Chiral squaramide derivatives are excellent hydrogen bond donor catalysts

Article abstract of DOI:10.1021/ja805693p

Thioureas represent the dominant platform for hydrogen bond promoted asymmetric catalysts. A large number of reactions, reported in scores of publications, have been successfully promoted by chiral thioureas. The present paper reports the use of squaramid

Full text of DOI:10.1021/ja805693p

Published on Web 10/11/2008
Chiral Squaramide Derivatives are Excellent Hydrogen Bond Donor Catalysts
Jeremiah P. Malerich, Koji Hagihara, and Viresh H. Rawal*
Department of Chemistry, The UniVersity of Chicago, Chicago, Illinois 60637
Received July 31, 2008; E-mail: vrawal@uchicago.edu
Hydrogen bonding promoted asymmetric catalysis has grown explo-
sively over the past decade.1 Of the different H-bond donor catalysts
reported to date, those based on the thiourea core dominate the field.2
The many reactions that have been promoted by thioureas underscores
the importance of this “privileged” platform.3 Inasmuch as chiral thioureas
Figure 1. Calculated H-bond distances in N,N′-dimethylthiourea and N,N′-
have proven to be a gold mine for catalyst discovery, other H-bond donor
motifs have been much less explored.4 We describe here the development
dimethylsquaramide.
and successful demonstration of a new family of H-bonding catalysts based
on the squaramide catalophore.
Scheme 1. Synthesis of Chiral Squaramide Catalyst 5
Essential to the overwhelming success of thiourea-based catalysts is
its ability to form two H-bonds to a reactant. The second H-bond not
only further activates the reactant but also constrains it to a well-defined
orientation, required for asymmetric induction. Examination of crystal-
lographic and computational data on the thiourea unit shows that the two
H atoms are positioned ∼2.1 Å apart, each canted in by ∼6° (Figure 1).5
The distance between the two hydrogens is defined by the fact that the
accompanying N atoms are connected by a one-carbon link. We postulated
that bisamides of squaric acid, which position the two hydrogens 0.6 Å
further apart, could serve as a versatile core activation unit for dual
H-bonding catalysts.6,7
pounds as nucleophiles (11; Table 3). Of the dozen nucleophiles utilized,
all gave the conjugate addition products in good to excellent yields.
Although several of the reactions proceeded with little diastereoselectivity,
each of the diastereomers was formed in very good to excellent enanti-
oselectivity. Cyclopentanones 11j and 11k proved to be exceptions, giving
the products with high diastereoselectivity. In all these reactions, squara-
mide 5 is believed to operate as a bifunctional catalyst, analogously to
Takemoto’s catalyst.8
To assess the utility of squaramides for asymmetric catalysis, several
differentially substituted chiral derivatives were synthesized. These
compounds are easy to prepare, as shown for the preparation of 5 (Scheme
1). Stirring dimethyl squarate with an amine in CH2Cl2 promotes the first
substitution reaction. Repeating the process with a second amine gives
the disubstituted squaramide, which precipitates out of solution. The crystal
structure of squaramide 5 displayed a distance of 2.85 Å between the acidic
H atoms (Figure 2), approximating the calculated distance.
A brief survey of different chiral squaramides identified the (-)-
cinchonine-substituted derivative (5) to be an effective H-bond donor
catalyst for the conjugate addition of 2,4-pentanedione (6) to ꢀ-nitrostyrene
(7), one of the earliest reactions to be catalyzed using a simple chiral
thiourea.8 When this reaction was carried out in ether at room temperature
with 2.0 mol % of 5, the conjugate addition product 8 was obtained in
88% yield and 96% ee, a result that compares favorably with previous
reports on this transformation (Table 1, entry 1).9,10 The same reaction in
toluene gave the product in higher yield and ee (entry 2). The best result
was obtained with methylene chloride: the reaction proceeded faster and
in higher yield and ee (entry 3). The improved enantioselectivity was
maintained when the catalyst loading was reduced to 0.5 mol % (entry
4). Indeed, the reaction proceeds well even at 0.1 mol % catalyst loading,
with only slight erosion in the observed ee (entry 5).
The results presented above show the squaramide unit to be an effective
scaffold on which to build chiral H-bond donor catalysts. For the conjugate
Figure 2. ORTEP of squaramide 5.
