Internal lewis acid assisted hydrogen bond donor catalysis

Article abstract of DOI:10.1021/ol102899y

Boronate ureas are introduced as a new class of noncovalent catalysts for conjugate addition reactions with enhanced activity. Through intramolecular coordination of the urea functionality to a strategically placed Lewis acid, rate enhancements up to 10 t

Full text of DOI:10.1021/ol102899y

ORGANIC
LETTERS
2011
Vol. 13, No. 4
716–719
Internal Lewis Acid Assisted Hydrogen
Bond Donor Catalysis
Sonia S. So, Julie A. Burkett, and Anita E. Mattson*
Department of Chemistry, The Ohio State University, 100 West 18th Avenue, Columbus,
Ohio 43210, United States
mattson@chemistry.ohio-state.edu
Received December 6, 2010
ABSTRACT
Boronate ureas are introduced as a new class of noncovalent catalysts for conjugate addition reactions with enhanced activity. Through
intramolecular coordination of the urea functionality to a strategically placed Lewis acid, rate enhancements up to 10 times that of more
conventional urea catalysts are observed. The tunable nature of boronate ureas is a particularly attractive feature and enables the rational design
of catalysts for optimal performance, in terms of both activity and stereocontrol, in new bond-forming processes.
Chemical transformations catalyzed by small organic mo-
lecules operating through hydrogen bonding interactions are
remarkable new tools for the preparation of important
synthetic building blocks.1 Urea and thiourea derived hydro-
gen bond donors (HBDs) have proven to be particularly
useful noncovalent organic catalysts employed in a variety of
reactions.2 While the potential associated with urea and
thiourea catalysis cannot be denied, current challenges in
the area, including low catalyst turnover and limited reaction
scopes, must be overcome before these catalysts can find more
widespread applications in both academia and industry. One
strategy to address the limitations includes the development
of enhanced urea catalysts. Reactions catalyzed by more ac-
tive ureas may benefit from lower catalyst loadings, improved
enantioselectivity, and expanded substrate scopes and,
ultimately, may lead to the development of novel reactivity
patterns.3 A 2007 report from Ellman and co-workers lending
support to this notion demonstrates that an N-sulfinyl group
on the urea significantly increases the urea acidity and results
in a more active HBD catalyst.4 More recently, Seidel and co-
€
workers have introduced the idea of internal Bronsted acid
activation of the urea functionality.5 Building on these found-
ing reports, a research program in our laboratory is focused
on developing modular and tunable internal Lewis acid
assisted urea catalysts that not only benefit from improved
activity but also have the added advantage of being rationally
designed for optimal performance.6 Herein we report signifi-
cant advances in the development of boronate ureas as
tunable HBD catalysts with enhanced reactivity.
Inspiration for this study of more active HBD catalysts
originated from both Etter’s pioneering work propos-
ing weak urea polarization due to internal hydrogen
(1) (a) Pihko, P. Hydrogen Bonding in Organic Synthesis; Wiley-VCH:
Weinheim, 2009. (b) Doyle, A. G.; Jacobsen, E. N. Chem. Rev. 2007, 107,
5713. (c) Akiyama, T. Chem. Rev. 2007, 107, 5744. (d) Taylor, M. S.;
Jacobsen, E. N. Angew. Chem., Int. Ed. 2006, 45, 1520. (e) Akiyama, T.;
Itoh, J.; Fuchibe, K. Adv. Synth. Catal. 2006, 348, 999. (f) Takemoto, Y.
Org. Biomol. Chem. 2005, 3, 4299.
(2) For examples, see: (a) Reisman, S. E.; Doyle, A. G.; Jacobsen, E. N.
J. Am. Chem. Soc. 2008, 130, 7198. (b) Okino, T.; Hoashi, Y.; Furukawa, T.;
Xu, X. N.; Takemoto, Y. J. Am. Chem. Soc. 2005, 127, 119. (c) Sigman,
M. S.; Jacobsen, E. N. J. Am. Chem. Soc. 1998, 120, 4901.
(3) Jensen, K. H.; Sigman, M. S. Angew. Chem., Int. Ed. 2007, 46,
4748.
(4) Robak, M. T.; Trincado, M.; Ellman, J. A. J. Am. Chem. Soc.
2007, 129, 15110.
(5) Ganesh, M.; Seidel, D. J. Am. Chem. Soc. 2008, 130, 16464.
(6) For a review of combined acid catalysis, please see: Yamamoto,
H.; Futatsugi, K. Angew. Chem., Int. Ed. 2005, 44, 1924.
r
10.1021/ol102899y
Published on Web 01/12/2011
2011 American Chemical Society

Table 1. Boronate Urea Catalyst Activity Studya
Figure 1. Internal Lewis acid assisted hydrogen bond donor
catalysis.
Figure 2. Key catalyst parameters.
Scheme 1. Boronate Ureas as Enhanced Hydrogen Bond Donor
Catalysts
features of internal Lewis acid assisted ureas include an
alterable Lewis acid component, an easily modified chiral
scaffold, and the ability to fine-tune the electronic nature and
chiral environment via modification of the ligands on the
Lewis acid and/or introduction of functional groups on the
aryl amino borane (Figure 2). While it was reasoned that
internal Lewis acid assisted HBD catalysis was a promising
avenue to explore, the study began with a number of
uncertainties. There were concerns regarding the synthesis
and stability of the activated ureas, and the potential issue of
low catalyst turnover as a result of overly strong hydrogen
bonding was also considered. Despite these concerns, we
were excited by the potential surrounding internal Lewis
acid assisted ureas and set out to investigate boronate ureas
(3 and 4) as new classes of enhanced HBD catalysts.
bonding7 (1) and Smith’s more recent discovery that an
appropriately placed internal Lewis acid enhances urea
polarization and significantly increases acetate anion recog-
nition of ureas (2, Figure 1).8 The possibility of applying the
concept of internal Lewis acid assisted urea polarization
toward organic catalysis intrigued us for two main reasons:
(1) the potential to access an entirely new family of activated
HBD catalysts and (2) the development of a class of HBDs
containing several tunable parameters to facilitate the devel-
opment of a highly active and stereoselective catalyst. Key
To rapidly evaluate the potential of internal Lewis acid
assisted HBD catalysis, the nucleophilic addition of indole
(6a) to β-nitrostyrene (5a) was selected as a test bed due to
literature precedent demonstrating the success of urea and
thiourea catalysts in this reaction (Scheme 1).9,10 Almost
(9) For reports of urea/thiourea catalyzed indole additions, see: (a)
Dessole, G.; Herrera, R. P.; Ricci, A. Synlett 2004, 13, 2374. (b) Herrera,
R. P.; Sgarzani, V.; Bernardi, L.; Ricci, A. Angew. Chem., Int. Ed. 2005,
44, 6576. (c) Fleming, E. M.; McCabe, T.; Connon, S. J. Tetrahedron
Lett. 2006, 47, 7037.
(7) Etter, M. C.; Urbanczyk-Lipkowska, Z.; Ziaebrahimi, M.; Pa-
nunto, T. W. J. Am. Chem. Soc. 1990, 112, 8415.
(8) (a) Hughes, M. P.; Shang, M. Y.; Smith, B. D. J. Org. Chem. 1996,
61, 4510. (b) Hughes, M. P.; Smith, B. D. J. Org. Chem. 1997, 62, 4492.
(10) For examples of phosphoric acid catalyzed indole additions, see:
(a) Rowland, G. B.; Rowland, E. B.; Liang, Y.; Perman, J. A.; Antilla,
J. C. Org. Lett. 2007, 9, 2609. (b) Itoh, J.; Fuchibe, K.; Akiyama, T.
Angew. Chem., Int. Ed. 2008, 120, 4016.
Org. Lett., Vol. 13, No. 4, 2011
717

immediately we were delighted to find 10 mol % of 3a
affords a quantitative yield of desired product 7a after 24 h
in dichloromethane in the presence of an alcohol additive.
A more in-depth investigation into the internal Lewis acid
assisted urea structure allowed the identification of a key
element of the catalyst design: the ligands on boron sig-
nificantly influence the activity of the catalyst. Difluorobor-
yl urea 3a is considerably more active than the analogous
pinacol ester 4a, which is able to provide only 41% of 7a
under identical reaction conditions. Fine-tuning of the
pinacol ester urea was achieved through the installation
of an additional electron-withdrawing group on the amino
phenyl borane side of the urea to afford the significantly
more active catalyst 4b. It was initially a surprise to find
difluoroboryl urea 3b operates as a less active catalyst with
10 mol % able to afford just 32% of 7a. However, after
consideration of the structure it was reasoned this may be
due to overly acidic NH protons.11
With highly active boronate urea catalysts 3a and 4b in
hand, attention was turned toward testing the limits of the
reaction with respect to catalyst loadings (Table 1). We were
pleased to find excellent yields of product can be obtained at
catalyst loadings of just 1 mol % with 3a or 4b after 72 h
(95% and 92%, entries 2 and 4). To examine the role of the
Lewis acid on the catalyst activity, we tested the effect of a
strategically placed silicon. The importance of the boron
became apparent when 20 mol % of 8 afforded only a 50%
yield of 7a (entry 5). Key control experiments further prob-
ing the catalyst activity revealed 3a and 4b provide enhanced
yields in otherwise identical reaction conditions when di-
rectly compared to more conventional catalysts 9a and 9b
(Table 1, entries 1 and 3 vs 6 and 7). This significant finding
demonstrates that internal Lewis acid activation of ureas is
one strategy to overcome the low turnover rates that limit the
synthetic utility of traditional urea catalysts. The reduced
activity observed with control catalysts 10a and 10b, ureas
unable to participate in internal Lewis acid coordination,
provided further support for this improved method of urea
activation (entries 8 and 9).
Table 2. Boronate Urea Catalysis Substrate Screena
mol % time yieldb
entry
R
R1
product
3a
(h)
(%)
To test the generality of internal Lewis acid assisted
hydrogen bond donor catalysis, a brief investigation eval-
uating the scope of the reaction was carried out, and the
results are listed in Table 2. The process tolerates both
electron-donating and electron-withdrawing substituents
on the nitrostyrene; just 2.5 and 5 mol % of 3a afford
excellent yields of corresponding products after 24 h (87%
and 88%, entries 2 and 3). Although alkyl nitroalkenes
derived from hexanal and cyclohexanecarboxaldehyde
1
2
3
4
5
6
7
Ph
H
H
H
H
H
7a
7b
7c
7d
7e
7f
5
48
24
24
48
48
24
48
91
87
88
64
69
89
70
4-Br-C6H4
4-MeO-C6H4
n-pentyl
cyclohexyl
Ph
2.5
5
10
10
5
5-MeO
5-Br
Ph
7g
10
a See Supporting Information for more details. b Isolated yields.
Figure 3. Comparison of the rate data of boronate ureas and more conventional urea and thiourea catalysts.
718
Org. Lett., Vol. 13, No. 4, 2011

of the traditional urea catalyst 9a. Pinacol ester 4b has an
observed rate constant of 2.4 Â 10-4 s-1, more than 7 times
faster than that of 9a. Both 3a and 4b were also found to be
nearly 5 times and 3 times faster, respectively, than thiourea
9b. The reaction was found to be first order with respect to
catalyst, as shown by the linear relationship between the
yield and concentration of the catalyst.
Scheme 2. Chiral Boronate Urea Catalysis
Initial investigations confirm that asymmetric catalysis
with internal Lewis acid assisted HBDs is an area filled
with opportunity (Scheme 2). Under relatively unopti-
mized reaction conditions cis-aminoindanol derived cata-
lyst 3c proved to be highly active, however; only moderate
levels of enantioselectivity were obtained (35% ee) after
48 h at -20 °C. Chiral boronate urea 4c, on the other
hand, gave rise to 64% of 7f with good enantioselectivity
(61% ee). Notably, these ureas differing only by their ligands
on boron have significantly different abilities to induce stereo-
selectivity into the transformation. These data demonstrate
the importance of a catalyst scaffold that contains several
tunable parameters to enable the development of the optimal
catalyst, in regard to both activity and stereoselectivity, for a
bond-forming reaction.
In summary, boronate ureas have been disclosed as a
new class of HBD catalysts with enhanced reactivity due to
the strategic placement of an internal Lewis acid. Impor-
tantly, the highly tunable nature of these ureas offers an
ideal platform for the rational design of HBD catalysts to
achieve optimal performance in terms of both activity and
stereocontrol. Investigations into internal Lewis acid as-
sistedHBD catalysis are ongoingin our laboratory, and we
look forward to reporting our progress in this area.
proved to be more challenging electrophiles, good yields of
the desired products were obtained after 48 h with 10 mol
% of 3a (64% and 69%, entries 4 and 5). A short investiga-
tion of indoles revealed certain substituents can be well
accommodated in the reaction. For example, more nucleo-
philic 5-methoxyindole afforded an 89% yield of the
desired adduct with 5 mol % of 3a after 24 h (entry 6).
The slightly less nucleophilic 5-bromoindole proved to
be somewhat more sluggish yet afforded a good yield of
product after 48 h (70%, entry 7).
Preliminary kinetic studies probing the activity of cata-
lysts 3a and 4b were conducted in direct comparison to
catalysts 9a and 9b. Using the method of initial rates, the rate
of the reaction was measured at several catalyst loadings.
The results at 5 mol % are depicted in Figure 3 and show that
there is strong evidence supporting boronate ureas as en-
hanced hydrogen bond donor catalysts. Most notably, the
observed rate constant of difluoroboryl urea 3a was found to
be 3.6 Â 10-4 s-1, a rate more than 10 times faster than that
Acknowledgment. Support for this work has been pro-
vided by the OSU Department of Chemistry. We thank the
Ohio BioProducts Innovations Center (OBIC) for helping
support our mass spectrometry facility. Professors James
Stambuli (OSU) and Dennis Bong (OSU) are acknowl-
edged for insightful discussions. Boehringer-Ingleheim is
thanked for a generous gift of cis-aminoindanol.
Supporting Information Available. Experimental pro-
cedures and spectral data. This material is available free
of charge via the Internet at http://pubs.acs.org.
(11) Investigations to better understand this result, including the
determinationof the boronate urea pKa’s, are ongoing in our laboratory.
Org. Lett., Vol. 13, No. 4, 2011
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