Internal Lewis acid assisted ureas: Tunable hydrogen bond donor catalysts

Article abstract of DOI:10.1039/c2cc37073e

The strategic incorporation of internal Lewis acids onto urea scaffolds gives rise to a family of tunable hydrogen bond donor catalysts. The nature of the Lewis acid and associated ligands affects the urea polarization, acidity, and activity in reactions

Full text of DOI:10.1039/c2cc37073e

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Internal Lewis acid assisted ureas: tunable hydrogen
bond donor catalysts†‡
Cite this: DOI: 10.1039/c2cc37073e
David M. Nickerson, Veronica V. Angeles, Tyler J. Auvil, Sonia S. So and
Anita E. Mattson*
Received 28th September 2012,
Accepted 31st October 2012
DOI: 10.1039/c2cc37073e
www.rsc.org/chemcomm
The strategic incorporation of internal Lewis acids onto urea
scaffolds gives rise to a family of tunable hydrogen bond donor
catalysts. The nature of the Lewis acid and associated ligands
affects the urea polarization, acidity, and activity in reactions of
nitrocyclopropane carboxylates and nitrodiazoesters.
Groundbreaking work from the Etter research group demonstrated
the ability of diarylureas to hydrogen bond and co-crystallize with
various guest molecules including cyclohexanone, p-nitroaniline
and tetrahydrofuran.1 Inspired by these early observations, Curran
and coworkers discovered that ureas and thioureas are able to
affect both the rate and stereochemical outcome of organic
transformations.2,3 These seminal discoveries unlocked a new area
of catalysis that has experienced tremendous growth over the past
two decades.4–7 A survey of the current literature quickly reveals the
utility of hydrogen bond donor (HBD) catalysis in highly stereo-
selective processes for the preparation of valuable, asymmetric
building blocks using urea or thiourea catalysts.5,8–16
The demonstrated success observed with urea and thiourea
catalysis suggests it is an area with tremendous opportunity; yet,
the field has been held back by high catalyst loadings and limited
reactivity patterns. These challenges have not gone unnoticed, and
stimulating advances in catalyst design have led to the develop-
ment of a second-generation set of urea catalysts (Fig. 1). For
example, Ellman and coworkers have taken advantage of ureas
derived from the electron-withdrawing N-sulfinyl group for the
activation of nitroalkenes, achieving catalyst loadings as low as
0.2 mol%.17,18 Other advances in HBD catalyst design have
included the Seidel group’s introduction of thioamides as highly
Fig. 1 Recent enhanced hydrogen bond donor catalyst design.
active catalysts for the addition of indoles to nitroalkenes11 as well
as Smith and his team’s cleverly designed urea-activated thiourea
catalyst system for the activation of imines for nucleophilic
addition.19
We also have been attracted to the potential of activated ureas
in the discovery of fruitful new directions in hydrogen bond
donor catalysis. Of particular interest to us was the design of
modular, enhanced urea catalysts capable of being easily tuned
for optimal performance in a desired transformation. Our studies
were initiated with the hypothesis that a strategically placed
Lewis acid on the urea scaffold would participate in internal
The Ohio State University, 100 W. 18th Ave., Columbus, OH, USA.
E-mail: mattson@chemistry.ohio-state.edu; Fax: +1-614-292-1685;
Tel: +1-614-247-7931
† This article is part of the ChemComm ‘Emerging Investigators 2013’ themed
issue.
‡ Electronic supplementary information (ESI) available: Detailed experimental
procedures and characterization data. CCDC 903666 (platinacycle) and 882366
(palladacycle). For ESI and crystallographic data in CIF or other electronic format
see DOI: 10.1039/c2cc37073e
Fig. 2 Internal Lewis acid assisted hydrogen bond donor catalysts.
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Table 2 Internal Lewis acid assisted urea catalysts compared in their ability to
activate nitrocyclopropane 4a
coordination resulting in an increased polarization of the urea
functionality and enhanced catalyst activity (Fig. 2).
An internal Lewis acid assisted urea catalyst design benefits
from the opportunity for activity tuning through straightforward
modification of the Lewis acid and associated ligands while also
maintaining modularity with respect to the chiral scaffold. Our
Yieldb (%)
kobs  10À4 (sÀ1
7.0
)
c
plans were supported by Etter’s pioneering report of weak urea Urea
polarization with the ortho hydrogen1 on the phenyl ring and
1a
87
73
67
65
34
31
Smith’s more recent demonstration of enhanced boronate urea
recognition of acetate anions compared to conventional ureas
(Fig. 2).20,21 The results of early studies initiated in our laboratory
to probe tuning of the urea catalyst activity through internal
Lewis acid incorporation are presented herein.