Table 1. Evaluation of 5 as a Catalyst for the Conjugate Addition
of 2,4-Pentanedione to ꢀ-Nitrostyrene
The scope of this squaramide catalyzed conjugate addition reaction was
examined next. Various substituted ꢀ-nitrostyrenes were reacted with 2,4-
pentanedione (6) in the presence of 0.5 mol % of 5, and all afforded
consistently high yields and enantioselectivities (Table 2). A somewhat
longer reaction time was required for 4-methoxy-ꢀ-nitrostyrene due to its
inherently lower reactivity toward nucleophiles, but it still gave excellent
results (entry 2). Halogen substitution was uniformly well tolerated (entries
3-5).
entry
mol % of 5
solvent
time
yield
ee
1
2
3
4
5
2.0
2.0
2.0
0.5
0.1
Et2O
PhMe
CH2Cl2
CH2Cl2
CH2Cl2
24 h
24 h
7 h
8 h
20 h
88%
94%
98%
94%
97%
96%
98%
>99%
>99%
96%
Given the consistently good results obtained with different styrenes,
we next examined the possibility of using various 1,3-dicarbonyl com-
9
14416 J. AM. CHEM. SOC. 2008, 130, 14416–14417
10.1021/ja805693p CCC: $40.75
2008 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Variation of Electrophile in Reaction with 6a
addition reactions of 1,3-dicarbonyl compounds to nitroolefins, cinchona
derivative 5 was a remarkably active catalyst, affording the conjugate
addition products in high yields and enantioselectivities. The modular
nature of the synthesis means that a wide range of squaramide catalysts,
tuned with regard to the pKa of the hydrogens as well as the chiral
environment, should be readily accessible. Further investigation of these
catalysts, as well as structures in which the distance between the donor
hydrogens is increased even further, can be expected to open new
opportunities for H-bond mediated asymmetric catalysis.
Acknowledgment. Financial support from the NIH is gratefully
acknowledged. We thank Kyowa-Hakko Kogyo Co., Japan, for a
sabbatical fellowship for K.H. and Dr. Ian Steele (U. Chicago, Dept. of
Geophysical Sciences) for obtaining the crystal structure of 5.
Supporting Information Available: Procedure for catalyst preparation,
characterization data, NMR spectra for new compounds, and HPLC data for
conjugate addition products. This information is available free of charge via
the Internet at http://www.pubs.acs.org.
References
(1) (a) Doyle, A. G.; Jacobsen, E. N. Chem. ReV. 2007, 107, 5713. (b) McGilvra,
J. D.; Gondi, V. B.; Rawal, V. H. In EnantioselectiVe organocatalysis;
Dalko, P. I., Ed.; Wiley-VCH: Weinheim, 2007; pp 189-254.
(2) Connon, S. J. Chem.sEur. J. 2006, 12, 5418. See also ref 1.
(3) Examples of reactions catalyzed by chiral thioureas include the Strecker
reaction: (a) Sigman, M. S.; Jacobsen, E. N. J. Am. Chem. Soc. 1998, 120,
4901. Michael addition: (b) Hoashi, Y.; Okino, T.; Takemoto, Y. Angew.
Chem., Int. Ed. 2005, 44, 4032. (c) Vakulya, B.; Varga, S.; Csampai, A.;
Soos, T. Org. Lett. 2005, 7, 1967. Morita-Baylis-Hillman reaction: Wang,
J.; Li, H.; Yu, X. H.; Zu, L. S.; Wang, W. Org. Lett. 2005, 7, 4293. (d)
Friedel-Crafts reaction: Wang, Y. Q.; Song, J.; Hong, R.; Li, H. M.; Deng,
L. J. Am. Chem. Soc. 2006, 128, 8156. Petasis reaction: (e) Yamaoka, Y.;
Miyabe, H.; Takemoto, Y. J. Am. Chem. Soc 2007, 129, 6686. Pictet-
Spengler cyclization : (f) Raheem, I. T.; Thiara, P. S.; Peterson, E. A.;
Jacobsen, E. N. J. Am. Chem. Soc. 2007, 129, 13404 Diels-Alder
reaction: (g) Singh, R. P.; Bartelson, K.; Wang, Y.; Su, H.; Lu, X.; Deng,
L. J. Am. Chem. Soc. 2008, 130, 2422.
a Reactions were carried out on 0.500 mmol of 9 with 2.0 equiv of 6 and
0.5 mol % 5 in 1.5 mL of CH2Cl2.
Table 3. Variation of Nucleophile in Reaction with 7
(4) Other chiral H-bond donor scaffolds include, inter alia, cinchona alkaloid
derivatives: (a) Hiemstra, H.; Wynberg, H. J. Am. Chem. Soc. 1981, 103,
417. Dipeptides: (b) Oku, J. I.; Inoue, S. J. Chem. Soc., Chem Commun.
1981, 229. Guanidinium ions: (c) Corey, E. J.; Grogan, M. J. Org. Lett.
