Structure-activity relationship studies of cyclopropenimines as enantioselective Bronsted base catalysts

Article abstract of DOI:10.1039/c4sc02402h

We recently demonstrated that chiral cyclopropenimines are viable Bronsted base catalysts in enantioselective Michael and Mannich reactions. Herein, we describe a series of structure-activity relationship studies that provide an enhanced understanding of the effectiveness of certain cyclopropenimines as enantioselective Bronsted base catalysts. These studies underscore the crucial importance of dicyclohexylamino substituents in mediating both reaction rate and enantioselectivity. In addition, an unusual catalyst CH...O interaction, which provides both ground state and transition state organization, is discussed. Cyclopropenimine stability studies have led to the identification of new catalysts with greatly improved stability. Finally, additional demonstrations of substrate scope and current limitations are provided herein.

Full text of DOI:10.1039/c4sc02402h

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Structure–activity relationship studies of
cyclopropenimines as enantioselective Brønsted
Cite this: DOI: 10.1039/c4sc02402h
base catalysts†
*
Jeffrey S. Bandar, Alexandre Barthelme, Alon Y. Mazori and Tristan H. Lambert
We recently demonstrated that chiral cyclopropenimines are viable Brønsted base catalysts in
enantioselective Michael and Mannich reactions. Herein, we describe a series of structure–activity
relationship studies that provide an enhanced understanding of the effectiveness of certain
cyclopropenimines as enantioselective Brønsted base catalysts. These studies underscore the crucial
importance of dicyclohexylamino substituents in mediating both reaction rate and enantioselectivity. In
addition, an unusual catalyst CH/O interaction, which provides both ground state and transition state
organization, is discussed. Cyclopropenimine stability studies have led to the identification of new
catalysts with greatly improved stability. Finally, additional demonstrations of substrate scope and current
limitations are provided herein.
Received 7th August 2014
Accepted 19th November 2014
DOI: 10.1039/c4sc02402h
www.rsc.org/chemicalscience
cyclopropenimine 1 could not be attributed solely to an
increase in catalyst basicity.
Introduction
Given our earlier observation of some peculiar structure–
activity relationships and a desire to further exploit the
effectiveness of the cyclopropenimine scaffold for enantiose-
lective Brønsted base catalysis, we have undertaken an in-
depth examination of cyclopropenimine 1 and related struc-
tures. These studies have revealed a number of important
structural elements that are critical to the high efficiency of
catalyst 1, especially regarding the dicyclohexylamino
substituents. In addition, the existence of an intramolecular
CH/O interaction in the ground state organization of 1 has
been identied.4 These studies have also led to the discovery
of catalysts with signicantly improved stability proles,
which should further expand the utility of cyclopropenimines
as chiral Brønsted base catalysts.
Brønsted base-mediated deprotonation represents a funda-
mental mode of HOMO-raising activation, and the anions thus
generated readily participate in a range of valuable trans-
formations.1 Although chiral Brønsted bases offer the promise
of rendering such transformations enantioselective, the eld of
enantioselective Brønsted base catalysis has not advanced as
rapidly as other areas of organocatalysis. This situation is
beginning to change, primarily due to the development in
recent years of a number of catalysts possessing more potent
basicities and useful reactivity proles.
In 2012, we disclosed that cyclopropenimine 1 (Fig. 1) is a
highly effective Brønsted base catalyst for enantioselective
Michael reactions of the O'Donnell glycine imine.2 More
recently, we demonstrated that 1 is also particularly effective
for enantioselective catalytic Mannich reactions of the same
pronucleophile with
a variety of imine electrophiles,
Background
including those bearing aliphatic substituents.3 Cyclo-
propenimines such as 1 have been found to be strongly
Brønsted basic as a result of aromatic stabilization of the
conjugate acid. Undoubtedly, the notable potency of catalyst 1
in comparison to related catalysts derived from guanidine or
tertiary amine functionality is largely attributed to its stronger
basicity. However, in the course of our investigations, it
became clear that the remarkable reactivity of
For obvious reasons, the position of the acid–base equilibrium
between substrate and catalyst provides an effective limit to the
Department of Chemistry, Columbia University, 3000 Broadway, New York, NY 10027,
USA. E-mail: tl2240@columbia.edu
† Electronic supplementary information (ESI) available: Experimental procedures
and product characterization data. CCDC 880701. For ESI and crystallographic
data in CIF or other electronic format see DOI: 10.1039/c4sc02402h
Fig.
