How does electrostatic activation control iminium-catalyzed cyclopropanations

Full text of DOI:10.1002/anie.200900933

Communications
DOI: 10.1002/anie.200900933
Organocatalysis
How Does Electrostatic Activation Control Iminium-Catalyzed
Cyclopropanations?**
Sami Lakhdar, Roland Appel, and Herbert Mayr*
Dedicated to Professor Hans-Ulrich Reißig on the occasion of his 60th birthday
Three-membered carbocycles are versatile building blocks in
organic chemistry and are found in numerous natural
products.[1] The use of sulfur ylides for their syntheses from
a,b-unsaturated carbonyl compounds was introduced in the
1960s by Corey and Chaykovsky.[2] Since then, numerous
syntheses of cyclopropanes have emerged that often provide
excellent levels of both enantio- and diastereocontrol.[3,4] In
2005 MacMillan and Kunz reported an enantioselective
Scheme 2. Imidazolidinones 4 and 5 and transition state 6 for the
cyclopropanation of iminium ions derived from 3 with sulfur ylides.
cyclopropanation reaction by using chiral indoline-2-carbox-
ylic acid (3) as a catalyst (Scheme 1).[5]
sulfonium fragment, was suggested to account for the high
reactivity and selectivity of the iminium ions derived from
3.[5,6] On the other hand, Cao et al. reported the highly
diastereoselective and enantioselective cyclopropanation of
cinnamaldehyde (2b) with the triphenylarsonium analogue of
1a when the diphenylprolinyl trimethylsilyl ether was used as
the catalyst.[7]
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 Equation (1), where k208C
Scheme 1. Diastereo- and enantioselective organocatalytic ylide cyclo-
propanation with indoline-2-carboxylic acid (3) by MacMillan and
Kunz.[5]
ꢀ C
lg k20 ¼ sðN þ EÞ
ð1Þ
is the second-order rate constant in mꢁ1 sꢁ1, s is the nucleo-
phile-specific slope parameter, N is the nucleophilicity
parameter, and E is the electrophilicity parameter.[8] Based
on unpublished reactivity parameters of sulfur ylides and the
recently reported electrophilicity parameters of iminium ions
(Scheme 3),[9] we had expected that in contrast to MacMil-
lanꢀs statement,[5] the reactions of cinnamaldehyde-derived
iminium ions 7 with sulfur ylide 1b should proceed readily, as
predicted by Equation (1).
From the observation that the imidazolidinones 4·TFA
and 5·TFA (Scheme 2, TFA = trifluoroacetic acid) did not
catalyze the reaction of (E)-hex-2-enal (2a) with the sulfur
ylide 1a (0% conversion), MacMillan and Kunz concluded
that the iminium ions derived from 2a and 4 or 5 are inert to
the ylides 1. Electrostatic stabilization of the transition state 6
(Scheme 2), that is, Coulombic attraction between the neg-
atively charged carboxylate group and the positively charged
Accordingly, treatment of the iminium triflates (7a–e)-
OTf with the sulfur ylide 1b yielded cyclopropane derivatives
in 42–77% yield. However, in contrast to MacMillanꢀs
[*] Dr. S. Lakhdar, R. Appel, Prof. Dr. H. Mayr
Department Chemie und Biochemie
Ludwig-Maximilians-Universitꢀt Mꢁnchen
Butenandtstrasse 5–13 (Haus F), 81377 Mꢁnchen (Germany)
Fax: (+49)89-2180-77717
E-mail: herbert.mayr@cup.uni-muenchen.de
Homepage: http://www.cup.lmu.de/oc/mayr
[**] We thank the Alexander von Humboldt Foundation (research
fellowship to S.L.), the Deutsche Forschungsgemeinschaft (Ma
673/21-3), and the Fonds der Chemischen Industrie for financial
support. Valuable suggestions by Dr. Armin R. Ofial are gratefully
acknowledged. We thank Konstantin Troshin for support with the
HPLC analysis.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200900933.
