Direct Mannich-Type Reactions Promoted by Frustrated Lewis Acid/Br?nsted Base Catalysts

Article abstract of DOI:10.1002/anie.201608583

Direct Mannich-type reactions that afford both α- and β-amino esters by the reaction of a broad range of carbonyl compounds and aldimines are disclosed. The transformation is promoted by a sterically frustrated Lewis acid/Br?nsted base pair, which is prop

Full text of DOI:10.1002/anie.201608583

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201608583
German Edition: DOI: 10.1002/ange.201608583
Frustrated Lewis Pairs
Direct Mannich-Type Reactions Promoted by Frustrated Lewis Acid/
Brønsted Base Catalysts
Jessica Z. Chan+, Wenzhi Yao+, Brian T. Hastings, Charles K. Lok, and Masayuki Wasa*
Abstract: Direct Mannich-type reactions that afford both a-
and b-amino esters by the reaction of a broad range of
carbonyl compounds and aldimines are disclosed. The trans-
formation is promoted by a sterically frustrated Lewis acid/
Brønsted base pair, which is proposed to operate coopera-
tively: Within the catalyst complex, an enolate is generated that
then reacts with a hydrogen-bond-activated imine. Noncova-
lent interactions between reactants and the catalyst provide
selectivity and new opportunities for future catalyst design.
employs a bifunctional catalyst whose acidic site can activate
a carbonyl pronucleophile towards enol formation by the
associated basic site, thus catalytically generating the enolate
equivalent. Although this approach to this important class of
molecules is attractive, in practice, most bifunctional catalysts
(Scheme 1, A, B) can only contain mildly acidic and basic
F
rustrated Lewis pairs (FLPs) consist of Lewis acids and
Lewis bases whose mutual quenching is sterically precluded.[1]
The cooperation of active nonquenched acids and bases has
proven to be an effective strategy for reaction development
and has led to notable discoveries in small-molecule activa-
tion.[1] Since the seminal reports by the research groups of
À
Stephan and Erker on the R B(C6F5)2/phosphine-mediated
splitting of H2,[2] an array of acid/base pairs has been exploited
for the stoichiometric activation of CO2, SO2, and N2O,
among other molecules.[1] However, FLP-catalyzed processes
reported to date remain limited in scope; examples include
the hydrogenation,[3] hydroboration,[4] and hydrosilylation[5]
of unsaturated substrates, the hydroamination of alkynes,[6]
Scheme 1. Use of acid/base catalysts to promote direct Mannich-type
reactions. EDG=electron-donating group.
the borylation of arenes,[7] and C C coupling between vinyl
À
phosphanes and aryl aldehydes.[8] The development of
practical FLP-catalyzed methods has been hampered by the
strong acidity of R B(C6F5)2, which can readily form adducts
groups.[9–11] Thus, the scope of pronucleophiles is often limited
À
À
with molecules containing unhindered basic moieties. Fur-
thermore, adducts between FLPs and small molecules are
often too stable and thus of limited synthetic utility. To
obviate these inherent problems associated with FLPs, we
envisioned their application as cooperative acid/base catalysts
capable of generating both nucleophiles and electrophiles
from otherwise unreactive substrates. We now describe our
initial studies in the context of the FLP-catalyzed dual
activation of enolizable carbonyl compounds and imines.
The addition of enolate nucleophiles to aldimines or
ketimines, known as Mannich-type reactions, is a useful way
of constructing important amino ester compounds.[9] In the
“direct” Mannich-type reaction, separate stoichiometric
preparation of the enolate is avoided by the in situ generation
of the active nucleophile.[9–11] For example, one approach
to those containing highly acidic C H bonds, such as 1,3-
dicarbonyl compounds.[10] With stronger acids or bases
capable of activating less acidic pronucleophiles, the forma-
tion of strongly associated acid/base adducts deactivates the
catalyst. As a result, only a limited number of catalyst systems
(e.g. C, D) that enable the direct Mannich-type reaction of
monocarbonyl compounds exist.[11–15] Although methyl
ketones are readily deprotonated with these catalysts,[14] the
enolization of less acidic ketones, esters, amides, and thio-
esters typically requires further activation of these substrates
by the installation of electron-withdrawing substituents (e.g.
OH,[15a–e] NCS,[15f] SMe,[15g] CF3,[15h,i] N3,[15j] F[15i,k]).
To create a cooperative acid/base catalyst capable of
enolizing a broader range of unactivated pronucleophiles, we
considered the development of a system based on an
unquenched pair of a potent Lewis acid catalyst and
a hindered Brønsted base catalyst (Scheme 1). This system
would have the advantage of independent and modular
control over the acid and base components, thus potentially
enabling the accommodation of a broad range of unreactive
pronucleophiles. Specifically, a boron-based Lewis acid would
[*] J. Z. Chan,[+] W. Yao,[+] B. T. Hastings, C. K. Lok, Prof. Dr. M. Wasa
Department of Chemistry, Merkert Chemistry Center, Boston College
Chestnut Hill, Massachusetts 02467 (USA)
E-mail: wasa@bc.edu
[+] These authors contributed equally.
À
bind to pronucleophiles to generate an acidic a-C H bond.
Deprotonation by a hindered soft amine would generate the
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/anie.201608583.
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boron enolate, which could then react with an imine to deliver
the b-amino ester products.
We examined the transformation between N-(tert-butoxy-
carbonyl)benzaldimine (1a) and a-tetralone (2a) with B-
(C6F5)3/amines as potential catalysts. We found that B(C6F5)3
(10 mol%) and Et3N (20 mol%) promoted the reaction
between 1a and 2a in toluene at 228C to afford 3a in 65%
yield with d.r. > 20:1 (Table 1, entry 2). No product formation
Table 1: Evaluation of reaction parameters.[a]
Scheme 2. Mannich-type reactions of N-(tert-butoxycarbonyl)benz-
aldimine (1a). Reaction conditions: imine (0.3 mmol), B(C6F5)3
(10 mol%), PMP (20 mol%), pronucleophile (0.33 mmol), toluene
(0.6 mL), hexanes (0.3 mL), N2 atmosphere, 228C, 12 h. Yields are for
the isolated product. Diastereomeric ratios were determined by
1H NMR analysis of the crude product. The structure and absolute
configuration of 3a were established by X-ray crystallography, and the
configuration of all other products was assigned by analogy. [a] The
1
yield was determined by H NMR analysis of the crude product with
mesitylene as the internal standard.
lacks a fused aromatic group, gave 3e in quantitative yield,
albeit with diminished diastereoselectivity. When we evalu-
ated ester, amide, and thioester substrates, the corresponding
products 3 f–h were formed in less than 20% yield.[17]
[a] Reaction conditions: imine (0.2 mmol), acid (10 mol%), base
(20 mol%), a-tetralone (0.22 mmol), toluene (0.6 mL), hexanes
(0.3 mL), N2 atmosphere, 228C, 12 h. Yields and d.r. values were
determined by 1H NMR analysis of the crude product with mesitylene as
the internal standard. [b] DBU=1,8-diazabicyclo[5.4.0]undec-7-ene,
Barton base=2-tert-butyl-1,1,3,3-tetramethylguanidine, TMP=2,2,6,6-
tetramethylpiperidine.
Next, we evaluated benzaldimine substrates bearing other
N-protecting groups. Reactions of N-tosylbenzaldimine (1b)
with ketones under the catalysis of B(C6F5)3/PMP afforded b-
amino ketone products in only poor yield (Scheme 3, 4a,b).
Nonetheless, the inclusion of CuOTf (5 mol%) as a soft Lewis
acid cocatalyst in the reactions as a means to activate the
imine resulted in a significant improvement in efficiency (4a,
98 versus 18%).[13a] Importantly, CuOTf was found not to
catalyze the direct Mannich-type reaction, as none of these
products could be obtained in the absence of B(C6F5)3.
Intriguingly, more nucleophilic ester and amide enolates were
found to react with 1b smoothly even in the absence of
CuOTf to give the corresponding products 4c–g in 72–98%
yield. Deprotonation of the less acidic amides required the
use of more basic DBU, as PMP did not furnish the desired
products 4e–g. The reaction of a thioester gave 4h in 54%
yield; no product was obtained when the cocatalyst was
added. The 2-furanyl- and cyclohexyl-substituted imines 1c
and 1d were also converted into the desired products 4i–l.