1 Enantioselective Brønsted base catalysis with cyclo-
propenimine 1.
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scope of any catalytic base. Therefore, much recent research in 9 that effectively catalyzes the asymmetric amination of tetra-
the area of asymmetric Brønsted base catalysis has focused on lone-like ketones.13 Finally, Dixon has developed a class of
the development of catalysts with the capacity to activate a chiral bifunctional thiourea iminophosphoranes 10 and
broader range of substrates, either via increased basicities or by employed them as catalysts for the asymmetric nitro-Mannich
co-activation through hydrogen-bonding.
reaction with ketimines.14
As a prime example of this latter approach, bifunctional
The chiral cyclopropenimine 1 developed in our lab has also
catalysts pairing tertiary amines with strong hydrogen-bond proven to be a highly effective enantioselective Brønsted base
donors have been vigorously studied.5 These bifunctional catalyst. For example, we reported that 1 catalyzes the highly
catalysts induce high selectivity in reactions of many relatively enantioselective Michael addition of O'Donnell glycine imine
acidic substrate classes, although they show limited success in 11a to methyl acrylate in only 5 min under neat conditions, and
the activation of less acidic substrates (pKa > 17 in DMSO). within 1 hour under reasonable concentration in ethyl acetate
Accordingly, a number of researchers have explored the instal- (eqn (1)).2 We further showed that 1 catalyzes enantioselective
lation of more basic functionality with the goal of increasing Mannich reactions rapidly (eqn (2)) and with a substrate scope
catalytic activity and thus expanding the range of viable surpassing that of established platforms (i.e. aliphatic imines).3
substrate classes.
In both of these cases, the reactivity of 1 was demonstrated to
´
For example, chiral guanidine 2 was rst developed by Najera far exceed that of less basic catalysts, a further indication that
in 1994 as an asymmetric catalyst for the addition of nitro- increased catalyst basicity can lead to signicantly improved
alkanes to aldehydes,6 albeit with limited selectivities (Fig. 2). reaction outcomes.
Since then, many effective scaffolds have been identied in the
area of chiral guanidine catalysis. These include Lipton's
dipeptide guanidine 3 (ref. 7) and Corey's C2-symmetric bicyclic
guanidine 4,8 both developed for the asymmetric Strecker
reaction. Other important chiral guanidine catalysts include
Ishikawa's bifunctional guanidine 5,9 Terada's binaphthyl-
based guanidine 6,10 and Tan's modied Corey-type bicyclic
guanidine 7.11
The recent development of several catalyst scaffolds with
signicantly stronger basicities has further enhanced the
impact of enantioselective Brønsted base catalysis. In partic-
ular, the P-spiro chiral bicyclic iminophosphoranes 8, pio-
neered by Ooi and Uraguchi have been utilized as catalysts for a
range of substrates, including azlactones, phosphonoacetates,
dialkylphosphites and nitroalkanes (Fig. 2).12 Terada recently
reported a highly basic chiral bis(guanidino)iminophosphorane
of asymmetric cyclopropenimine catalysis, we recently under-
With the goal of further expanding the range of applications
took a study of the factors that govern this type of catalysis, with
the particular goal of understanding the structural aspects of
catalyst 1 that lead to the observed high levels of reactivity and
enantioselectivity. In this Article, we disclose our ndings from
this study along with a full account of the development of chiral
cyclopropenimines as a unique platform for enantioselective
Brønsted base catalysis.
Results and discussion
Catalyst synthesis
To prepare cyclopropenimine catalysts, we relied on the method
rst reported by Yoshida,15 in which amines are added to either
tetrachlorocyclopropene or, more conveniently, penta-
chlorocyclopropane (14, eqn (3)).16 For example, addition of six
equivalents of N,N-dicyclohexylamine to 14 results in the rapid
and quantitative production of 15, which is an isolable, stable
solid that can be stored indenitely. Large-scale batches (up to
60 g) of 15 have been prepared using this method.
The head group or “imino” nitrogen can be subsequently
installed, either in a separate step or in situ, by the simple
treatment of 15 with an equivalent of the desired chiral primary
Fig.
basicities.