1b
1c
1d
1e
1f
2.0
0.43
3.0
0.28
0.30
a
Reactions performed using 1.5 equivalents of aniline at a concen-
tration of 0.5 M. See ESI for detailed experimental procedures.
Isolated yield. An average of kobs determined at multiple catalyst
loadings. See ESI for detailed experimental data.
Early observations with boronate urea 1a in the activation of
both nitrocyclopropane carboxylates and nitrodiazoesters led
b
c
Table 1 Internal Lewis acid assisted urea catalysts compared in their ability to
us to reason that the strategic installation of a boron difluoride
moiety can render the urea catalyst higher yielding and faster
than conventional ureas in the activation of electrophiles
containing a nitro group.22–24 Interested in how catalyst activity
and acidity were related to the type of internal Lewis acid and
its associated ligands, a small family of internal Lewis acid
assisted ureas was prepared and directly compared in two
separate reactions: the activation of ethyl nitrodiazoacetate
(Table 1) and the activation of a nitrocyclopropane carboxylate
(Table 2). The family of ureas investigated in this study
included boronate ureas 1a and 1e, urea palladacycle 1b,25
urea platinacycle 1c, and silicate urea 1f.
activate ethyl nitrodiazoacetatea
Yieldb kobs  10À5
c
d
Urea
(%)
(sÀ1
)
pKa
83
9.2
7.5 Æ 0.2
After their examination in two separate reaction platforms, we
were pleased to find that the effect of internal urea activation was
dependent on the Lewis acid and associated ligands. The most
active catalyst from this family in the activation of both nitro-
diazoester 2 and nitrocyclopropane carboxylate 4 was identified as
difluoroboronate urea 1a. The activation of 2 with 20 mol% of 1a
gave rise to arylglycine derivative 3 in 83% yield at a rate over eight
78
3.6
6.8 Æ 0.5
times faster than conventional urea 1d (kobs = 9.2 Â 10À5
s
À1).
65
58
2.8
1.4
NAe
Similarly, catalytic activation of nitrocyclopropane 4 occurred best
with difluoroboronate urea 1a and high yields of nitroester 5 were
isolated (87%). The urea palladacycle 1b was found to be slightly
superior to urea platinacycle 1c in the activation of both nitrodia-
zoester 2 and nitrocyclopropane 4 in terms of yield and reaction
rate. The ability to tune the reactivity of the ureas through the
ligands on the Lewis acid was supported with the observation that
pinacol ester boronate urea’s (1e) performance as a catalyst was
significantly decreased when compared to difluoroboronate urea 1a.
The attempted activation of the urea functionality by introduction of
silicon met with little success and low yields of products 3 and 5
were isolated with catalyst 1f.
13.8 Æ 0.226
61
35
0.77
0.77
9.49 Æ 0.05
With the discovery that urea activity can be significantly
enhanced by internal Lewis acid coordination, our interest
turned to the effect the Lewis acid was having on urea acidity
and polarization. With the recent collection of acid dissociation
constants of ureas and thioureas reported by Schreiner and
coworkers as an encouraging starting point, we determined the
pKa of ureas 1a–1f in dimethylsulfoxide (DMSO) (Table 1).26,27
15.96 Æ 0.09
a
Reactions performed using 10 equiv. of aniline at a concentration of
b
c
1 M. See ESI for detailed experimental procedures. Isolated yield. An
average of kobs determined at multiple catalyst loadings. Value in
DMSO. This catalyst was incompatible with the pKa determination
d
e
procedure used. See ESI for more details.
c
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ureas, although the carbonyl bond length was slightly less
elongated when compared to 1a.
Internal Lewis acid assisted ureas offer highly tunable scaf-
folds for development as enhanced hydrogen bond donor
catalysts. The type of Lewis acid incorporated onto the urea
scaffold can affect the urea acidity, polarization and catalytic
activity in the activation of ethyl nitrodiazoacetate and nitro-
cyclopropane carboxylates. Ongoing studies in our laboratory
are geared toward probing the limits of internal Lewis acid
assisted urea catalysis as a new direction in the field of
hydrogen bond donor catalysis.
Support for this work has been provided by the OSU Depart-
ment of Chemistry and the American Chemical Society Petro-
leum Research Foundation (Award No. 52183-DNI1). Dr Judith
Gallucci is thanked for expert crystallographic analysis.
