Kinetics and mechanism of organocatalytic aza-Michael additions: Direct observation of enamine intermediates

Article abstract of DOI:10.1039/c2cc31224g

The imidazoles 1a-g add to the CC-double bond of the iminium ion 2 with rate constants as predicted by the equation log k = s_N(N + E). Unfavourable proton shifts from the imidazolium unit to the enamine fragment in the adduct 3 account for the failure of imidazoles to take part in iminium-activated aza-Michael additions to enals.

Full text of DOI:10.1039/c2cc31224g

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COMMUNICATION
Kinetics and mechanism of organocatalytic aza-Michael additions: direct
observation of enamine intermediateswz
Sami Lakhdar, Mahiuddin Baidya and Herbert Mayr*
Received 17th February 2012, Accepted 13th March 2012
DOI: 10.1039/c2cc31224g
The imidazoles 1a–g add to the CC-double bond of the iminium
ion 2 with rate constants as predicted by the equation log k =
sN(N + E). Unfavourable proton shifts from the imidazolium
unit to the enamine fragment in the adduct 3 account for the
failure of imidazoles to take part in iminium-activated aza-
Michael additions to enals.
We now report the kinetics and mechanism of the reactions
of imidazoles with the iminium ion 2 and rationalise why
imidazoles, in contrast to triazoles and tetrazoles, do not
undergo organocatalytic aza-Michael additions.
In previous work we have shown that the rates of the
reactions of carbocations and Michael acceptors with n, p,
and s nucleophiles can be described by eqn (1),7 where k2 is a
second-order rate constant in Mꢀ1 ꢀ1, sN is a nucleophile-
s
Since MacMillan’s pioneering work in 2000,1 the so-called iminium
activation has become one of the most attractive methods in
asymmetric synthesis.2 In his seminal paper, MacMillan showed
that a,b-unsaturated aldehydes can be activated by the addition of
catalytic amounts of chiral secondary amines; the initially generated
iminium ions undergo fast Diels–Alder reactions with dienes
to give cycloadducts, which release the chiral catalyst upon
hydrolysis.1 By using this strategy it has become possible to
realise a large variety of enantioselective organic reactions.3
In 2007, Jørgensen et al.4 and Vicario et al.5 independently
reported the first enantioselective aza-Michael additions of nitrogen
heterocycles to aliphatic unsaturated aldehydes (Scheme 1), using
diarylprolinol silyl ethers or imidazolidinones as catalysts.6
While these reactions proceeded readily with tetrazoles and
triazoles, they generally failed with imidazoles and benzimidazoles.
Only 4,5-dicyano-imidazole was found to react with moderate
yield and low enantioselectivity with aliphatic enals utilizing
MacMillan’s second generation imidazolidinone as a catalyst.5
Under the same conditions, the parent imidazole 1c gave only
traces of the product.
specific sensitivity parameter, N is a nucleophilicity parameter,
and E is an electrophilicity parameter.
log k2 (20 1C) = sN(N + E)
(1)
Using the known reactivity parameters N and sN of the
imidazoles 1a–g8 (Table 1) and the electrophilicity parameter
of the cinnamaldehyde-derived iminium ion 29 (E = ꢀ7.37),
we had calculated second-order rate constants of 300–3000
M
should proceed readily.
ꢀ1 sꢀ1 by eqn (1) indicating that the reactions of 2 with 1a–g
Accordingly, treatment of the iminium salt 2-PF6 with 4
equivalents of imidazole 1c leads to the formation of the
enamine 3c, which bears a protonated imidazole ring. Adduct
3c, which incorporates two stereocenters, was formed as a 1 : 1
1
mixture of two diastereoisomers, as revealed by H and 13C
Table 1 Nucleophile-specific reactivity parameters N and sN for
azoles in acetonitrile8
Azoles
N
sN
Azoles
N
sN
1a
10.50a
0.79a
1e
11.74
0.76
1b
1c
11.43
0.79
1f
11.79
11.90
0.77
0.73
Scheme 1 Aza-Michael additions of N-heterocycles to enals catalysed
by chiral secondary amines.4–6
11.47
11.51
0.79
0.84
1g
Department Chemie, Ludwig-Maximilians-Universitat Munchen,
¨
¨
Butenandtstr. 5-13 (Haus F), 81377 Munchen, Germany.