2 Examples of chiral Brønsted base catalysts with strong
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amine (e.g. phenylalaninol). The resulting trisamino-cyclo- energy barrier and in biasing the competing diastereomeric
propenium chlorides are typically crystalline materials that are transition states.
stable and can be stored without decomposition at room
To gain further insight into the role of H-bonding, we
temperature. Using this approach, we have prepared up to 47 g examined the reaction conditions employed for the cyclo-
of the salt 1$HCl in a single run.
propenimine-catalyzed enantioselective Michael reaction.
Specically, we were interested in the correlation between
enantioselectivity and the solvent dielectric constant.17 Table 1
shows ten solvents with dielectric constants ranging from 2.3 to
21. Notably, all solvents with a dielectric constant #6.0 resulted
in Michael adduct with 98–99% ee, including, notably, trieth-
ylamine. With the use of solvents with dielectric constants
higher than 6.0, enantioselectivity decreased relatively
modestly. These observations suggest that transition state
organization is governed by reasonably strong intermolecular
forces. Only high dielectric constant solvents, including acetone
and especially n-butanol, resulted in product with signicantly
decreased enantioenrichment.
Further insight into the role of H-bonding came from a
screen of the electrophile (Table 2). Notably, an increase in the
steric demand of the ester group in the acrylate series led to
signicant increase in reaction time, although with no impact
on selectivity (entries 1 and 2). On the other hand, reaction of
triuoroethyl acrylate, despite its enhanced electrophilicity, was
also slower and less selective (entry 3). A reasonable explanation
for this observation is that the more electron-decient ester is a
less capable H-bond acceptor, which leads to a less well-orga-
nized transition state. Tellingly, acrylonitrile and phenyl vinyl
sulfone (entries 4 and 5), which presumably have signicantly
different H-bonding geometries than the carbonyl-based elec-
trophiles, were found to be substantially less reactive and poorly
selective.
To generate the cyclopropenimine free base, a CH2Cl2 solu-
tion of the salt can be simply washed with 1 M NaOH, and the
organic layer then dried and concentrated. The resulting solid is
of sufficient purity to be directly used as a catalyst without
further purication. For cyclopropenimines with sterically less-
demanding amino groups in the 2,3-positions, the higher
basicity may necessitate deprotonation with a stronger base,
such as NaH or KOtBu.
The role of catalyst H-bonding
It is well understood that, generally, in order to impart high
reactivity and enantioselectivity, a chiral Brønsted base catalyst
must incorporate both a basic functionality and an H-bonding
moiety. It can be assumed that the H-bonding groups may serve
to: (1) activate the pronucleophile by lowering the energy barrier
to deprotonation, (2) activate the electrophile via LUMO-
lowering general acid catalysis, and/or (3) provide two-point
organization (along with the conjugate acid of the base func-
tionality) in the enantiodetermining transition state.
Consistent with earlier reports, we also observed the
requirement for H-bonding functionality in our cyclo-
propenimine catalyst systems. As an illustration, while catalyst
1 effected the Michael reaction shown in eqn (4) in 1 h with
complete conversion and 98% ee, imines 16 and 17, lacking H-
We continued to explore the role of H-bonding by examining
strategically modied glycine imine substrates (eqn (5)). We
Table 1 Solvent screen for cyclopropenimine-catalyzed enantiose-
bonding functionality, resulted in no enantioselectivity and lective Michael reactiona
little or no conversion over 24–48 h (Fig. 3). On the other hand,
imine 18, bearing alternative H-bonding functionality, gener-
ated product with a signicant level of enantioselection, albeit
with only poor conversion. Clearly, the hydroxyl group in cata-
lyst 1 plays an essential role in lowering the overall reaction
Entry
Solvent
3
Time (h)
Yield (%)
ee (%)
1
2
3
4
5
6
7
8
9
1,4-Dioxane
PhMe
NEt3
Et2O
EtOAc
2.3
2.4
2.4
4.3
6.0
7.5
9.1
14.3
17.5
21
8
5
6
2
2
24
10
4
24
1.5
95
95
95
95
86
95
95
95
45
95
98
99
99
98
98
89
86
89
55
80
THF
CH2Cl2
1,2-F2–C6H4
n-BuOH
Acetone
10
Conversion determined by 1H NMR based on Bn2O standard.
Enantiomeric excesses (ee) were determined by chiral HPLC. 3:
dielectric constant.
a
Fig. 3 Necessity of H-bonding functionality for high reactivity and
enantioselectivity.
