH)1(F3CCOOH)1 is
also poorly reactive.
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