The utility of this transformation is illustrated by a diaste-
reoselective Mannich-type reaction with an iminoester sub-
strate incorporating the Ellman chiral sulfinamide auxiliary
(Scheme 4, 1e).[18] The direct Mannich-type reaction of 1e
offers an efficient route to enantiomerically enriched b-
carbonyl a-amino ester derivatives. The possibility of the
chromatographic separation of stereoisomers is another
advantage (versus enantioselective catalysis). Indeed,
a range of pronucleophiles led to the corresponding a-
amino ester products 5a–h with d.r. > 20:1–3:1.[19] b-Substi-
tuted amino esters 5b–d, which are inaccessible by transition-
was observed in the absence of an amine (entry 1). The
selection of an amine of appropriate basicity appears to be
important. Whereas the use of less basic N,N-dimethylaniline
gave 3a in less than 20% yield (entry 4), the presence of DBU
or the Barton base led to decomposition of 1a and poor yields
(entries 5 and 6). Optimal results were observed with steri-
cally encumbered 1,2,2,6,6-pentamethylpiperidine (PMP;
Table 1, entry 8, > 95%). No desired product was observed
either without B(C6F5)3 or in the presence of weaker and/or
less hindered boron Lewis acids (entries 11–14). These
observations are consistent with the hypothesis that a steri-
cally frustrated pair composed of highly acidic B(C6F5)3 and
hindered PMP would serve as the most efficient catalyst
combination for the direct Mannich-type reaction.[16]
Various ketones were found to participate effectively in
direct Mannich-type reactions of 1a catalyzed by B(C6F5)3
and PMP (Scheme 2). A 2:1 mixture of toluene and hexanes
was found to further improve the product yield. Cyclic as well
as acyclic ketones were converted into the desired products in
48–98% yield (products 3a–e). Cyclic ketones, including 2-
fluoroindanone, underwent highly diastereoselective reac-
tions (products 3a–c, d.r. > 20:1). Cyclopentanone, which
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metal-catalyzed asymmetric hydrogenation, were readily
synthesized. A versatile Weinreb amide could be converted
into 5g. No epimerization of 5d was observed when treated
with 1 equivalent of B(C6F5)3 and PMP.[20]
The broad range of compatible pronucleophiles
(Tables 2–4) suggests that B(C6F5)3/amine pairs are highly
efficient catalysts for the enolization of monocarbonyl com-
pounds. However, a lack of intrinsic electrophilicity and
instability of the imines appear to be the reasons for
decreased efficiency. This observation is somewhat unex-
pected because the B(C6F5)3-catalyzed Mannich-type reaction
of less electrophilic N-benzylbenzaldimine (1 f) and silyl
ketene acetal (6) is known (Scheme 5); the reaction is
Scheme 3. Mannich-type reactions of N-tosylaldimines. Reaction con-
ditions: imine (0.3 mmol), B(C6F5)3 (10 mol%), base (20 mol%),
pronucleophile (0.33 mmol), toluene (0.6 mL), hexanes (0.3 mL), N2
atmosphere, 228C, 12 h. Diastereomeric ratios were determined by
1H NMR analysis of the crude product. The relative configuration of
the major diastereomer was assigned as anti (see the Supporting
Information). For 4a–d, 4h, 4i, 4k, and 4l, PMP was used as the base.
For 4e–g and 4j, DBU was used as the base. [a] Yield determined by
1H NMR analysis of the crude product with mesitylene as the internal
standard. [b] Yield of the isolated product. [c] Copper(I) triflate (CuOTf,
5 mol%) was added as a cocatalyst.
Scheme 5. Mannich-type reactions of N-benzylbenzaldimine (1f).
TMS=trimethylsilyl.
proposed to proceed through the activation of 1 f by
B(C6F5)3.[21] Still, in our direct Mannich-type reactions, 1 f
failed to react with any of the evaluated pronucleophiles, thus
implying that another species may be involved in imine
activation instead of B(C6F5)3.[22]
A possible pathway involving B(C6F5)3/PMP activation of
N-(tert-butoxycarbonyl)benzaldimine (1a) and a-tetralone
(2a) is outlined in Scheme 6. B(C6F5)3-activated 2a possessing
Scheme 6. Possible catalytic cycle.