¨
E-mail: Herbert.Mayr@cup.uni-muenchen.de;
Fax: +49 89 2180 77717
1d
w This article is part of the joint ChemComm–Organic & Biomolecular
Chemistry ‘Organocatalysis’ web themed issue.
z Electronic supplementary information (ESI) available: Details of the
kinetic experiments, synthetic procedures and product characterisation.
See DOI: 10.1039/c2cc31224g
a
N and sN refer to DMSO, as 4-(dimethylamino)pyridine was reported to
have identical reactivity parameters in DMSO and acetonitrile (DN =
0.15)10 the variation of solvent does not affect the analysis in Table 2.
c
4504 Chem. Commun., 2012, 48, 4504–4506
This journal is The Royal Society of Chemistry 2012

Fig. 1 Exponential decay of the absorbance at 370 nm during the
reaction of 2-OTf (5.10 ꢁ 10ꢀ5 M) with imidazole 1c (5.47 ꢁ 10ꢀ3 M).
Inset: determination of the second-order rate constant k2 from the
dependence of the first-order rate constant kobs on the concentration of
imidazole 1c (20 1C in CH3CN).
Scheme 2
NMR spectroscopy. NOE analysis showed the preference
of the (s-E)-conformation of the C(sp2)–N bond in both
diastereoisomers as depicted in Scheme 2. As kinetically
controlled additions of nucleophiles to 2 often proceed with
high diastereoselectivity, the formation of 3c as a 1 : 1 mixture
of diastereomers may either be explained by a reversible
reaction of the iminium ion 2 with the imidazole 1c or by
deprotonation of the imidazolidinone moiety in the intermediate
iminium ion in the a-position to the carbonyl group, as suggested
by Seebach et al.11 The latter mechanism can be excluded under the
conditions of this work because we have recovered the enantiopure
imidazolidinone 5 after hydrolysis of 3c, confirming that the
configuration of the asymmetric center of the imidazolidinone
5 has not been affected.
nucleophiles 1a–g. From the exponential decays of the UV-
absorbances of the electrophile 2, the first-order rate constants
kobs were obtained.
Plots of kobs (sꢀ1) against the concentrations of the nucleophiles
1a–g were linear (Fig. 1) and their slopes gave the second-order
rate constants k2 (Mꢀ1 sꢀ1) which are summarised in Table 2.
The second-order rate constants thus obtained (Table 2)
have been compared with those calculated by eqn (1) from the
electrophilicity parameter E = ꢀ7.37 of the iminium ion 29
and the N and sN parameters of the azoles.8 Table 2 shows that
all calculated (kcalc) and experimental rate constants (kexp) match
within a factor of two. This good agreement is impressive, as E(2)
has been derived from reactions with C-nucleophiles and N and
sN for the azoles 1a–g have been derived from their reactions with
benzhydrylium ions.7
In acetonitrile solution, the enamine intermediates 3c (or 4c
in the presence of excess imidazole) are stable for more than
8 hours but decompose during several days. Addition of water
to the enamine 3c leads to the formation of cinnamaldehyde.
However, stirring of a solution of 3c-PF6 in CD3CN with dry
K2CO3 led to the formation of 4c, which was characterised by
1H and 13C NMR spectroscopy (see ESIz).12,13
Some of the reactions of the iminium ion 2 with imidazoles
proceeded incompletely, and for the reactions with 1b and 1g
the equilibrium constants K (Scheme 4) have been determined
photometrically as described in the ESI.z
Jørgensen’s DFT calculations on the organocatalytic conjugate
addition of 1,2,4-triazole to a,b-unsaturated aldehydes showed
that the addition of the triazole to the iminium ion is followed by
a water-assisted proton transfer from the triazolium ring to the
enamine as depicted in Scheme 3.4 In the case of the reactions of
the azoles 1 with the iminium ion 2, the enamines 3 or their
conjugate bases 4 were observed by NMR spectroscopy, and we
did not observe an analogous proton transfer which may be
explained by the lower acidities of the imidazolium ions compared
to triazolium ions.