Scheme 3. Iminium ions 7 derived from cinnamaldehyde (2b) and
their electrophilicity parameters E (from Ref. [9]).
5034
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2009, 48, 5034 –5037

Angewandte
Chemie
conditions,[5] which gave only two diastereomers in a ratio of
33:1 and high enantioselectivity, no significant stereoselectiv-
ity was observed (Scheme 4). None of the diastereoisomers
obtained with 7d was formed with high enantioselectivity.
Table 1: Second-order rate constants for the reactions of the benzhy-
drylium ions 8a–e with the sulfur ylide 1b (208C, CH2Cl2).
Electrophile
E[a]
k2 [mꢁ1 sꢁ1
]
8a
8b
X=N(Me)2
X=N(CH2)4
ꢁ7.02
5.82ꢂ103
1.84ꢂ103
ꢁ7.69
8c
ꢁ8.76
2.45ꢂ102
8d (n=2)
8e (n=1)
ꢁ9.45
8.40ꢂ101
2.91ꢂ101
ꢁ10.04
[a] E from Ref. [8b].
Scheme 4. Reactions of iminium triflates 7 with the sulfur ylide 1b
(Ar=p-Br-C6H4).
To elucidate whether electrostatic activation really
accounts for the catalytic activity of 3 in cyclopropanation
reactions with sulfur ylides, we determined the nucleophilicity
parameter of 1b as well as the electrophilicity parameter of
the zwitterion 7 fꢂ derived from chiral 3 and cinnamaldehyde
(2b).
The nucleophile-specific parameters N and s of the sulfur
ylide 1b were derived from the second-order rate constants k2
of the reactions of 1b with the reference electrophiles 8a–e
(see Table 1),[8b] which gave the addition products 9a–e as
confirmed by the isolation and characterization of the ylide
10a (Scheme 5, for details see the Supporting Information).
The kinetics were monitored photometrically by following the
disappearance of the colored benzhydrylium ions 8 as
described previously[8,10] and specified in the Supporting
Information.
Figure 1. Plot of lgk2 for the reactions of the sulfur ylide 1b with the
benzhydrylium ions 8a–e in CH2Cl2 at 208C versus the electrophilicity
parameters E of 8a–e.
explained by the low nucleophilicity of sulfur ylides. Instead it
can be rationalized by the high basicity of sulfur ylides, which
inhibits the formation of iminium ions; this is in line with the
observation that the sulfur ylide 1b is quantitatively proton-
ated in CHCl3 solution when treated with 4·TFA. Because of
the poor solubility of 3, sulfur ylide 1b was not protonated
when 3 was added to a solution of 1b in CHCl3.
For the determination of its electrophilicity parameter,
the zwitterion 7 fꢂ was synthesized by treatment of 3 with
cinnamaldehyde (2b) in methanol at room temperature.
When this reaction was carried out in the presence of triflic
acid, the corresponding iminium triflate 7 f-OTf was obtained.
NOESY experiments showed strong correlations between the
protons marked in Scheme 6, indicating (Z)-7 f as the favored
conformation. Analogous NMR experiments with the zwit-
terion 7 fꢂ were less conclusive because of the slow decom-
position of 7 fꢂ in CD3OD.
Scheme 5. Reactions of the sulfur ylide 1b with the reference electro-
philes 8 in CH2Cl2 at 208C.
As required by Equation (1), lgk2 for the reactions of 1b
with 8a–e correlated linearly with the electrophilicity param-
eters E of 8a–e (Table 1) and yielded the nucleophile-specific
parameters N(1b) = 11.95 and s(1b) = 0.76 (Figure 1). The
nucleophilicity of sulfur ylide 1b is thus similar to that of an
alkoxycarbonyl- or cyano-stabilized triphenylphosphonium
ylide,[10] and 1b is more nucleophilic than indoles,[8e] pyrro-
les,[8g] and dihydropyridines,[8h] which have previously been
employed as substrates in iminium-catalyzed reactions.