Scheme 4. Diastereoselective Mannich-type reactions. Reaction condi-
tions: imine (0.3 mmol), B(C6F5)3 (10 mol%), base (20 mol%), pronu-
cleophile (0.33 mmol), toluene (1.0 mL), N2 atmosphere, 228C, 12 h.
Yields are for the isolated product. Diastereomeric ratios were deter-
mined by 1H NMR analysis of the crude product. The structure and
absolute configuration of 5d were established by X-ray crystallography,
and the configuration of all other products was assigned by analogy.
For 5a–e and 5h, PMP was used as the base. For 5 f and 5g, DBU was
used as the base.
À
an acidic a-carbonyl C H bond (intermediate A) is depro-
tonated by PMP to form an ion pair B consisting of a boron
enolate and an ammonium ion. The ammonium ion in B can
serve as a Brønsted acid catalyst to activate the imine toward
nucleophilic attack by the boron enolate. The higher reaction
efficiency with less polar solvents may support the importance
of the ionic or H-bonding interactions.[11] Subsequent C C
À
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bond formation generates the Mannich-type product 3a and
simultaneously regenerates the catalyst. Further elucidation
of the catalyst–substrate interactions is in progress.
In summary, we have developed a B(C6F5)3/amine-cata-
lyzed direct Mannich-type reaction that provides access to an
assortment of a- and b-amino esters from ketone, ester,
amide, and thioester pronucleophiles. This protocol can be
used for the diastereoselective synthesis of important a-
amino ester derivatives. On the basis of our mechanistic
hypothesis, it should be possible to control the stereochemical
outcome of these addition reactions through the design of
appropriate chiral Lewis acid/Brønsted base catalyst combi-
nations. Investigations along these lines are currently under
way and will be reported in due course.
Acknowledgements
We gratefully acknowledge Boston College for financial
support. We are thankful to Professors Amir H. Hoveyda, T.
Ross Kelly, James P. Morken (Boston College), and Mr.
Richard Y. Liu (MIT) for helpful discussions, as well as to Dr.
Bo Li and Malte S. Mikus (Boston College) for X-ray
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Keywords: acid–base catalysis · boron · frustrated Lewis pairs ·
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[20] The B(C6F5)3/PMP catalyst does not efficiently deprotonate
À
tertiary a-C H bonds. Although cyclobutyl(phenyl)methanone
was converted into 5b, 2-methyl-1-phenylpropan-1-one only
afforded the Mannich product in less than 10% yield.
[21] K. Ishihara, N. Hanaki, M. Funahashi, M. Miyata, H. Yamamoto,
Bull. Chem. Soc. Jpn. 1995, 68, 1721.
[16] Lower efficiency with less hindered N-alkyl amines could be due
to reversible abstraction of a hydride in the a-position to
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[17] The decomposition of 1a to tert-butyl carbamate and benzalde-
hyde was observed. The use of DBU gave 3 f in 34% yield (anti/
syn 3:4); however, 3g and 3h were obtained in less than 10%
yield.
[22] The possibility that another molecule of B(C6F5)3 reversibly
interacts with and activates less basic imines 1a–e can not be
excluded.
[23] CCDC 1504251 and 1504252 contain the supplementary crystal-
lographic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre.
[18] J. A. Ellman, T. D. Owens, T. P. Tang, Acc. Chem. Res. 2002, 35,
984.
Received: September 2, 2016
[19] DBU was used as the base for the synthesis of 5 f and 5g.
Published online: && &&, &&&&
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Communications
Frustrated Lewis Pairs
J. Z. Chan, W. Yao, B. T. Hastings,
C. K. Lok, M. Wasa*
&&&& — &&&&
Direct Mannich-Type Reactions Promoted
by Frustrated Lewis Acid/Brønsted Base
Catalysts
It pays to be direct if you’re frustrated: A
sterically frustrated Lewis acid/Brønsted
base pair was found to serve as a potent
cooperative acid/base catalyst for direct
Mannich-type reactions (see scheme;
EDG=electron-donating group, PG=
protecting group). An array of ketone,
ester, amide, and thioester pronucleo-
philes underwent enolization by the cat-
alyst and reaction with aldimines to
afford both a- and b-amino esters.
6
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Angew. Chem. Int. Ed. 2016, 55, 1 – 6
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