On the roles of protic solvents in imidazolidinone-catalyzed transformations

Article abstract of DOI:10.1002/anie.201005892

Step by step: The effect of protic solvents on the rate and stereochemical outcome of the imidazolidinone-catalyzed Diels-Alder cycloaddition was rationalized. The following picture emerges: the solvent accelerates iminium ion formation (stepa 1), the Diels-Alder cycloaddition is reversible (stepa 2), and the solvent intercepts the iminium ion adduct (stepa 3).

Full text of DOI:10.1002/anie.201005892

DOI: 10.1002/anie.201005892
Organocatalysis
On the Roles of Protic Solvents in Imidazolidinone-Catalyzed
Transformations**
John B. Brazier, Kevin M. Jones, James A. Platts,* and Nicholas C. O. Tomkinson*
Over the past decade, organocatalysis has caught the imag-
ination of synthetic chemists, advancing the boundaries of
chemical synthesis.[1] Of particular note is the use of
secondary amines in iminium ion[2] and enamine-catalyzed[3]
processes. Within iminium ion catalyzed reactions the imida-
zolidinone architecture (Scheme 1) has emerged as a priv-
makes them operationally simple and has undoubtedly been
instrumental in the rapid development of the field. Inves-
tigations focussing on the reactivity of the imidazolidinone
scaffold and improvements in catalyst activity have been
previously reported[16] and experimental evidence to ration-
alize selectivities and kinetic profiles in iminium ion catalyzed
transformations have also received attention.[17–19] However,
to date the precise role of protic solvents in affecting the
outcome of an iminium ion catalyzed process has yet to be
rigorously examined experimentally. Here we report on the
subtle roles of protic solvents in determining the rate and
stereochemical outcome of the Diels–Alder cycloaddition
catalyzed by imidazolidinone 1·HCl.
As a starting point to this investigation we confirmed and
further exemplified the effect of water on the stereochemical
outcome and yield in the Diels–Alder cycloaddition between
cinnamaldehyde (7) and cyclopentadiene catalyzed by imida-
zolidinone 1·HCl in a series of solvents (Table 1). This data
was not explicitly included in the initial report.[5a]
Scheme 1. Principal imidazolidinone catalysts.
ileged catalyst scaffold.[4] Imidazolidinone 1 has been used in
the acceleration of [4 + 2],[5] [3 + 2],[6] and [4 + 3][7] cyclo-
additions as well as the conjugate addition of pyrroles[8] to
a,b-unsaturated aldehydes. The pivaldehyde-derived imida-
zolidinone 2 has been used for the conjugate addition of
Table 1: Solvent effect in the Diels–Alder cycloaddition between cyclo-
pentadiene and cinnamaldehyde catalyzed by imidazolidinone 1·HCl.[a]
indoles[9] and electron-rich aromatics[10] to form new C C
À
bonds, the addition of nitrogen-[11] and hydride-based[12]
nucleophiles and for intramolecular [4 + 2] cycloadditions.[13]
Imidazolidinone 3 has been used in iminium ion catalyzed
Diels–Alder cycloaddition[14] and conjugate reduction[15] reac-
tions of a,b-unsaturated ketones.
Entry
Solvent
endo/exo[b]
endo ee[c]
exo ee[c]
Yield
[%][d]
1
2
MeOH/H2O
MeOH
MeOH/H2O
MeOH
CH3CN/H2O
CH3CN
CH3NO2/H2O
CH3NO2
1:1.3
1:1.3
1:1.3
1:1.3
1:1.2
1:1.2
1:1.3
1:1.3
93%
93%
93%
n.d.
93%
89%
90%
79%
93%
91%
93%
n.d.
90%
87%
86%
81%
93
88
3[e]
4[e]
5
92[f]
64[f]
88
In the initial publication on the Diels–Alder cycloaddition
using catalyst 1·HCl it was noted that water had a dual role in
the reaction, increasing both yield and ee obtained for the
products.[5a] These observations have yet to be explained
through experimental findings. In subsequent reports using
catalysts 1–3[5–15] the majority of optimized reaction condi-
tions involve use of a protic solvent in the reaction medium
(water, isopropyl alcohol, or ethanol).