The observation made by MacMillan and Kunz that 4-H+
fails to catalyze the reaction of 1 with 2 thus cannot be
Scheme 6. Assignment of the conformations of iminium ion 7 f by
NOESY experiments (CD3OD, 208C).
Angew. Chem. Int. Ed. 2009, 48, 5034 –5037
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5035

Communications
In analogy to the previously reported determination of the
the sulfur ylide 1b proceed by a stepwise mechanism, in which
electrophilicity parameters for the iminium ions 7a–e,[9] E of
7 fꢂ was derived from the second-order rate constants of the
reactions of 7 fꢂ with the reference nucleophiles 11 and 12
(Scheme 7). The zwitterion 7 fꢂ reacts about 102 times more
the formation of the first C C bond is rate-determining
ꢁ
(Scheme 8).
Scheme 8. Stepwise mechanism for the cyclopropanation of iminium
ions 7 with sulfur ylides 1. rds=rate-determining step.
While good agreement between observed and calculated
rate constants has also been observed for the reactions of 7d
with pyrroles, indoles, and furans,[12] the situation changes
dramatically for the reaction of the ylide 1b with the
zwitterion 7 fꢂ. Now, the observed rate constant is more
than 105 times (!) higher than predicted by Equation (1) (last
entry in Table 2). Obviously, the reaction of 7 fꢂ with 1b is
accelerated by a special factor which is not taken into account
when we parametrized the nucleophilicity of 1b through its
reactions with the reference electrophiles 8a–e and when we
parametrized the electrophilicity of 7 fꢂ through its reactions
with the reference nucleophiles 11 and 12. Electrostatic
interaction between the carboxyl group of 7 fꢂ and the
sulfonium group of 1b, as depicted in transition state 6
(Scheme 2), may account for this more than 105-fold accel-
eration. The remarkable magnitude of this electrostatic
activation moreover rationalizes the high stereoselectivity of
the cyclopropanation reaction depicted in Scheme 1. As
described in Scheme 4, only low diastereoselectivity and
enantioselectivity were observed in the reaction of 7d with 1b
where this electrostatic activation is absent.
In conclusion, we have shown that electrostatic activation
is, indeed, responsible for the more than 105-fold acceleration
of the reaction of the zwitterion 7 fꢂ with the sulfur ylide 1b
and the high stereoselectivity of this reaction. However, in
contrast to previous statements,[5] also iminium ions 7a–e
react readily with the benzoyl-stabilized sulfur ylide 1b,
though with low stereoselectivity. The previously reported
failure of 4-H+ to catalyze the cyclopropanation of a,b-
unsaturated aldehydes with sulfur ylides thus is not a result of
the low rate of the reaction 7d + 1b but because of the high
basicity of sulfur ylides, which inhibits the formation of
iminium ions.
Scheme 7. Reactions of the zwitterion 7 fꢂ with the ketene acetals 11
and 12 in CH2Cl2/MeOH (9:1, v/v) at 208C.
slowly with the ketene acetals 11 and 12 than the iminium ion
7d derived from MacMillanꢀs catalyst 4.[9] Substitution of the
N and s parameters for the reference nucleophiles 11 and 12
and of the second-order rate constants from Scheme 7 into
Equation (1) gave E(7 fꢂ) = ꢁ9.5 by least-squares minimiza-
tion. A comparison with the iminium ions 7a–e (Scheme 3)
shows that 7 fꢂ is one of the weakest electrophiles derived
from cinnamaldehyde. Yet, 3 was reported to be the most
effective catalyst for the organocatalytic cyclopropanation
reactions of unsaturated aldehydes with sulfur ylides 1.[5] In
order to rationalize this discrepancy, we have investigated the
kinetics of the reactions of the sulfur ylide 1b with the
iminium ions 7a–e and the zwitterion 7 fꢂ.
