Enantioselective Bronsted base catalysis with chiral cyclopropenimines

Article abstract of DOI:10.1021/ja3015764

Cyclopropenimines are shown to be a highly effective new class of enantioselective Bronsted base catalysts. A chiral 2,3-bis(dialkylamino) cyclopropenimine catalyzes the rapid Michael reaction of a glycine imine substrate with high levels of enantioselectivity. A preparative scale reaction to deliver 25 g of product is demonstrated, and a trivial large scale synthesis of the optimal catalyst is shown. In addition, the basicity of a 2,3-bis(dialkylamino)cyclopropenimine is measured for the first time and shown to be approximately equivalent to the P₁-tBu phosphazene base. An X-ray crystal structure of the protonated catalyst is shown along with a proposed mechanistic and stereochemical rationale.

Full text of DOI:10.1021/ja3015764

Communication
pubs.acs.org/JACS
Enantioselective Brønsted Base Catalysis with Chiral
Cyclopropenimines
Jeffrey S. Bandar and Tristan H. Lambert*
Department of Chemistry, Columbia University, New York, New York 10027, United States
S
* Supporting Information
ABSTRACT: Cyclopropenimines are shown to be a highly
effective new class of enantioselective Brønsted base catalysts.
A chiral 2,3-bis(dialkylamino)cyclopropenimine catalyzes the
rapid Michael reaction of a glycine imine substrate with high
levels of enantioselectivity. A preparative scale reaction to
deliver 25 g of product is demonstrated, and a trivial large
scale synthesis of the optimal catalyst is shown. In addition,
the basicity of a 2,3-bis(dialkylamino)cyclopropenimine is
measured for the first time and shown to be approximately
equivalent to the P1-tBu phosphazene base. An X-ray crystal
structure of the protonated catalyst is shown along with a
proposed mechanistic and stereochemical rationale.
Figure 1. Cyclopropenimines as strong Brønsted bases.
ue to the prevalence of chemical reactions involving
proton transfer as a key mechanistic event, Brønsted
system that satisfies Huckel’s rules, the 2π-electron cyclopropenium
̈
ion6,7 provides substantial aromatic resonance stabilization to the
conjugate acid of the cyclopropenimine. In comparison to the
analogous guanidines, this additional stabilization renders 2,3-
bis(dialkylamino)cyclopropenimines highly basic.
D
bases have become indispensable tools for the practice of
organic synthetic chemistry.1 Of particular interest in recent
years has been the development of chiral Brønsted bases
capable of catalyzing proton transfer reactions enantioselec-
tively for the production of optically enriched products.2
Although enantioselective Brønsted base catalysis holds great
promise, this area has arguably lagged far behind the
development of other modes of asymmetric catalysis.
Although the principle behind the strong basicity of
cyclopropenimines is well appreciated, to the best of our
knowledge no measurement of this basicity has been reported,8
and the use of cyclopropenimines as reagents or catalysts is
unknown.9 We have measured the acidity of the conjugate acid
(pKBH+) of cyclopropenimine 1 in acetonitrile (26.9) and found
it to be comparable to the bicyclic guanidine TBD (26.03) and
the phosphazene base P1-tBu (26.98), both considered to be
exceptionally strong “superbases” (Figure 2).10 Notably,
In general, a Brønsted base catalyst must possess a strength
of basicity properly tuned to the acidity of a given substrate. In
this regard, strong, neutral organic bases such as DBU
(diazabicycloundecene) or TMG (tetramethylguanidine) have
proven highly useful as reagents or catalysts for numerous
transformations.2 However, the amidine and guanidine
functionalities upon which these and related reagents are
built have inherent limitations of basicity, which has inhibited
the development of broadly effective chiral catalysts based on
these structures. Significantly stronger basicities can be realized
with phosphazene3 or phosphatrane4 structures, and a number
of these reagents have become important additions to the
Brønsted base arsenal. Nevertheless, broadly effective chiral
catalysts based on these functionalities have not yet been
realized. Clearly, there exists a strong need for novel Brønsted
bases that provide potent yet tunable basicity, are trivial to
prepare, and offer unique opportunities for asymmetric
transition state organization. In this regard, we report here
the development of 2,3-bis(dialkylamino)cyclopropenimines as
a highly effective platform for chiral Brønsted base catalysis.
The signature feature of the cyclopropenimine scaffold5 is the
presence of a latent cyclopropenium ion, which is revealed upon
protonation of the imino nitrogen (Figure 1). As the smallest ring
Figure 2. Basicity of cyclopropenimine 1 and several common strong
organic bases. Bold numbers are pKBH+ values in acetonitrile.
cyclopropenimine 1 is 3 orders of magnitude more basic than
a comparable guanidine, BTMG (23.56). These findings con-
firm for the first time that 2,3-bis(dialkylamino)cyclopro-
penimines are indeed potent Brønsted bases.
We hypothesized that the strong basicity of cyclopropeni-
mines might offer advantages in terms of reactivity and reaction
Received: February 16, 2012
Published: March 14, 2012
© 2012 American Chemical Society
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Communication
scope for Brønsted base catalyzed transformations. To test this
hypothesis, we selected the Michael reaction of glycine imine 2
with methyl acrylate 311 as a forum for comparison to reported
chiral guanidine catalysts. In this regard, we have identified cyclo-
propenimine 5 as a highly effective catalyst, which at 10 mol %
loading effects the production of adduct 4 in essentially quanti-
tative yield and 91% ee in only 5 min under neat conditions.
When the reaction was performed in ethyl acetate, product was
obtained in quantitative yield and with 98% ee in 1 h. In
comparison to the high performance of this cyclopropenimine
catalyst, reported chiral guanidine catalysts have been far less
effective. For example, 20 mol % of guanidine 6 catalyzes the
production of 4 in high yield and good ee only after 3 days of
reaction time at high concentration (neat).12,13 Notably, these
guanidine catalyzed reactions have not been viable in solution. This
comparison clearly illustrates the potential of cyclopropenimines to
serve as a powerful new platform for chiral Brønsted base catalysis.
A selection of the optimization studies we conducted to
arrive at the conditions shown in eq 1 is shown in Table 1.
acetate (entry 6) proved to be most convenient. Reactions can
be significantly accelerated by increasing concentration, with a
concentration of 0.35 M resulting in the optimized reaction
shown in eq 1 (entry 7). Reduction of catalyst loading down to
2.5 mol % could be achieved without loss of conversion or
enantioselectivity (entries 8−9). Even the use of only 1 mol %
catalyst was possible although in this case the conversion after
24 h was reduced to 78% (entry 10).
In terms of catalyst structure, we found the presence of a
hydroxyl group to be crucial for both reactivity and
enantioselectivity, with catalysts such as 7 producing low
conversions of product with 0% ee (entry 11). Sterically
demanding dialkylamino substituents at the 2 and 3 positions
were also found to be important for optimal performance.
Interestingly, the diisopropylamine derived catalyst 8 was
markedly less efficient and selective than catalyst 5 under the
same conditions (entry 12).
A screen of Michael acceptors revealed that various acrylate
esters are also viable substrates for catalyst 5. Thus in addition
to methyl acrylate (Table 2, entry 1), n-butyl, tert-butyl, and
a
Table 2. Substrate Scope of Michael Acceptors
Table 1. Optimization of Enantioselective
Cyclopropenimine Catalyzed Michael Addition
a
a
b
Yield based on isolated and purified product. Yield determined by
1H NMR versus Bn2O standard.
benzyl acrylates also participated in nearly quantitative yield
and with high enantioselectivity (entries 2−4). Notably,
tert-butyl acrylate reacted significantly slower than either methyl or
n-butyl acrylate, which is consistent with the hypothesis that
interaction of the catalyst with the ester carbonyl via H-bonding
plays an important role in the catalysis of this reaction. Methyl
vinyl ketone was quite reactive, proceeding to full conversion in
only 15 min (entry 5). In contrast, both acrylonitrile (entry 6)
and phenyl vinyl sulfone (entry 7) reacted dramatically slower
and with greatly diminished enantioselectivity. We speculate
that differences in H-bonding geometry between these sub-
strates and the carboxylate substrates may account for these
disparities. Lastly, a chalcone substrate reacted with high
efficiency to produce the Michael addition adduct in high yield
and 95% ee as a 6:1 mixture of diastereomers (entry 8).
One of the most attractive features of 2,3-bis(dialkylamino)-
cyclopropenimines is their extreme ease of synthesis. As a
prime example, we have developed a trivial large scale synthesis
a
1
Conversion determined by H NMR versus Bn2O standard.
In terms of solvent, ethers including THF, Et2O, and dioxane
were viable media for this process using catalyst 5 (entries 1−3)
albeit with significant variation in reaction time. The reaction
was fast in acetonitrile but enantioselectivity was greatly com-
promised (entry 4), which may be a reflection of the propensity
for this solvent to engage in H-bonding and thus to disrupt
transition state organization. On the other hand, ester solvents
such as methyl propionate (entry 5) and, optimally, ethyl
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of catalyst 5 starting from inexpensive and readily available
materials (eq 2).14 Thus tetrachlorocyclopropene15 (9) was
Scheme 1. Stereochemical Rationale for Cyclopropenimine 5
Catalyzed Enantioselective Conjugate Addition of 2 to
Methyl Acrylate
treated with an excess of dicyclohexylamine for 4 h, followed by
the addition of phenylalaninol. From this procedure the salt
5·HCl was isolated in essentially quantitative yield as a
crystalline solid. As discussed below, we have found it most
convenient to store the catalyst as its HCl salt, and we have
prepared as much as 45 g in a single run. The generation of
cyclopropenimine 5 requires only a simple wash with an
aqueous inorganic base and can be used without purification
after concentration from solvent.
The crystalline nature of 5·HCl allowed an X-ray structure to
be obtained (Parkin group, Columbia University), which
revealed several key structural features (Figure 3). First, the
(cf. 11). Rapid proton transfer from the cyclopropenium ion to
the resultant enolate as shown in structure 12 then closes the
catalytic cycle.
It should be noted that the activity of catalyst 5 was observed
to slowly diminish over several days when stored at rt. Analysis
of a pure sample over the course of 30 days indeed revealed a
steady conversion (t1/2 ≈ 12 days; see Supporting Information)
from the cyclopropenimine 5 to a new compound, which we
have identified as 13 (Scheme 2). A reasonable proposal for the
Scheme 2. Decomposition Pathway of Cyclopropenimine 5
Figure 3. Molecular structure of protonated cyclopropenimine 5·HCl
cocrystallized with a molecule of H2O.
steric demand of the dicyclohexylamino groups causes these
substituents to torque out of planarity with the cyclopropenium
ring.16 This phenomenon is likely the reason for the slightly
diminished basicity of 5 relative to other cyclopropenimines.
Second, the chiral appendage appears to be oriented with the
proton directed toward a cyclohexyl ring so as to minimize
steric conflict. We propose this element of organization is key
to the observed high levels of stereocontrol. Finally, it can be
seen that the chloride counterion is H-bonded to the H-bearing
amino group, rather than associated with the cationic cyclopro-
penium ring,17 and that a cocrystallized molecule of water is
H-bonded to the hydroxyl group. It can be readily imagined
that such interactions are involved in transition state organi-
zation of the conjugate addition of glycine imine 2.
The structure of protonated 5 allows us to propose a tenta-
tive mechanistic and stereochemical rationale for this trans-
formation (Scheme 1). Thus we suggest that the catalyst 5
deprotonates glycine imine 2 to generate the cyclopropenium
enolate salt 10. This complex is presumed to involve a H-bond
with the N−H of the cyclopropenium, but the precise organi-
zation of 10 is at this time unknown. Nevertheless, because the
alcohol moiety of the catalyst was found to be required for
enantioselectivity, we speculate that methyl acrylate is directed
for conjugate attack via H-bonding with the pendant hydroxyl
production of this compound is that internal deprotonation of
the pendant hydroxyl of 5 generates the alkoxy cyclopropenium
14, which can then cyclize to the oxazolidine 15. Destructive
ring opening to produce vinyl anion 16 followed by proton
transfer would then lead to the observed product 13.
Importantly, this decomposition pathway was greatly slowed
by storing the cyclopropenimine 5 at −20 °C, with a sample
still 94% intact after 30 days. Alternatively, we have found that
the HCl salt of 5 is indefinitely stable at rt, and given that
conversion of 5·HCl to 5 requires only a simple wash with an
aqueous base, we have found it most convenient to store the
catalyst as its acid co-salt.
Finally, we have investigated the performance of cyclo-
propenimine 5 for asymmetric catalysis on a preparative scale.
Thus the addition of glycine imine 2 to methyl acrylate was
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Communication
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ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures and product characterization data.
This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
TL2240@Columbia.edu
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Funding for this work was provided by the National Science
Foundation under CHE-0953259. Acknowledgment is also
made to the donors of the American Chemical Society
Petroleum Research Fund (49279-DNI) for partial support of
this research. T.H.L. is grateful for an Alfred P. Sloan Research
Fellowship and Young Investigator Awards from Abbott and
Amgen. J.S.B. is grateful for NDSEG and NSF fellowships. We
thank Aaron Sattler and the Parkin group for X-ray structure
determination, and the National Science Foundation (CHE-
0619638) is thanked for acquisition of an X-ray diffractometer.
We also thank the Leighton and Sames groups (Columbia
University) for use of their instrumentation.
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