Notes and references
1 M. C. Etter, Z. Urbanczyk-Lipkowska, M. Ziaebrahimi and
T. W. Panunto, J. Am. Chem. Soc., 1990, 112, 8415.
2 D. P. Curran and L. H. Kuo, J. Org. Chem., 1994, 59, 3259.
3 D. P. Curran and L. H. Kuo, Tetrahedron Lett., 1995, 36, 6647.
4 Z. G. Zhang and P. R. Schreiner, Chem. Soc. Rev., 2009, 38, 1187.
5 Y. Takemoto, Chem. Pharm. Bull., 2010, 58, 593.
6 S. J. Connon, Synlett, 2009, 354.
7 A. Berkessel and H. Groger, Asymmetric Organocatalysis, Wiley-VCH,
1st edn, 2005.
8 M. S. Sigman, P. Vachal and E. N. Jacobsen, Angew. Chem., Int. Ed.,
2000, 39, 1279.
9 C. Uyeda and E. N. Jacobsen, J. Am. Chem. Soc., 2008, 130, 9228.
10 T. Okino, Y. Hoashi, T. Furukawa, X. N. Xu and Y. Takemoto, J. Am.
Chem. Soc., 2005, 127, 119.
11 M. Ganesh and D. Seidel, J. Am. Chem. Soc., 2008, 130, 16464.
12 S. E. Reisman, A. G. Doyle and E. N. Jacobsen, J. Am. Chem. Soc.,
2008, 130, 7198.
Fig. 3 Comparison of crystal structures of catalysts 1a, 1b and 1c drawn with
50% probability displacement ellipsoids.
13 W. Zhang, S. Q. Zheng, N. Liu, J. B. Werness, I. A. Guzei and
W. P. Tang, J. Am. Chem. Soc., 2010, 132, 3664.
14 T. Bui, S. Syed and C. F. Barbas, J. Am. Chem. Soc., 2009, 131, 8758.
Difluoroboronate urea 1a and urea palladacycle 1b, the most
active catalysts identified in the activation of nitrocyclopropane
carboxylate 4 and nitrodiazoester 2 (Tables 1 and 2), were also 15 B. Tan, N. R. Candeias and C. F. Barbas, Nat. Chem., 2011, 3, 473.
16 Q. S. Guo, M. Bhanushali and C. G. Zhao, Angew. Chem., Int. Ed.,
found to be the most acidic (pKa of 1a = 7.5 and 1b = 6.8).
Notably, these catalysts are significantly more acidic than the
2010, 49, 9460.
17 J. A. Ellman, K. L. Kimmel and M. T. Robak, J. Am. Chem. Soc., 2009,
more conventional bis(3,5-trifluoro-methylphenyl)urea (pKa
=
131, 8754.
18 M. T. Robak, M. Trincado and J. A. Ellman, J. Am. Chem. Soc., 2007,
129, 15110.
19 C. R. Jones, G. D. Pantos, A. J. Morrison and M. D. Smith, Angew.
Chem., Int. Ed., 2009, 48, 7391.
20 M. P. Hughes, M. Y. Shang and B. D. Smith, J. Org. Chem., 1996,
61, 4510.
21 M. P. Hughes and B. D. Smith, J. Org. Chem., 1997, 62, 4492.
13.8) and bis(3,5-trifluoromethyl-phenyl)thiourea (pKa = 8.5)
catalysts. The poorly performing boronate urea pinacol ester
1e and silicate urea 1f were less acidic (pKa of 1e = 9.49 and 1f =
15.96). We also found that the acidity of the catalysts can be
loosely linked to urea polarization as revealed by the carbonyl
bond lengths found in X-ray crystallographic data of ureas 22 S. S. So, T. J. Auvil, V. J. Garza and A. E. Mattson, Org. Lett., 2012,
14, 444.
1a–1c (Fig. 3). The urea carbonyl bond length observed in
23 S. S. So, J. A. Burkett and A. E. Mattson, Org. Lett., 2011, 13, 716.
24 S. S. So and A. E. Mattson, J. Am. Chem. Soc., 2012, 134, 8798.
difluoroboronate urea 1a co-crystallized with nitrobenzene24
was found to be 1.274 Å, similar to the length reported by Smith 25 D. M. Nickerson and A. E. Mattson, Chem.–Eur. J., 2012, 18, 8310.
26 G. Jakab, C. Tancon, Z. G. Zhang, K. M. Lippert and P. R. Schreiner,
Org. Lett., 2012, 14, 1724.
27 F. G. Bordwell, J. C. Branca, D. L. Hughes and W. N. Olmstead,
and coworkers. Urea palladacycle 1b (CQO: 1.258 Å) and urea
platinacycle 1c (CQO: 1.270 Å) were also found to have more
polarized urea functionalities when compared to conventional
J. Org. Chem., 1980, 45, 3305.
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun.