Cyclopropyl iminium activation: Reactivity umpolung in enantioselective organocatalytic reaction design

Article abstract of DOI:10.1002/anie.201103360

Trick the iminium! The concept of cyclopropyl iminium activation for the organocatalytic desymmetrization of meso-cyclopropylcarbaldehydes is presented. A combination of nucleophilic and electrophilic chlorinating reagents leads to a formal addition of Cl₂ across one of the cyclopropyl bonds giving access to 1,3-dichlorides in an enantioselective, catalytic fashion.

Full text of DOI:10.1002/anie.201103360

DOI: 10.1002/anie.201103360
Reaction Design
Cyclopropyl Iminium Activation: Reactivity Umpolung in
Enantioselective Organocatalytic Reaction Design**
Christof Sparr* and Ryan Gilmour*
Dedicated to Professor Dieter Seebach
The intrinsic donor–acceptor reactivity pattern of conjugated,
unsaturated carbonyl compounds predictably alternates along
the carbon chain (Scheme 1). Consequently, electrophiles are
Cyclopropane behaviour has striking parallels with that of
olefins.[5] In addition to their ability to interact with adjacent
p systems, cyclopropanes function as effective donors when
activated by adjacent low-lying empty orbitals: this can be
rationalized by considering the Walsh orbitals.[6,7] Striking
manifestations of the electron-donating aptitude of cyclo-
propanes include: 1) the unusual thermodynamic stability of
the cyclopropylcarbinyl cation,[8] and 2) the bond-length
asymmetry of cyclopropanecarbonitirile (Dd(distalꢀvicinal)
=
0.033 ꢀ) as a consequence of hyperconjugation.[9,10] Of
particular pertinence to this study is the latter observation.
It was envisaged that the well described conjugation between
a cyclopropane moiety and polar multiple bonds might form
the basis of an activation strategy involving cyclopropyl
iminium salts. Indeed, Wang and co-workers have described
that the nucleophilic addition of benzenethiols to cyclo-
propanecarbaldehydes can be catalyzed by proline.[11] The
similarities in bonding between this species and that of
conventional a,b-unsaturated iminium ions, together with the
expected interaction of the cyclopropyl moiety with the
conjugated iminium functionality, motivated us to investigate
the reactivity of cyclopropane carbaldehydes[12] upon uni-
fication with secondary amines (Scheme 2). Formally, nucle-
ophilic addition to the transient cyclopropyl iminium species
would constitute a formal umpolung of the g-position of a
dienamine;[2c] d4!a4 (Scheme 1). Moreover, by intercepting
the transient enamine with an electrophile, this strategy
would give an unprecedented method for the organocatalytic
formation of 1,3-difunctionalized products in a single oper-
ation (Scheme 2). Herein, we report the first secondary-
Scheme 1. Organocatalytic cyclopropyl iminium activation
(a=acceptor, d=donor).
predisposed to react at the a (d2) and g (d4) donor positions,
whereas nucleophiles add to the b (a3) and d (a5) acceptor
positions. Direct inversion of this inherent selectivity is known
as reactivity umpolung,[1] and often provides a platform for
the development of novel transformations. While various
activation modes that allow for a (a2/d2), b (a3), g (d4), and e
(d6) functionalization have been reported through secondary
amine organocatalysis,[2] umpolung strategies remain elusive
outwith the confines of SOMO activation[2b] and processes
mediated by N-heterocyclic carbenes (NHCs).[3,4] Because
pyrrolidine- and imidazolidinone-based organocatalysts
require carbonyl substrates to generate the transient inter-
mediates that are central for catalysis, the substrate scope is
limited to aldehydes and ketones with varying degrees of
unsaturation. With a view to extending the substrate scope of
secondary-amine-catalyzed processes, and providing an entry
point into the design of homologous variants of addition
reactions to a,b-unsaturated iminium ions, we began explor-
ing the reactivity of cyclopropane carbaldehydes.
[*] C. Sparr, Prof. Dr. R. Gilmour
ETH Zꢀrich, Laboratory for Organic Chemistry
Wolfgang-Pauli-Strasse 10, 8093 Zꢀrich (Switzerland)
E-mail: christof.sparr@org.chem.ethz.ch
ryan.gilmour@org.chem.ethz.ch
Homepage: http://www.gilmour.ethz.ch
[**] We acknowledge generous financial support from the Alfred Werner
Foundation (assistant professorship to R.G.), the Roche Research
Foundation, Novartis AG (doctoral fellowships to C.S.), and the
ETH Zurich. We thank Dr. W. B. Schweizer for X-ray crystal structure
analysis.
Scheme 2. A comparison of classical iminium activation and cyclo-
propyl iminium activation. Bn=benzyl, E=electrophile, Nu=nucleo-
phile.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201103360.
Angew. Chem. Int. Ed. 2011, 50, 8391 –8395
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8391

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amine-catalyzed enantioselective activation/desymmetriza-
10 minutes the starting material was completely consumed
and the expected chlorinated product was clearly identifiable
(dCHCl = 5.25 ppm). Having observed that chloride readily
adds to activated cyclopropyl iminium species, we conceived
that this reactivity could form an entry point for the develop-
ment of a catalytic process. Initially, we elected to study the
organocatalytic monochlorination of cyclopropanecarbalde-
hydes using pyridinium hydrochloride to furnish enantioen-
riched g-chloroaldehydes. However, it was observed that the
product was susceptible to racemization under the reaction
conditions prompting a re-evaluation of the strategy. To
circumvent this racemization pathway, we anticipated that the
intermediate enamine that is formed after the initial addition
could function as a second activated species that could be
intercepted by an electrophile giving rise to an unusual a4!d2
reactivity sequence. Cognizant of the fact that this enamine
reacts readily with electrophilic chlorine sources,[17] we
envisaged that this strategy would provide an unprece-
dented method for the enantioselective synthesis of 1,3-
dichlorides; a formal addition of Cl2 across a cyclopropane
bond.[18] Initially, we investigated the chlorination of the
cyclopropane carbaldehyde[19] derived from cyclopentene
(Table 1); the chlorination products of this material can be
readily analyzed by GC on a chiral stationary phase. To
facilitate analysis by 1H NMR spectroscopy, CDCl3 was
chosen as a screening solvent. Initially, the commonly used
reagents 9 and 11 were selected as the Clꢀ and Cl+ sources,
respectively. Catalyst screening using a variety of secondary
amine organocatalysts (1–8) quickly revealed that the first-
generation MacMillan catalyst 5 furnished the expected
1,3-dichloride with the highest levels of diastereo- and
enantiocontrol (Table 1, entry 5; e.r. 84:16, d.r. 91:9). It is
important to note that no reaction is observed in the
absence of a secondary amine catalyst. Having identified
imidazolidinone 5 as the catalyst of choice for this trans-
formation, we examined the effect of counterions on the
stereoselectivity. The hydrochloride, trichloroacetate and
trifluoroacetate salts of catalyst 5 (Table 1, entries 9, 10 and 11
respectively) were prepared and screened under analogous
conditions. Notably higher levels of both diastereo- and
enatioselectivity were observed with the HCl and TFA salts
(Table 1, entries 9 and 11, respectively; up to e.r. 86:14,
d.r. 91:9). For the remainder of the optimization process, the
5·TFA was employed as the catalyst of choice. Interestingly,
the selectivity of the reaction showed a clear solvent depen-
dence (Table 1, entries 11–17) with the highest enantioselec-
tivities being observed in CDCl3. Finally, the chlorine sources
were explored using combinations of 9 with N-chlorosuccin-
imide 12, and 10 with perchlorinated quinone 11. As is evident
from Table 1, entry 18, using N-chlorosuccinimide 12 had a
detrimental effect on the enantiomeric ratio. However, a
substantial improvement was observed when pyridine hydro-
chloride 9 was replaced by the bulkier sym-collidine hydro-
chloride 10 (Table 1, entries 19 and 11, respectively; e.r. 91:9
versus 86:14).
tion[13] of meso-cyclopropanecarbaldehyde compounds and
demonstrate the synthetic value of this concept in the
catalytic, asymmetric synthesis of 1,3-dichlorides.
Consistent with previous organocatalyst design
approaches reported by our research group,[14] the catalytic
process was deconstructed to first investigate the transient
cyclopropyl iminium intermediate that was central to our
working hypothesis. To that end, the cyclopropane carbalde-
hyde derived from cis-stilbene and diazoethylacetate was
prepared and condensed with MacMillanꢁs first-generation
catalyst in the presence of hexafluoroantimonic acid. Pleas-
ingly, the product cyclopropyl iminium salt could be gener-
ated and single crystals suitable for X-ray analysis were
obtained (Scheme 3). Inspection of the solid-state structure
Scheme 3. OTREP structure and reactivity of a preformed cyclopropyl
iminium salt. Couterion omitted for clarity and thermal ellipsoids drawn at
50% probability.
revealed a 0.03 ꢀ bond-length asymmetry between the distal
and vicinal bonds of the cyclopropane (dC2ꢀC3 = 1.480 ꢀ
versus dC1ꢀC2 = 1.511 ꢀ and dC1ꢀC3 = 1.507 ꢀ; the mean bond
length in cyclopropanes is 1.509(2) ꢀ).[10f] It is also evident
from this analysis that the iminium functionality bisects the
average plane of the cyclopropane ring, and that the benzyl
group of the imidazolidinone is positioned over the catalyst
core such that the system benefits from a stabilizing CH–p
interaction.[15] The 1H NMR studies confirmed that the
dominant solution-phase conformer also has the benzyl
group positioned in proximity to the methyl group of the
catalyst core by virtue of the significant up-field shift of the
syn-methyl group (dH = 0.64 ppm versus dH = 1.73 ppm for
Me’).[14c]
Collectively, these features contribute to a highly preor-
ganized transient intermediate for reaction development,
where the symmetry of the starting material is broken.
Consequently, it was envisaged that nucleophilic addition to
the cyclopropane moiety would proceed in an enantioselec-
tive fashion. To probe this hypothesis, we elected to study the
reaction of the iminium salt with pyridinium hydrochloride[16]
by 1H NMR spectroscopy. To our delight, after only
Having developed an optimized set of conditions for the
organocatalytic dichlorination of meso-cyclopropylcarbalde-
hydes, our attention was turned to investigating the scope and
limitations of the method. In all cases the product dichlorides
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Angew. Chem. Int. Ed. 2011, 50, 8391 –8395

Table 1: Optimization of the organocatalytic desymmetrization of meso-
Table 2: Enantioselective synthesis of 1,3-dichlorides.[a]
cyclopropane carbaldehydes.[a]
Entry Substrate
Product[b]
Yield e.r.
[%][c]
d.r.
1
2
70
91:9[d]
94:6[d]
68[e]
86:14[d]
92:8[d]
3
4
70[e]
72
89:11[f]
86:14[g]
95:5[d,h]
86:14[d,h]
Entry
Cat.
Solvent
“Clꢀ”
“Cl+”
e.r.[b]
d.r.[b]
5
6
68
91:9[d]
96:4[f]
93:7[d]
1
2
3
4
5
6
7
8
1
2
3
4
5
6
7
8
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
CH2Cl2
acetone
MeCN
toluene
THF
9
9
9
9
9
9
9
9
9
9
9
9
9
9
9
9
9
9
10
11
11
11
11
11
11
11
11
11
11
11
11
11
11
11
11
11
12
11
53:47
63:37
52:48
62:38
84:16
66:34
40:60
35:65
85:15
75:25
86:14
80:20
64:36
80:20
83:17
81:19
80:20
75:25
91:9
78:22
79:21
82:18
75:25
91:9
71:29
83:17
80: 20
91: 9
78:22
91:9
94:6
85:15
93:7
95:5
97:3
67[e]
>95:<5[g]
[a] Reactions performed with 100 mmol of aldehyde at room temperature
with 2.00 equivalents of 10, 1.05 equivalents of 11 and a concentration of
100 mmolLꢀ1 for 57–82 h. [b] Absolute and relative configuration
assigned by X-ray crystallographic analysis and analogy. [c] Yield of
isolated product over three steps (dichlorination, reduction using
NaBH4, and subsequent conversion into the 3,5-dinitrobenzoate). [d] GC
measurements performed on a Supelco b-DEX 120 column (1208C
isotherm). [e] X-ray crystal structure was determined. [f] HPLC meas-
urements performed on a Reprosil Chiral-OM column. [g] Determined by
1H NMR spectroscopy. [h] This experiment was repeated with a exo/endo
(1:1) mixture of the meso-aldehyde substrate resulting in e.r. 70:30 and
d.r. 64:36.
9
5·HCl
5·TCA
5·TFA
5·TFA
5·TFA
5·TFA
5·TFA
5·TFA
5·TFA
5·TFA
5·TFA
10
11
12
13
14
15
16
17
18
19
EtOAc
CDCl3
CDCl3
95:5
81:19
94:6
starting with the simplest dimethyl-substituted meso-cyclo-
propanecarbaldehyde (Table 2, entry 3). Despite the rela-
tively low steric demand of the substituents, efficient discrim-
ination of the two carbon centers led to the optically enriched,
linear 1,3-dichloride (e.r. 89:11). The corresponding ethyl and
n-propyl substrates were also effortlessly converted into the
expected dichloride compounds (Table 2, entries 4 and 5). To
gain an additional insight into the substrate requirements, the
reaction involving isomerically pure exo-meso-carbaldehyde
(Table 2, entry 4) was compared to that of a 1:1 mixture of
exo- and endo-meso-substrates. Comparable results would
indicate that a pre-endo to exo isomerization is operational[20]
similar to that observed for E/Z mixtures of a,b-unsaturated
aldehydes.[21] Reactions involving an isomeric substrate
mixture consistently gave lower levels of enantio- and
diasteroselectivity (e.r. 70:30 and d.r. 64:36 versus e.r. 84:16
and d.r. 95:5). These results suggest that under the reactions
condition reported here preisomerization is slower than
chloride addition, and that high isomeric purity is essential
to ensure high levels of chiral induction. Finally, the cyclo-
propane derived from cis-stilbene was processed to the 1,3-
dichloride to test the tolerance of aromatic substrates. This
[a] Reactions performed at room temperature with 2.00 equivalents of
“Clꢀ” and 1.05 equivalents of “Cl+”. TCA=trichloroacetic acid, TFA=
trifluoroacetic acid, THF=tetrahydrofuran, TMS=trimethylsilyl. [b] GC
measurements performed on a Supelco b-DEX 120 column (1208C
isotherm).
were reduced and converted into the dinitrobenzoate esters to
1) generate crystalline derivatives to determine the relative
and absolute configuration of the product dichlorides by X-
ray analysis, and to 2) allow for analysis by HPLC, thus
providing an additional method to determine the enantiose-
lectivities of each transformation. All yields in Table 2 refer to
this three-step sequence. Initially, we elected to study bicyclic
substrates (Table 2, entries 1 and 2). Reaction of the bicyclo-
[3.1.0] system (Table 2, entry 1) furnished the desired 1,3-
dichloride in excellent yield and with impressive levels of
enantio- and diastereocontrol (91:9 and 94:6, respectively).
Similarly, the bicyclo-[4.1.0] system (Table 2, entry 2) was
smoothly converted into the desired product with comparable
levels of chiral induction (e.r. 86:14 and d.r. 92:8, respec-
tively). We then turned our attention to acyclic substrates
Angew. Chem. Int. Ed. 2011, 50, 8391 –8395
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8393