Table 2 shows that the experimental rate constants for the
reactions of iminium ions 7a–e with the sulfur ylide 1b agree
within a factor of 3 to 32 with those calculated by Equation (1)
from E(7a)–E(7e)[9] and the nucleophile-specific parameters
N and s for 1b given in Figure 1. This agreement is quite
remarkable in view of the simplicity of Equation (1) and the
reactivity range of 40 orders of magnitude covered by this
correlation, and it demonstrates the applicability of our
nucleophilicity parameters N/s for exploring the scope of
iminium-catalyzed reactions.[11] The similarity of calculated
and experimental rate constants suggests, moreover, that the
cyclopropanation reactions between iminium ions 7a–e and
Table 2: Experimental and calculated second-order rate constants (in
mꢁ1 sꢁ1) for the reactions of the sulfur ylide 1b with the iminium ions
7a–e and with 7 fꢂ in CH2Cl2 at 208C.
Received: February 17, 2009
Published online: June 2, 2009
exp
calcd[a]
calcd
Iminium ion
k2
k2
k2exp/k2
7a
7b
7c
7d
7e
7 fꢂ
1.08ꢂ104
1.19ꢂ102
4.01ꢂ103
1.31ꢂ105
1.22ꢂ102
4.19ꢂ102
4.31ꢂ101
3.52ꢂ102
4.07ꢂ103
1.79ꢂ101
7.15ꢂ101
26
Keywords: cyclopropanation · electrophilicity · iminium ions ·
kinetics · organocatalysis
.
2.8
11
32
6.8
@105
[1] Reviews: a) J. Salaun, Chem. Rev. 1989, 89, 1247 – 1270; b) A.-H.
Li, L.-X. Dai, V. K. Aggarwal, Chem. Rev. 1997, 97, 2341 – 2372;
c) A. Pfaltz in Comprehensive Asymmetric Catalysis (Eds.: E. N.
Jacobsen, A. Pfaltz, H. Yamamoto), Springer, Heidelberg, 1999,
pp. 513 – 538; d) R. Faust, Angew. Chem. 2001, 113, 2312 – 2314;
@107[b]
[a] Calculated by Equation (1) by using the electrophilicity parameters E
for 7a–e (from Ref. [9]) and 7 fꢂ (E=ꢁ9.5, see above) as well as the N
and s values for 1b (from Figure 1). [b] Too fast for our instrumentation.
5036
www.angewandte.org
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2009, 48, 5034 –5037

Angewandte
Chemie
Angew. Chem. Int. Ed. 2001, 40, 2251 – 2253; e) H.-U. Reissig, R.
Zimmer, Chem. Rev. 2003, 103, 1151 – 1196.
[2] a) E. J. Corey, M. Chaykovsky, J. Am. Chem. Soc. 1962, 84, 867 –
868; b) E. J. Corey, M. Chaykovsky, J. Am. Chem. Soc. 1962, 84,
3782 – 3783; c) E. J. Corey, M. Chaykovsky, J. Am. Chem. Soc.
1965, 87, 1353 – 1364.
[3] For selected examples on organocatalytic ylide cyclizations, see:
a) N. Bremeyer, S. C. Smith, S. V. Ley, M. J. Gaunt, Angew.
Chem. 2004, 116, 2735 – 2738; Angew. Chem. Int. Ed. 2004, 43,
2681 – 2684; b) C. D. Papageorgiou, M. A. De Dios, S. V. Ley,
M. J. Gaunt, Angew. Chem. 2004, 116, 4741 – 4744; Angew.
Chem. Int. Ed. 2004, 43, 4641 – 4644; c) C. C. C. Johansson, N.
Bremeyer, S. V. Ley, D. R. Owen, S. C. Smith, M. J. Gaunt,
Angew. Chem. 2006, 118, 6170 – 6175; Angew. Chem. Int. Ed.
2006, 45, 6024 – 6028; d) M. J. Gaunt, C. C. C. Johansson, Chem.
Rev. 2007, 107, 5596 – 5605; e) X. L. Sun, Y. Tang, Acc. Chem.
Res. 2008, 41, 937 – 948.
[4] For stereoselective cyclopropanations see: a) A. B. Charette, H.
Lebel, J. Org. Chem. 1995, 60, 2966 – 2967; b) H. Lebel, J.-F.
Marcoux, C. Molinaro, A. B. Charette, Chem. Rev. 2003, 103,
977 – 1050.
[5] R. K. Kunz, D. W. C. MacMillan, J. Am. Chem. Soc. 2005, 127,
3240 – 3241.
[6] For related electrostatic activation see: A. Hartikka, P. I.
Arvidsson, J. Org. Chem. 2007, 72, 5874 – 5877.
[7] Y-H. Zhao, G. Zhao, W.-G. Cao, Tetrahedron: Asymmetry 2007,
18, 2462 – 2467.
Soc. 2001, 123, 9500 – 9512; c) H. Mayr, B. Kempf, A. R. Ofial,
Acc. Chem. Res. 2003, 36, 66 – 77; d) H. Mayr, A. R. Ofial, Pure
Appl. Chem. 2005, 77, 1807 – 1821; e) S. Lakhdar, M. West-
ermaier, F. Terrier, R. Goumont, T. Boubaker, A. R. Ofial, H.
Mayr, J. Org. Chem. 2006, 71, 9088 – 9095; f) H. Mayr, A. R.
Ofial, J. Phys. Org. Chem. 2008, 21, 584 – 595; g) T. A. Nigst, M.
Westermaier, A. R. Ofial, H. Mayr, Eur. J. Org. Chem. 2008,
2369 – 2374; h) D. Richter, H. Mayr, Angew. Chem. 2009, 121,
1992 – 1995; Angew. Chem. Int. Ed. 2009, 48, 1958 – 1961.
[9] S. Lakhdar, T. Tokuyasu, H. Mayr, Angew. Chem. 2008, 120,
8851 – 8854; Angew. Chem. Int. Ed. 2008, 47, 8723 – 8726.
[10] R. Appel, R. Loos, H. Mayr, J. Am. Chem. Soc. 2009, 131, 704 –
714.
[11] Reviews: a) A. Berkessel, H. Grꢁger, Asymmetric Organocatal-
ysis, Wiley-VCH, Weinheim, 2004; b) J. Seayad, B. List, Org.
Biomol. Chem. 2005, 3, 719 – 724; c) G. Lelais, D. W. C. Mac-
Millan, Aldrichimica Acta 2006, 39, 79 – 87; d) Enantioselective
Organocatalysis (Ed.: P. I. Dalko), Wiley-VCH, Weinheim, 2007;
e) A. Erkkilꢂ, I. Majander, P. M. Pihko, Chem. Rev. 2007, 107,
5416 – 5470; f) M. J. Gaunt, C. C. C. Johansson, A. McNally,
N. C. Vo, Drug Discovery Today 2007, 12, 8 – 27; g) S. B.
Tsogoeva, Eur. J. Org. Chem. 2007, 1701 – 1716; h) D. W. C.
MacMillan, Nature 2008, 455, 304 – 308; i) P. Melchiorre, M.
Marigo, A. Carlone, G. Bartoli, Angew. Chem. 2008, 120, 6232 –
6265; Angew. Chem. Int. Ed. 2008, 47, 6138 – 6171; For structural
investigations of a,b-unsaturated iminium ions: j) D. Seebach, U.
Groselj, D. M. Badine, W. B. Schweizer, A. K. Beck, Helv. Chim.
Acta 2008, 91, 1999 – 2034; k) U. Groselj, W. B. Schweizer, M.-O.
Ebert, D. Seebach, Helv. Chim. Acta 2009, 92, 1 – 13.
[8] a) H. Mayr, M. Patz, Angew. Chem. 1994, 106, 990 – 1010;
Angew. Chem. Int. Ed. Engl. 1994, 33, 938 – 957; b) H. Mayr, T.
Bug, M. F. Gotta, N. Hering, B. Irrgang, B. Janker, B. Kempf, R.
Loos, A. R. Ofial, G. Remennikov, H. Schimmel, J. Am. Chem.
[12] S. Lakhdar, H. Mayr, unpublished results.
Angew. Chem. Int. Ed. 2009, 48, 5034 –5037
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5037