6
7
8
37
88
22
[a] Reaction of cinnamaldehyde and cyclopentadiene in solvent/H2O
(19:1) or anhydrous solvent, 1m, 258C, 24 h, 5 mol% 1·HCl; aldehyde
products isolated following hydrolysis of the crude reaction mixture (see
the Supporting Information for details). [b] endo/exo ratio determined by
1H NMR spectroscopy. [c] Determined by conversion to 2,4-dinitro-
phenyl hydrazine derivative and examination by HPLC using Chiracel
OD-R (see Ref. [21]). [d] Yield of isolated product. [e] Reaction carried out
for 6 h in the presence of 10 mol% 1·HCl. [f] Conversions determined by
1H NMR spectroscopy.
From a practical perspective, the ability to perform these
transformations without the rigorous exclusion of moisture
[*] Dr. J. B. Brazier, Dr. K. M. Jones, Dr. J. A. Platts,
Dr. N. C. O. Tomkinson
School of Chemistry, Main Building, Cardiff University
Park Place, Cardiff, CF10 3AT (UK)
Fax: (+44)2920-874-030
E-mail: platts@cardiff.ac.uk
tomkinsonnc@cardiff.ac.uk
Homepage: http://www.cardiff.ac.uk/chemy
In anhydrous methanol the Diels–Alder reaction between
cyclopentadiene and cinnamaldehyde (7) provided the endo
and exo adducts in 93% ee and 91% ee, respectively (88%
yield) (Table 1, entry 2). Similar levels of asymmetric induc-
tion but higher yield were obtained in a methanol/water
system (entry 1; 93% ee endo, 93% ee exo, 93% yield).
Addition of water therefore increases the yield obtained but
does not substantially alter selectivities in an alcoholic
[**] The authors thank the EPSRC for financial support under grant
reference EP/E018718/1, and the Mass Spectrometry Service,
Swansea, for high-resolution spectra.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201005892.
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1613

Communications
solvent. The effect on yield is better exemplified by shorter
water in the reaction is low (< 20 mol%) such that retro
Diels–Alder reaction can occur prior to iminium ion hydrol-
ysis, resulting in lower ee values for the products (Table 1;
entries 6 and 8). By increasing the concentration of water in
the catalytic reaction, rapid hydrolysis of the iminium ions 9
and 10 occurs resulting in high levels of asymmetry in the
products.
Along with providing the products in higher ee water also
leads to enhanced reaction rates in CH3CN and CH3NO2. As
well as increasing the rate of catalyst turnover (described
above) we propose this is due to an increased rate of
formation (and hence concentration) of the reactive iminium
ion 4·Cl. Figure 1 shows the reaction of cinnamaldehyde (7)
reaction times (entries 3 and 4). In the presence of water
(entry 3) a 92% conversion to the products is observed,
whereas, running the same reaction in anhydrous methanol
leads to a substantially reduced 64% conversion (entry 4). In
nonprotic solvents the results are more complex. Changing
the reaction medium to CH3CN or CH3NO2 and examining
the Diels–Alder cycloaddition under anhydrous conditions
(entries 6 and 8) or in the presence of water (5 vol%)
(entries 5 and 7) shows two clear trends: Both the rate of
product formation and the ee of the cycloadducts is higher in
the presence of water.
The origins of the effect of water on the stereochemical
outcome of reactions conducted in the aprotic solvents
CH3CN and MeNO2 (Table 1; entries 6 and 8) can be clarified
by reaction of 4·PF6 with cyclopentadiene under anhydrous
conditions (Table 2).
Table 2: Effect of time on the Diels–Alder cycloaddition of imidazolidi-
none 4·PF6 and cyclopentadiene.[a]
Figure 1. Relative rates of iminium ion formation: a) Cinnamaldehyde
(7) in CD3CN/D2O (19:1) 1m, 258C, 20 mol% 1·HCl (purple trace);
b) cinnamaldehyde (7) in CD3CN 1m, 258C, 20 mol% 1·HCl (blue
trace); c) cinnamaldehyde (7) in CD3OD/D2O (19:1) 1m, 258C,
20 mol% 1·HCl (dark red trace); d) cinnamaldehyde (7) in CD3OD
1m, 258C, 20 mol% 1·HCl (red trace); e) cinnamaldehyde dimethyl
acetal (8) in CD3OD 1m, 258C, 20 mol% 1·HCl (green trace).