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Table 2 Electrophile screen as a probe for H-bonding interactiona
Entry
EWG
Time (h)
Yield (%)
ee (%)
Attribution
1
2
3
4
5
CO2Et
2.5
12
6
30
24
96
98
90
97
89
99
99
58
77
41
CO2tBu
CO2CH2CF3
CN
Increased steric hindrance / slower rate
More electron-withdrawing / slower rate, lower ee
Non-carbonyl / slower rate lower ee
SO2Ph
a
Yields based on isolated and puried product. Enantiomeric excesses (ee) were determined by chiral HPLC.
found methyl and benzyl glycinate imines to be somewhat more preference for the electrophile to adopt an s-cis conformation in
reactive but as selective as the t-Bu glycinate imine (19 and 20). the enantiodetermining transition state, which is in good
This result parallels our previous observations in cyclo- agreement with the modelled transition states discussed below.
propenimine-catalyzed Mannich reactions with glycinate
imines. Tellingly, the reaction with a nitrile imine substrate,
while faster presumably due to increased acidity, resulted in
essentially no enantioselectivity (21). On the other hand, a
substrate in which the imine nitrogen is replaced with carbon
had lower reactivity, but resulted in a moderate enantiomeric
excess of 70%, indicating that H-bonding to the nitrogen
atom in the glycinate imines is not critical for asymmetric
induction (22).
The role of the catalyst 2,3-amino substituents
At the outset of this program, we assumed that the 2,3-amino
substituents of the cyclopropenimine framework would play a
relatively minor role in the operation of these catalysts and that
any modications to these substituents that resulted in an
attenuation of basicity would lead to a corresponding decrease
in catalyst reactivity. In fact, we have found that the nature of
these substituents has a substantial impact on the reactivity and
selectivity of these cyclopropenimine catalysts. Most remark-
able was the nding that N,N-dicyclohexylamino groups are
critical for the optimal performance of catalyst 1, despite the
fact that these groups lead to cyclopropenimines with lower
basicity than those bearing sterically less-demanding groups.
Conformational requirements of the electrophile
As a probe of the conformational requirements of the Michael
acceptor, we compared the performance of two cyclic unsatu-
rated ketones (Table 3). Cyclopent-2-enone was found to
undergo addition over the course of 48 h, albeit with a notable
An illustration of the importance of the dicyclohexylamino
lack of diastereoselectivity and enantioselectivity (entry 1). On substituents is shown in eqn (6). Thus while catalyst 1 effects
the other hand, 2-methylenecyclopentanone reacted in only 45 the Michael addition of 11a to methyl acrylate in 1 hour with
min to furnish the Michael adduct in essentially quantitative 98% ee, the diisopropylamino-bearing catalyst 23 proceeds to
yield with 95% ee, albeit as a 1 : 1 mixture of diastereomers only 80% conversion aer 24 h and results in signicantly
(entry 3). This lack of diastereoselection is almost surely due to a reduced enantioselectivity (87% ee). Pyrrolidinyl catalyst 24 is
nonselective protonation (or keto–enol tautomerization) of the even less reactive, resulting in only 18% conversion over 24 h
initial conjugate addition intermediate. We propose that the and low product enantioselectivity.
dramatic difference in enantioselection between cyclopent-2-
To better understand these results, we obtained single-
enone and 2-methylenecyclopentenone reects
a
marked crystal X-ray structures (Parkin group, Columbia University) of
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Table 3 Comparison of s-trans vs. s-cis Michael acceptorsa
Entry
1
Electrophile
Product
Time (h)
48
Yield (%)
88
dr
ee (%)
4/30
78 : 22
2
0.75
99
1 : 1
95/95
a
Yields based on isolated and puried product. Enantiomeric excesses (ee) were determined by chiral HPLC.
1$HCl (Fig. 4a and b) and 23$HCl (Fig. 4e and f). The structure cyclohexyl and isopropyl substituents, and we hypothesize that
of 1 differs conformationally from that of 23 in several key ways these differences might manifest in the observed discrepancies
that can be readily attributed to the difference between the in reactivity and selectivity between 1 and 23. First, it can be
Fig. 4 Molecular structure of (a) 1$HCl side view; (b) 1$HCl top view; (c) depiction of amino group torquing phenomenon of 1$HCl; (d) depiction
of cyclohexyl gearing effect and key CH/O interaction of 1$HCl; (e) 23$HCl side view; and (f) 23$HCl top view. For (a) and (b) a co-crystallized
molecule of H2O has been omitted for clarity. For (e) and (f) the hydroxymethyl group was disordered and only one of the crystal forms is shown
for clarity. A molecule of co-crystallized benzene was also removed for 23$HCl. The unmodified structures are included in the ESI file.†
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seen in Fig. 4a and c that the cyclohexyl rings induce torqueing
The second notable conformational feature of 1 arising from
(ꢀ18ꢁ) of the 2,3-amino substituents relative to the cyclo- the cyclohexyl rings can be readily seen in the top view structure
propenium ring, a phenomenon that has been previously (Fig. 4b). Specically, the cyclohexyl rings are all geared in the
reported for the tris(diisopropylamino)cyclopropenium ion.18 same direction, a feature not present in the isopropyl-
This torqueing clearly decreases the overlap of the amine lone substituted structure (Fig. 4f). One of the consequences of this
pairs with the cyclopropenium ring, and thus readily explains gearing effect is that signicantly more steric congestion is
the lower basicity of this cyclopropenimine in comparison to present next to the N–H function in 1 than in 23, which could
the isopropyl-substituted structure, which experiences no such plausibly impact the transition state organization of a substrate
torqueing (Fig. 4e).
H-bonded to this group. However, we do not at this time have
To quantify this difference in basicity, we prepared the N–Me evidence, either computational or experimental, for any such
cyclopropenimines 25 and 26 and determined their pKBH+ impact.
values by measuring (1H NMR) their equilibrium with the
The second and more attributable structural consequence of
known P1–tBu phosphazene base (Fig. 5). By this analysis, the the cyclohexyl gearing effect is that one of the cyclohexyl rings is
isopropyl-substituted imine 25 is 1.5 units more basic than the predisposed to engage in a CH/O interaction with the hydroxyl
cyclohexyl-substituted imine 26. Incidentally, N–Me imine 25 of the phenylalaninol substituent, an effect rst suggested
was found to be greater than 1 pK unit more basic than the N–t- through computational analysis.4 This interaction is apparent
Bu analogue 27, which suggests there is a notable steric effect of in the orientation of the hydroxymethyl substituent in 1 (Fig. 4b)
the imino head group on basicity. The basicity of the N–t-Bu and in the distance between the oxygen and the implied cyclo-
˚
cyclohexyl-substituted imine 28 could not be determined hexyl a-hydrogen (2.51 A). Although this interaction is
because it is apparently unstable, presumably due to severe undoubtedly weak, the gearing of the cyclohexyl rings clearly
steric conict.
predisposes the C–H bond in a favorable orientation, removing
It is not clear whether the decreased basicity of 1 is in any much of the entropic penalty that might otherwise offset it.
way responsible for its greater reactivity versus 23, or whether Vetticatt and we propose4 that the presence of this interaction
the correlation is merely circumstantial. One possible provides an important organizational element that contributes
explanation for why the less basic cyclopropenimine catalyst to the high levels of enantioselection observed with this catalyst.
1 is more reactive than its isopropyl analogue is that the
Although CH/O hydrogen bonds are weak (ꢀ0.5 kcal
diminished electron density of the p-system of 1 results in molꢂ1), they are known to be an important structural factor in
better H-bond donor capability for the N–H function of the enzymes,19 other biomolecules,20 and supramolecular
protonated catalyst. Since hydrogen bond activation and complexes.21 In addition, such interactions have been proposed
organization by this N–H group is almost certainly operative in numerous examples in the eld of asymmetric catalysis.22
in the rate and enantiodetermining transition state for the These proposed interactions are typically between catalyst and
reactions we have demonstrated,4 it stands to reason that substrate and have been posited primarily to rationalize tran-
reaction rate and enantioselectivity would be correlated to sition state organization. In contrast, the present case repre-
the H-bond donating capacity of this group. While this sents an example in which the presence of a CH/O interaction
hypothesis seems reasonable, as discussed below, computa- is also part of the ground state structure of the catalyst itself.23
tional studies4 have suggested that the major enantiomer
Theoretical calculations suggest this interaction is also
transition state for the Michael reaction shown in eqn (1) present in the transition state for the addition of glycine imine
involves the glycinate enolate H-bonded to the N–H function to methyl acrylate, with the H/O distance undergoing
4
˚
of the protonated catalyst, rather than to the O–H group. In compression to ꢀ2.2 A. Calculated transition states lacking
this scenario, the increased acidity of the N–H group would this interaction were found to be much higher in energy (>10
stabilize the enolate and therefore presumably reduce the kcal molꢂ1), lending condence to this proposal.
reaction rate. Thus we conclude that the amino torqueing
phenomenon is not directly responsible for the greater
reactivity of 1, at least insofar as it impacts the electronic
The role of the catalyst chiral substituent
nature of the N–H group.
For the nal part of our catalyst SAR study, we examined vari-
ation of the chiral imino substituent. Interestingly, we found
that the size of this group had relatively little impact on catalyst
efficiency or enantioselectivity. For example, catalysts derived
from phenylalaninol (1), alaninol (29), and valinol (30) operated
with relatively minor differences in reaction rate and enantio-
selectivity (Table 4, entries 1–3). As can be appreciated from the
crystal structures in Fig. 4a and b, we believe this chiral
substituent is conformationally locked to minimize steric
conict with the dicyclohexylamino substituent, and that this
conformation is further stabilized by the CH/O interaction
discussed above. From this point of view, it is reasonable that
the size of the substituent (Bn, Me, i-Pr) would have minimal
Fig.
5 Basicities of representative cyclopropenimines. The pKBH+
values were determined by 1H NMR in d3-MeCN in reference to the
P1–tBu phosphazene base. The number in parentheses is the value
previously determined by an alternative method.
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Table 4 Screen of chiral substituent in the cyclopropenimine-cata-
catalyst 37 was signicantly worse in terms of efficiency and
selectivity (entry 9).
lyzed enantioselective Michael reactiona
Mechanistic rationale
Based on the results described above, along with other
mechanistic and computational insights, we propose the
following model for the operation of catalyst 1 in the enan-
tioselective Michael addition of glycinate 11a to methyl acry-
late (Fig. 6). The rst step in the catalytic cycle involves
deprotonation of glycinate 11a by the catalyst 1 to produce
either the (E)- or (Z)-cyclopropenium enolate complex. The
organization of these intermediate complexes is not currently
known, however, because the Keq of proton transfer lies
heavily in favor of the starting material, making spectroscopic
analysis challenging. Nevertheless, computational studies4
have suggested that the lowest-energy enantiodetermining
transition state involves the (E)-enolate H-bonded to the N–H
function of the protonated catalyst, with the acrylate H-
bonded to the catalyst hydroxyl group (cf. 38). Natural abun-
dance kinetic isotope analysis4 of this reaction has demon-
strated conclusively that this conjugate addition step is also
rate-limiting. The resulting enolate intermediate 39 is expec-
ted to undergo rapid protonation to produce the observed
a
Conversion determined by 1H NMR based on Bn2O standard.
Enantiomeric excesses (ee) were determined by chiral HPLC.
impact on catalyst operation. On the other hand, the catalyst
derived from phenylglycinol (31) was signicantly less reactive
and selective (entry 4), perhaps due to the electron-withdrawing
nature of the phenyl substituent.
A comparison of catalysts bearing vicinal stereocenters, 32
and 33, revealed divergent matched-mismatched proles, with
32 being slower but more selective than 33 (entries 5 and 6).
Interestingly, use of cyclopropenimine 34, which bears only a
single stereocenter one carbon removed from the imino
nitrogen (entry 7, R ¼ Ph), resulted in product with appreciable
enantioenrichment despite the lack of an obvious conforma-
tional lock. We believe the ability of 34 to induce asymmetric
organization is understandable in the context of the CH/O
interaction discussed above, which serves as a pseudo-ring that
biases the catalyst toward one major conformation. Even the
methyl-substituted catalyst 35 induced enantioselectivity of
65% (entry 7, R ¼ Me), a notable level for such a succinct
stereochemical motif.
Perhaps the most important nding from this portion of our
SAR study was the identication of the 1-aminoindanol-derived
cyclopropenimine 36, the effectiveness of which nearly rivalled
that of 1 (entry 8). As will be discussed (see Catalyst stability
studies below), the long-term stability of 36 is much improved
over 1, making 36 an important addition to the chiral cyclo-
propenimine arsenal. Not surprisingly, the cis-aminoindanol Fig. 6 Mechanistic rationale.
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Table 5 Catalyst stability screena
major enantiomeric product 12a while returning the cyclo-
propenimine 1 to the catalytic cycle.
Entry
Catalyst
Conditions
t1/2
Interestingly, calculations suggested that a competing tran-
sition state 40, which is only 0.9 Kcal molꢂ1 higher in energy
than 38, involves the (E)-enolate H-bonded to the hydroxyl
function and the acrylate activated by the N–H group. Since it
also involves addition to the si face of the (E)-enolate, this
transition state increases the level of enantioselection observed
in this reaction. The next lowest energy transition state, 41,
leading to the minor enantiomeric product, involves the same
H-bonding organization as 40, but with the (Z)-enolate geom-
etry. As to why 38 and 40 are lower in energy than 41, the answer
is undoubtedly complex. However, from a close analysis of the
computed transition states, we hypothesize that 38 and 40
experience a secondary orbital interaction between the acrylate
a-carbon and the C]N carbon of the enolate (Fig. 6, blue
orbitals), which serves to stabilize the incipient anionic charge
on the acrylate fragment. Transition state 41, which involves the
(Z)-enolate, is not capable of such an interaction. In any case,
the competition between not only enolate geometries but also
N–H vs. O–H binding modes underscores the complexity of
factors that lead to successful enantioselection with this
catalyst.
(a) Solid rt
15 days
8 months
>5 years
7 h
(b) Solid ꢂ20 ꢁ
C
1
(c) HCl salt, rt
(d) 0.035 M PhMe
Solid, rt
2
3
16 h
Solid, rt
5 months
(a) Solid, rt
(b) 0.035 M
>5 years
36 h
4
(a) Solid, rt
(b) 0.035 M
12 h
3 h
5
Catalyst stability studies
a
Decomposition monitored by 1H NMR; see ESI for method used for
During the course of our initial development studies, we
noticed a slow but appreciable decrease in the efficiency of
catalyst 1 when it was stored in its free base form. Further
analysis revealed that 1 undergoes rearrangement to oxazoline
43, likely via intermediate 42 (eqn (7)).
each cyclopropenimine.
Most notably, indanol-derived catalyst 36, which showed
outstanding performance in the Michael addition reaction (cf.
Table 4) was found to have signicantly improved stability
(Table 5, entry 4). As a solid at room temperature, we have
observed no decomposition over 3 months, leading to a calcu-
lated half-life of at least 5 years (entry 4a). In solution, 36 does
undergo decomposition, but with a notably improved half-life
of 36 h (entry 4b). Although further efforts to increase catalyst
stability are clearly warranted, the improvements offered by
structures 29 and 36 make the storage (as free bases) and use of
these catalysts signicantly more convenient.25 Notably, we
found the stability of catalyst 23 to be signicantly lower than 1
(entries 1 vs. 5), further underscoring the benet of the switch
from diisopropylamino to dicyclohexylamino substituents. It is
worth noting that although part of the difference in catalyst
efficiency observed between cyclopropenimine 1 and 23 (see
eqn (6)) can be attributed to the faster decomposition of the
latter, catalyst 1 is inherently faster, as can be seen from a
comparison of the initial rates of reaction (Chart 1). In fact, the
initial rate (10 min) of reaction with the bis(dicyclohexylamino)
catalyst 1 is nearly ve times as fast as with 23.
The half-life for this process was found to be approximately
15 days at room temperature (Table 5, entry 1a), and 8 months
at ꢂ20 ꢁC (entry 1b). As the HCl salt, 1 is essentially indenitely
stable (entry 1c). Under conditions relevant to catalysis (i.e.
0.035 M in PhMe), however, 1 decomposes to the inactive
species, 43, with a half-life of only 7 h (entry 1d).24 Although the
very short reaction times we have observed using catalyst 1
partially mitigate this instability issue, an eye toward broader
application of these types of cyclopropenimine catalysts clearly
compels the identication of more stable structures. In this
regard, while isoleucinol-derived catalyst 30 was found to be
signicantly less stable than 1, with a half-life of only 16 h in
solid form at rt (entry 2), alaninol-derived catalyst 29 had
markedly improved stability, with a half-life of 5 months (entry
3). Since the only obvious trend between catalysts 1, 30, and 29
is a correlation of rearrangement rate to substituent size, we
speculate that more sterically demanding substituents lead to
Michael addition: expanded substrate scope
angle compression, akin to the gem-dimethyl (Thorpe-Ingold) Finally, we undertook further exploration of the substrate scope
effect, which thus accelerates the conversion to intermediate 42 of the enantioselective Michael addition of glycine imine 11a
and hence to 43 (eqn (7)).