1999, 1, 157–160. Diols: (d) Huang, Y.; Unni, A. K.; Thadani, A. N.; Rawal,
V. H. Nature 2003, 424, 146. (e) Thadani, A. N.; Stankovic, A. R.; Rawal,
V. H. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5846. Phosphoric acids : (f)
Akiyama, T.; Itoh, J.; Yokota, K.; Fuchibe, K. Angew. Chem., Int. Ed. 2004,
43, 1566. (g) Uraguchi, D.; Terada, M. J. Am. Chem. Soc. 2004, 126, 5356.
Amidinium ions: (h) Nugent, B. M.; Yoder, R. A.; Johnston, J. N. J. Am.
Chem. Soc. 2004, 126, 3418.
(5) Structures were optimized with Hartree-Fock calculations using the 6-31G*
basis set (Spartan ’04 for Macintosh, Wavefunction, Inc.). The calculated
H-H distance in the thiourea approximates that found in the crystal structure
of Takemoto’s thiourea catalyst: Okino, T.; Hoashi, Y.; Furukawa, T.; Xu,
X. N.; Takemoto, Y. J. Am. Chem. Soc. 2005, 127, 119.
(6) Squaramides have been used in molecular recognition studies: (a) Tomas,
S.; Prohens, R.; Vega, M.; Rotger, M. C.; Deya, P. M.; Ballester, P.; Costa,
A. J. Org. Chem. 1996, 61, 9394. (b) Ramalingam, V.; Domaradzki, M. E.;
Jang, S.; Muthyala, R. S. Org. Lett. 2008, 10, 3315, and references cited
therein.
(7) Squaramides have been recognized as bioisosteres of ureas: Merritt, J. R.;
Rokosz, L. L.; Kingsley, H. N.; Kaiser, B.; Wang, W.; Stauffer, T. M.;
Ozgur, L. E.; Schilling, A.; Li, G.; Baldwin, J. J.; Taveras, A. G.; Dwyer,
M. P.; Chao, J. P Bioorg. Med. Chem. Lett. 2006, 16, 4107.
(8) Okino, T.; Hoashi, Y.; Takemoto, Y J. Am. Chem. Soc. 2003, 125, 12672.
Please see Supporting Information for more details.
(9) Previous reports of organocatalytic conjugate additions of 1,3-dicarbonyl
compounds to nitroolefins include: (a) Li, H. M.; Wang, Y.; Tang, L.; Deng,
L. J. Am. Chem. Soc. 2004, 126, 9906. (b) Kotrusz, P.; Toma, S.; Schmalz,
H. G.; Adler, A. Eur. J. Org. Chem. 2004, 1577. (c) Li, H. M.; Wang, Y.;
Tang, L.; Wu, F. H.; Liu, X. F.; Guo, C. Y.; Foxman, B. M.; Deng, L.
Angew. Chem., Int. Ed. 2005, 44, 105. (d) McCooey, S. H.; Connon, S. J.
Angew. Chem., Int. Ed. 2005, 44, 6367. (e) Wang, J.; Li, H.; Duan, W. H.;
Zu, L. S.; Wang, W. Org. Lett. 2005, 7, 4713. (f) Terada, M.; Ube, H.;
Yaguchi, Y. J. Am. Chem. Soc. 2006, 128, 1454. (g) McCooey, S. H.;
McCabe, T.; Connon, S. J. J. Org. Chem. 2006, 71, 7494. (h) Comer, E.;
Rohan, E.; Deng, L.; Porco, J. A. Org. Lett. 2007, 9, 2123. (i) Lubkoll, J.;
Wennemers, H. Angew. Chem., Int. Ed. 2007, 46, 6841. (j) Andres, J. M.;
Manzano, R.; Pedrosa, R. Chem.sEur. J. 2008, 14, 5116. (k) Peng, F. Z.;
Shao, Z. H.; Fan, B. M.; Song, H.; Li, G. P.; Zhang, H. B. J. Org. Chem.
2008, 73, 5202.
a Values are listed for major and minor diastereomers respectively.
b Reaction was carried out with 0.500 mmol of 7, 2.0 equiv of 11,
and 0.5 mol % 5 in 1.5 mL of CH2Cl2. c Reaction was carried out
with 0.200 mmol of 7, 2.0 equiv of 11, and 2.0 mol % 5 in 0.6 mL
of CH2Cl2.
(10) The absolute stereochemistry of 8 was assigned by comparison of the optical
rotation with the value determined in ref 9e.
JA805693P
9
J. AM. CHEM. SOC. VOL. 130, NO. 44, 2008 14417