Entry
t [h]
endo ee[b]
exo ee[b]
1
2
3
4
1
6
88%
70%
42%
<3%
86%
75%
53%
<3%
24
2352
[a] Reaction of 4·PF6 and cyclopentadiene in acetonitrile, 0.2m, 258C.
[b] Determined by conversion to the 2,4-dinitrophenyl hydrazine deriv-
ative and examination by HPLC using Chiracel OD-R (see Ref. [21]).
and 1·HCl (20 mol%) in different solvent mixtures. In
CD3CN/D2O (19:1) ((a), purple trace) iminium ion formation
is substantially faster than in anhydrous CD3CN ((b), blue
trace). Therefore, water increases the rate of iminium ion
formation, perhaps due to hydrogen bonding activating
cinnamaldehyde toward nucleophilic attack.[20]
A third role of water in aprotic solvents (e.g. CH3CN) is to
dissolve the catalyst. Solubility of 1·HCl in nonpolar solvents
is limited, such that under typical concentrations for a
catalytic reaction the mixture is heterogeneous. Addition of
water (5 vol%) solubilizes the catalyst at standard concen-
tration promoting reaction.
In the absence of water, the ee for both the endo- and exo-
adducts erodes over time, showing the Diels–Alder cyclo-
addition to be a reversible process (Table 2; entries 1–4).
Under these conditions, cycloaddition is under thermody-
namic control. In the presence of a nucleophilic protic solvent
(such as water or methanol) the iminium ions of the Diels–
Alder adducts (9 and 10) are rapidly hydrolyzed leading to the
kinetic Diels–Alder adducts. We therefore believe that the
role of water in increasing the ee values in the reaction is due
to interception of the iminium ion adducts before they
undergo retro Diels–Alder reaction.
Stirring the Diels–Alder products 5 (93% ee) and 6
(93% ee) with 1·HPF6 in either acetonitrile or acetonitrile/
H2O (19:1) for 24 h leads to no change in the ee of the adducts
or in the endo/exo ratio. The equilibrium constant for the
reaction between imidazolidinone 1·HCl and Diels–Alder
adducts 5 or 6 is low, presumably due to steric reasons, and in
a typical catalytic reaction 1·HCl will form an iminium ion
with cinnamaldehyde (7) rather than the Diels–Alder adducts
5 or 6. When the catalytic reaction is carried out in the
absence of a protic (nucleophilic) solvent the concentration of
The origins of rate acceleration by addition of water to
methanol are less apparent but were revealed by monitoring
1
the reaction by H NMR spectroscopy. Figure 2 shows two
graphs for the reaction of cinnamaldehyde (7) (1 equiv) and
cyclopentadiene (3 equiv) catalyzed by 1·HCl (20 mol%) in
CD3OD (Figure 2a) and CD3OD/D2O (19:1) (Figure 2b).
Under these reaction concentrations, Diels–Alder cycloaddi-
tion is faster than iminium ion formation. In each reaction,
prior to the addition of cyclopentadiene, equilibrium was
established between cinnamaldehyde (7), cinnamaldehyde
dimethyl acetal (8), and iminium ion (4·Cl). At equilibrium,
the ratio of cinnamaldehyde/dimethyl acetal/iminium ion is
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catalyst 1·HCl is therefore faster than reaction of acetal 8 with
the catalyst.
It is appropriate to reconsider the overall catalytic cycle
for this transformation to account for the precise reaction
pathway (Scheme 2). Within this revised reaction sequence
the dimethyl acetal of cinnamaldehyde (8) and the Diels–
Alder adducts (11 and 12) are present within the reaction
mixture. The secondary equilibrium which occurs between
cinnamaldehyde and methanol is a rapid acid-catalyzed
process but the position of this equilibrium alters the rate of
the catalytic cycle. Addition of water perturbs the equilibrium
position (7/8) leading to an increased concentration of
cinnamaldehyde (7) and therefore a higher overall rate of
reaction. As would be expected, there will be a point at which
increasing water concentration further would inhibit iminium
ion formation. Indeed, conducting the reaction in the
presence of 10 vol% H2O led to a lower overall rate for
Diels–Alder cycloaddition (see the Supporting Information).
One of the distinct advantages provided by iminium ion
catalyzed processes is the highly practical reaction conditions:
reactions proceed without the need for rigorous exclusion of
moisture and air. It is clear that water (or an alternative
protic/nucleophilic solvent) is an essential component of these
transformations, and for Diels–Alder cycloaddition, increases
both the rate and ee values observed. Under the optimized
literature reaction conditions, water alters the position of
equilibrium between cinnamaldehyde (7) and cinnamalde-
hyde dimethyl acetal (8) increasing the concentration of 7. In
nonprotic solvents, water accelerates iminium ion formation
through hydrogen bonding, intercepts iminium ion products
preventing retro Diels–Alder reaction and loss of enantiose-
lectivity, and solubilizes the catalyst. An important goal in this
area of organocatalysis is improving reaction efficiency. These
results show that both catalyst and solvent play critical roles in
dictating reaction outcomes and should both be considered in
catalyst and protocol development.
Figure 2. Diels–Alder reaction between cinnamaldehyde and cyclopen-
tadiene catalyzed by 1·HCl in a) CD3OD and b) CD3OD/D2O (19:1).
1.9:3.9:1 in CD3OD and 5.8:1.9:1 in CD3OD/D2O (19:1).
Water therefore alters the equilibrium position between
cinnamaldehyde (7) and cinnamaldehyde dimethyl acetal (8).
For the equilibrium (7/8/4·Cl) to affect the rate of the
catalytic cycle it would be necessary for the conversion of
cinnamaldehyde dimethyl acetal (8) to iminium ion 4·Cl to be
slower than the conversion of cinnamaldehyde (7) to iminium
ion 4·Cl. We therefore monitored the equilibrium between 7,
8, and 4·Cl in CD3OD and CD3OD/D2O mixtures (Figure 1).
The rate of iminium ion formation from reaction of
cinnamaldehyde (7) in CD3OD/D2O (19:1) (Figure 1c, dark
red trace) is higher than in anhydrous CD3OD (Figure 1d, red
trace). Reaction of cinnamaldehyde dimethyl acetal (8) and
1·HCl in anhydrous CD3OD (Figure 1e, green trace) is slower
still. Reaction of cinnamaldehyde (7) with imidazolidinone
Received: September 20, 2010
Published online: January 5, 2011
Scheme 2. Revised reaction sequence for the iminium ion catalyzed Diels–Alder reaction.
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Communications
List, J. Am. Chem. Soc. 2005, 127, 15036; c) J. B. Tuttle, S. G.
Ouellet, D. W. C. MacMillan, J. Am. Chem. Soc. 2006, 128,
12662.
Keywords: Diels–Alder reaction · imidazolidinone ·
iminium ion catalysis · organocatalysis
.
[13] Ref. [5c].
[14] Ref. [5b].
[1] D. W. C. MacMillan, Nature 2008, 455, 304, and references cited
therein.
[2] a) A. Erkkilꢀ, I. Majander, P. M. Pihko, Chem. Rev. 2007, 107,
5416; b) J. B. Brazier, N. C. O. Tomkinson, Top. Curr. Chem.
2010, 291, 281.
[15] J. B. Tuttle, S. G. Ouellet, D. W. C. MacMillan, J. Am. Chem. Soc.
2006, 128, 12662.
[16] a) J. L. Cavill, J.-E. Peters, N. C. O. Tomkinson, Chem. Commun.
2003, 728; b) J. L. Cavill, R. L. Elliott, G. Evans, I. L. Jones, J. A.
Platts, A. M. Ruda, N. C. O. Tomkinson, Tetrahedron 2006, 62,
410; c) G. J. S. Evans, K. White, J. A. Platts, N. C. O. Tomkinson,
Org. Biomol. Chem. 2006, 4, 2616; d) G. Evans, T. J. K. Gibbs,
R. L. Jenkins, S. J. Coles, M. B. Hirsthouse, J. A. Platts, N. C. O.
Tomkinson, Angew. Chem. 2008, 120, 2862; Angew. Chem. Int.
Ed. 2008, 47, 2820; e) J. B. Brazier, J. L. Cavill, R. L. Elliott, G.
Evans, T. J. K. Gibbs, I. L. Jones, J. A. Platts, N. C. O. Tomkin-
son, Tetrahedron 2009, 65, 9961.
[3] S. Mukherjee, J. W. Yang, S. Hoffmann, B. List, Chem. Rev. 2007,
107, 5471.
[4] For a review on the use of imidazolidinone catalysts see: G.
Lelais, D. W. C. MacMillan, Aldrichimica Acta 2006, 39, 79.
[5] a) K. A. Ahrendt, C. J. Borths, D. W. C. MacMillan, J. Am.
Chem. Soc. 2000, 122, 4243; b) A. B. Northrup, D. W. C.
MacMillan, J. Am. Chem. Soc. 2002, 124, 2458; c) R. M.
Wilson, W. S. Jen, D. W. C. MacMillan, J. Am. Chem. Soc.
2005, 127, 11616.
[6] W. S. Jen, J. J. M. Wiener, D. W. C. MacMillan, J. Am. Chem.
Soc. 2000, 122, 9874.
[7] M. Harmata, S. K. Ghosh, X. Hong, S. Wacharasindhu, P.
Kirchhoefer, J. Am. Chem. Soc. 2003, 125, 2058.
[8] N. A. Paras, D. W. C. MacMillan, J. Am. Chem. Soc. 2001, 123,
4370.
[9] a) J. F. Austin, D. W. C. MacMillan, J. Am. Chem. Soc. 2002, 124,
1172; b) J. F. Austin, S.-G. Kim, C. J. Sinz, W.-J. Xiao, D. W. C.
MacMillan, Proc. Natl. Acad. Sci. USA 2004, 101, 5482.
[10] a) N. A. Paras, D. W. C. MacMillan, J. Am. Chem. Soc. 2002, 124,
7894; b) S. P. Brown, N. C. Goodwin, D. W. C. MacMillan, J. Am.
Chem. Soc. 2003, 125, 1192.
[11] Y. K. Chen, M. Yoshida, D. W. C. MacMillan, J. Am. Chem. Soc.
2006, 128, 9328.
[12] a) S. G. Ouellet, J. B. Tuttle, D. W. C. MacMillan, J. Am. Chem.
Soc. 2005, 127, 32; b) J. W. Yang, M. T. Hechavarria Foncesca, B.
[17] J. B. Brazier, G. Evans, T. J. K. Gibbs, S. J. Coles, M. B. Hurst-
house, J. A. Platts, N. C. O. Tomkinson, Org. Lett. 2009, 11, 133.
ˇ
[18] a) D. Seebach, U. Groselj, W. B. Schweizer, S. Grimme, C. Muck-
ˇ
Lichtenfeld, Helv. Chim. Acta 2010, 93, 1; b) U. Groselj, W. B.
Schweizer, M.-O. Ebert, D. Seebach, Helv. Chim. Acta 2009, 92,
ˇ
1; c) D. Seebach, U. Groselj, D. M. Badine, W. B. Schweizer,
A. K. Beck, Helv. Chim. Acta 2008, 91, 1999.
[19] S. Lakhdar, T. Tokuyasu, H. Mayr, Angew. Chem. 2008, 120,
8851; Angew. Chem. Int. Ed. 2008, 47, 8723.
[20] For reviews on the acceleration of organic transformations by
water through H-bonding catalysis see: a) Hydrogen Bonding in
Organic Synthesis (Ed.: P. M. Pihko), Wiley-VCH, Weinheim,
2009; b) C. M. Kleiner, P. R. Schreiner, Chem. Commun. 2006,
4315; c) P. R. Schreiner, Chem. Soc. Rev. 2003, 32, 289; d) A.
Lubineau, J. Augꢁ, Y. Queneau, Synthesis 1994, 741.
[21] A. Hall, L. D. Harris, C. L. Jones, N. C. O. Tomkinson, Tetrahe-
dron Lett. 2003, 44, 111.
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