using the new catalyst 36 as shown in Table 6. Notably, dimethyl
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fumarate participated well in this chemistry to furnish the anti-
Michael adduct in 93% yield with >20 : 1 dr and 96% ee aer 3 h
(entry 1). Dimethyl maleate, on the other hand, was essentially
unreactive (entry 2). Certain unsaturated ketones were found to
be viable substrates for this chemistry, including 4-phenylbut-3-
en-2-one (entry 3) and chalcone (entry 4). Heteroaryl products
containing furyl (entry 5) or thiophenyl (entry 6) substituents
were also accessible in high yield and with high stereo-
selectivities. A bis-unsaturated acceptor proved to be somewhat
poorly reactive with catalyst 36 (entry 5); however, efficient
reaction with this substrate was achieved by reverting to catalyst
1, which resulted in exclusive 1,4-selectivity to produce the
b-styrenyl Michael adduct with >20 : 1 dr and 93% ee (entry 7).
It should be noted that this 1,4-selectivity contrasts with the
Chart 1 Conversion rates of catalysts 1 and 23 for the Michael reaction
of 11a.
Table 6 Substrate scope studies of cyclopropenimine-catalyzed Michael reaction with catalyst 36a
Entry
1
Michael acceptor
Product
Time (h)
3
Yield (%)
94
dr
ee (%)
96
>20 : 1
2
3
4
48
7
<5
99
99
—
—
91
96
>20 : 1
>20 : 1
2
5
7
99
94
>20 : 1
>20 : 1
96
88
6
48
7b
8
63 (with catalyst 1)
>20 : 1
9 : 1
93
92
8
22
99
a
Yield based on isolated and puried product. Diastereomeric ratios (dr) and enantiomeric excesses (ee) were determined by chiral HPLC. b 1,4-
Addition : 1,6-addition ratio $20 : 1.
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1,6- and 1,8-regioselectivites observed in related reactions.26
Finally, b-alkyl substitution in the Michael adduct could be
achieved by using an alkylidine malonate electrophile (entry 8).
The resulting product was obtained in essentially quantitative
yield and with high stereoselectivity.
4 J. S. Bandar, G. S. Sauer, W. D. Wulff, T. H. Lambert and
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Wiley-VCH, 2009, pp. 141–251.
´
´
´
6 R. Chinchilla, C. Najera and P. Sanchez-Agullo, Tetrahedron:
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Conclusions
The 2,3-diaminocyclopropenimine framework offers a unique
new catalyst platform for enantioselective Brønsted base catal-
ysis. The potent basicity of the cyclopropenimine scaffold
clearly contributes to the effectiveness of these catalysts for
certain applications. However, as our work has demonstrated,
basicity is by no means the sole contributor to catalyst effi-
ciency, as H-bonding ability and other organizational elements
also play a crucial role. Most striking is the impact of the dicy-
clohexylamino substituents on the optimal catalyst efficiency,
which serve to modulate both the electronic and conforma-
tional properties of the catalyst framework in unexpected ways.
Future efforts will be aimed at exploiting the information
gained from this work for the development of other chiral
cyclopropenimine catalysts and applying these catalysts to
enantioselective transformations of high value.
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Acknowledgements
Funding for the initial development of cyclopropenimine cata-
lysts and portions of this work aimed at understanding the
physical properties of these materials was provided by the
National Science Foundation under CHE-0953259. Acknowl-
edgement is also made to the donors of the American Chemical
Society Petroleum Research Fund (49279-DNI) for partial
support of this research. Financial support for the portions of
this work concerning enantioselective catalysis was provided by
NIHGMS (R01 GM102611). THL is grateful for an Ely Lilly
Grantee Award. J.S.B. is grateful for NDSEG and NSF graduate
fellowships. We thank Dr Aaron Sattler, Dr Neena Chakrabarti,
and the Parkin group for X-ray structure determination; the
National Science Foundation (CHE-0619638) is thanked for
acquisition of an X-ray diffractometer. We also thank the
Leighton group (Columbia University) for use of their
instrumentation.
Notes and references
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