Communications
proved to be the case leading to the highest levels of enantio-
Received: May 16, 2011
Revised: June 30, 2011
Published online: July 22, 2011
and diasterocontrol observed to date (e.r. 96:4, d.r. > 95: < 5).
With a view to establishing a stereoinduction model, the
relative and absolute configuration of the product 1,3-
dichloride compounds was assigned by single-crystal X-ray
analysis of the dinitrobenzoate derivatives (Scheme 4, see the
Keywords: activation modes · cyclopropanes · dichlorination ·
.
organocatalysis · umpolung
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Scheme 4. Regioselectivity of addition to cyclopropyl iminium ions and
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at 50% probability. Ar=3,5-NO2C6H3.
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propane occurs at C3 with concomitant cleavage of the C1
C3 bond (Scheme 3). The origin of this counterintuitive
regioselectivity is currently under investigation in our labo-
ratory and will be reported in due course.
In summary, we report an unprecedented enantioselective
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umpolung of the g position of conventional dienamines using
the cyclopropane trick; d4!a4. Not only does activation of the
substrates by union with a secondary amine facilitate ring
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intercepted by an electrophilic chlorinating reagent. This
ꢀ
constitutes a formal addition of Cl2 across the C1 C2 bond of
cyclopropylcarbaldehyde compounds. Efforts to extent the
synthetic utility of cyclopropyl iminium activation and under-
stand the interactions that are responsible for orchestrating
chiral induction[14c] are ongoing.
8394 www.angewandte.org
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2011, 50, 8391 –8395

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