Table 2 Comparison of experimental (kexp) and calculated rate
constants (kcalc, using eqn (1)) for the reactions of the azoles 1a–g
with the iminium ion 2 (E = ꢀ7.37) in CH3CN at 20 1C
Azoles
kexp/Mꢀ1 sꢀ1
kcalc/Mꢀ1 sꢀ1
kexp/kcalc
1a
1b
1c
1d
1e
1f
2.75 ꢁ 102
2.88 ꢁ 103
3.01 ꢁ 103
3.00 ꢁ 103
2.84 ꢁ 103
4.62 ꢁ 103
4.15 ꢁ 103
2.97 ꢁ 102
1.61 ꢁ 103
1.73 ꢁ 103
3.00 ꢁ 103
2.10 ꢁ 103
2.53 ꢁ 103
2.03 ꢁ 103
0.93
1.8
1.7
1.0
1.4
1.8
2.0
The different UV-absorbances of the iminium ions 2 and the
adducts 3 allowed us to follow the kinetics of the reactions of 2
with the azoles 1a–g photometrically at the absorption maximum
of the iminium ion 2 (370 nm). All kinetic experiments were
performed under first-order conditions using a high excess of the
1g
Scheme 4 Reversible additions of the imidazoles 1b and 1g to the
iminium ion 2 in CH3CN.
Scheme 3
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 4504–4506 4505

Table 3 Equilibrium constants (K) for the reactions of azoles 1b and
1g with the iminium ion 2 (counterion PF6ꢀ) in CH3CN at 20 1C
2 For reviews on asymmetric iminium catalysis, see: (a) A. Berkessel
and H. Groger, Asymmetric Organocatalysis, Wiley-VCH,
Weinheim, 2005; (b) G. Lelais and D. W. C. MacMillan, Aldrichimica
Acta, 2006, 39, 79; (c) A. Erkkila, I. Majander and P. M. Pihko, Chem.
Rev., 2007, 107, 5416; (d) S. B. Tsogoeva, Eur. J. Org. Chem., 2007,
1701; (e) D. Alma-si, D. A. Alonso and C. Najera, Tetrahedron:
Asymmetry, 2007, 18, 299; (f) J. Seayad and B. List, Org. Biomol.
Chem., 2005, 3, 719; (g) B. List and J.-W. Yang, Science, 2006,
313, 1584; (h) B. List, Chem. Commun., 2006, 819.
DGa
/
DG0/
DGa0
/
Azoles
K/Mꢀ1
kJ molꢀ1
kJ molꢀ1
kJ molꢀ1
k’/sꢀ1
1b
1g
1.61 ꢁ 103
1.84 ꢁ 102
52.3
51.4
ꢀ18.0
ꢀ12.7
61.0
57.6
1.79
22.6
3 (a) D. W. C. MacMillan, Nature, 2008, 455, 304; (b) J. B. Brazier
and N. C. O. Tomkinsson, Top. Curr. Chem., 2010, 291, 281.
4 P. Diner, M. Nielsen, M. Marigo and K. A. Jørgensen, Angew.
Chem., 2007, 119, 2029 (Angew. Chem., Int. Ed., 2007, 46, 1983).
5 U. Uria, J. L. Vicario, D. Badia and L. Carrillo, Chem. Commun.,
2007, 2509.
6 For a comprehensive review on organocatalytic aza-Michael
additions, see: D. Enders, C. Wang and J. X. Liebich, Chem.–Eur. J.,
2009, 15, 11058.
7 (a) H. Mayr and M. Patz, Angew. Chem., 1994, 106, 990 (Angew.
Chem., Int. Ed. Engl., 1994, 33, 938); (b) H. Mayr, T. Bug,
M. F. Gotta, N. Hering, B. Irrgang, B. Janker, B. Kempf,
R. Loos, A. R. Ofial, G. Remennikov and H. Schimmel, J. Am.
Chem. Soc., 2001, 123, 9500; (c) H. Mayr, B. Kempf and
A. R. Ofial, Acc. Chem. Res., 2003, 36, 66; (d) H. Mayr
and A. R. Ofial, Pure Appl. Chem., 2005, 77, 1807; (e) H. Mayr
and A. R. Ofial, J. Phys. Org. Chem., 2008, 21, 584.
8 M. Baidya, F. Brotzel and H. Mayr, Org. Biomol. Chem., 2010,
8, 1929.
9 (a) S. Lakhdar, T. Tokuyasu and H. Mayr, Angew. Chem., 2008,
120, 8851 (Angew. Chem., Int. Ed., 2008, 47, 8723); (b) S. Lakhdar,
J. Ammer and H. Mayr, Angew. Chem., 2011, 123, 10127 (Angew.
Chem., Int. Ed., 2011, 50, 9953).
10 F. Brotzel, B. Kempf, T. Singer, H. Zipse and H. Mayr, Chem.–
Eur. J., 2007, 13, 336–345.
11 D. Seebach, U. Groselj, D. M. Badine, W. B. Schweizer and
A. K. Beck, Helv. Chim. Acta, 2008, 91, 1999.
Table 3 shows that 1-(trimethylsilyl)-imidazole 1b, which is
1.4 times less nucleophilic than 1-methylimidazole 1g (Table 2),
is a nine-fold stronger Lewis base than 1g. Substitution of the rate
and equilibrium constants into the Marcus equation (2) yields the
intrinsic barriers DGa0 , which are defined as the activation
energies of processes with DG0 = 0.14
DGa = DGa0 + 0.5 DG0 + ((DG0)2/16DGa0 )
(2)
Remarkably, the intrinsic barrier for the addition of the
azole 1g to the iminium ion 2 is about 10 kJ molꢀ1 lower
than that for its reaction with diarylcarbenium ions.8 This
difference reflects that more reorganisation energy is needed
for the reactions of nucleophiles with diarylcarbenium ions
than with unsaturated iminium ions due to the more extensive
delocalization of the positive charge in diarylcarbenium ions.
In conclusion, we have shown that the reactions of the
iminium ion 2 with imidazoles proceed readily with formation
of stable enamines which have been fully characterised by
NMR spectroscopy. The failure of the azoles 1a–g to act as
nucleophiles in iminium-activated processes is rationalised by
the low acidities of the initially generated azolium species
which do not undergo proton shifts. The rate constants
determined for the reactions of the iminium ion 2 with the
azoles 1a–g are in good agreement with those calculated by
eqn (1), showing the suitability of the benzhydrylium-based
reactivity parameters N and sN for predicting reactivities
toward iminium ions.
12 For recent reports on the isolation of enamines derived from chiral
amines, see: (a) U. Groselj, D. Seebach, D. M. Badine,
W. B. Schweizer, A. K. Beck, I. Krossing, P. Klose, Y. Hayashi
and T. Uchimaru, Helv. Chim. Acta, 2009, 92, 1225;
(b) P. Dominguez de Maria, P. Bracco, L. Fernando Castelhano
and G. Bargeman, ACS Catal., 2011, 1, 70; (c) K. P. Komisarska,
M. Benohoud, H. Ishikawa, D. Seebach and Y. Hayashi, Helv.
Chim. Acta, 2011, 94, 719.
13 For recent reports on the NMR spectroscopic detection of chiral
enamines as reaction intermediates see: (a) M. B. Schmid,
K. Zeitler and R. M. Gschwind, J. Am. Chem. Soc., 2011,
133, 7065; (b) M. B. Schmid, K. Zeitler and R. M. Gschwind,
Angew. Chem., 2010, 122, 5117 (Angew. Chem., Int. Ed., 2010,
49, 4997); (c) M. B. Schmid, K. Zeitler and R. M. Gschwind,
Chem. Sci., 2011, 2, 1793.
We thank Dr Armin R. Ofial and Biplab Maji for helpful
discussions and the Deutsche Forschungsgemeinschaft (SFB 749)
for generous support.
Notes and references
1 K. A. Ahrendt, C. J. Borths and D. W. C. MacMillan, J. Am.
Chem. Soc., 2000, 122, 4243.
14 (a) R. A. Marcus, J. Phys. Chem., 1968, 72, 891; (b) W. J. Albery,
Annu. Rev. Phys. Chem., 1980, 31, 227.
c
4506 Chem. Commun., 2012, 48, 4504–4506
This journal is The Royal Society of Chemistry 2012