Development of Chiral, Bifunctional Thiosquaramides: Enantioselective Michael Additions of Barbituric Acids to Nitroalkenes

Article abstract of DOI:10.1021/jacs.7b01115

We report a general method for the synthesis of chiral thiosquaramides, a class of bifunctional catalysts not previously described in the literature. Thiosquaramides are found to be more acidic and significantly more soluble in nonpolar solvents than their oxosquaramide counterparts, and they are excellent catalysts for the unreported, enantioselective conjugate addition reaction of the barbituric acid pharmacaphore to nitroalkenes, delivering the chiral barbiturate derivatives in high yields and high enantioselectivities, even with catalyst loadings as low as 0.05 mol%.

Full text of DOI:10.1021/jacs.7b01115

Communication
pubs.acs.org/JACS
Development of Chiral, Bifunctional Thiosquaramides:
Enantioselective Michael Additions of Barbituric Acids to
Nitroalkenes
Michael Rombola, Chintan S. Sumaria, Thomas D. Montgomery, and Viresh H. Rawal*
Department of Chemistry, University of Chicago, 5735 South Ellis Avenue, Chicago, Illinois 60637, United States
S
* Supporting Information
The high effectiveness of squaramides stands in contrast to
their poor solubility in nonpolar solvents, which are commonly
employed for hydrogen bond mediated reactions. The reason
for the low solubility is that squaramides self-aggregate through
dual H-bonds into head-to-tail ladder networks and precip-
itate.8,9 Among the structural modifications to overcome this
issue, we considered the prospect of converting the carbonyl
groups to thiocarbonyls.10 Replacement of even one of the
carbonyl groups to a thiocarbonyl was expected to disrupt
ladder formation and, as a result, increase solubility. Further-
more, this interconversion was also expected to increase the
acidity of the N−H bonds, as observed when going from an
amide to a thioamide or urea to a thiourea (Figure 1).11−13
ABSTRACT: We report a general method for the syn-
thesis of chiral thiosquaramides, a class of bifunctional
catalysts not previously described in the literature.
Thiosquaramides are found to be more acidic and
significantly more soluble in nonpolar solvents than their
oxosquaramide counterparts, and they are excellent cata-
lysts for the unreported, enantioselective conjugate addi-
tion reaction of the barbituric acid pharmacaphore to
nitroalkenes, delivering the chiral barbiturate derivatives in
high yields and high enantioselectivities, even with catalyst
loadings as low as 0.05 mol%.
onceptual insights and key advances in catalyst design
Chave fueled many breakthroughs in asymmetric catalysis.
Over the past two decades, chemists have witnessed
unparalleled growth in enantioselective reactions promoted
by chiral organic catalysts, such as bases, secondary amines, and
hydrogen bond donors. In the last category, early examples of
enantioselection through hydrogen bond activation paved the
way for broader application of this modality to asymmetric
catalysis,1,2 with the development of bifunctional catalysts
playing a pivotal role in propelling this activation paradigm into
the discovery of new enantioselective processes.3 Among the
earliest and most-enabling bifunctional catalysts are those based
on the thiourea scaffold, wherein the two donor hydrogens
serve to organize and activate the reaction substrate.4 In the
hope of expanding the classes of reactions that can be rendered
enantioselective, we examined many new scaffolds for bifunc-
tional catalysis, particularly those in which the distance between
the donor hydrogens was significantly greater than found in
thioureas, and introduced chiral squaramides as bifunctional
hydrogen bonding catalysts.5 Squaramides are easily synthe-
sized, through two addition−elimination reactions, and this
has allowed the development of a large number of derivatives.
Squaramides have proven to be excellent catalysts and have
been adopted widely for the development of new method-
ology.6,7 Despite their widespread use, the inherent properties
of squaramides, such as low solubility in nonpolar solvents
and a limited ability to modulate the pKa of the donor hydro-
gens, restricts their performance in some reactions. Faced with
these limitations, we have developed chiral dithiosquaramides
as bifunctional catalysts and report herein their use in the
unreported enantioselective conjugate addition reaction of the
barbituric acid pharmacaphore to nitroalkenes.
Figure 1. Development of relevant chiral organocatalyst scaffolds.
This ability to dial up the acidity of squaramides by converting
one or both carbonyls to thiocarbonyls presented an
opportunity to expand the catalyst’s reaction footprint.
The selection of barbituric acid derivatives to test the
capability of new thiosquaramides was motivated by their
known biomedical applications. Historically used as sedatives,
anti-convulsants, and analgesics, barbiturates have recently been
shown to possess anti-tumor, immune system modulatory, and
anti-depressive activity.14 The varied biological properties of
barbituric acids and the limited reports on their use in
enantioselective reactions,15 and none using organic catalysts,
prompted us to select them as nucleophiles for demonstrating
the effectiveness of chiral thiosquaramide catalysts.
Received: February 1, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/jacs.7b01115
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
Direct synthesis of chiral, bifunctional thiosquaramides by
dithionation of the corresponding “oxo”-squaramides eluded us
for many years.16 Even in instances where the desired product
was observed, the isolation of a pure bifunctional thiosquar-
amide was complicated by its decomposition during silica gel
chromatography and the presence of various byproducts.
An alternative approach was thus explored. The preferred
route to bifunctional thiosquaramides proceeded through the
butyl squarate ester 1, rather than the more common
vinylogous methyl ester (Figure 2). Treatment of vinylogous
of A, the two N−H hydrogen atoms are positioned 2.43 and
2.64 Å apart, as opposed to ∼2.1 Å for thioureas20 and ∼2.7 Å
for squaramides (see Crystallographic Information File).5a The
smaller H−H distance in thiosquaramide A likely results from
the steric and electronic repulsion between the tert-butyl group
and the proximal thiocarbonyl group. Hartree−Fock calcu-
lations for the same structure at the 3-21G level of theory gives
the H−H distance as 2.60 Å, indicating that the smaller H−H
distance is due to the interactions with the sulfur atoms rather
than packing forces or other interactions in the crystal
structure.21 As anticipated, intermolecular hydrogen bonds to
give ladder structures, found in analogous oxosquaramides, are
not seen.22
The procedure described above was used to synthesize
several chiral thiosquaramides (A−E), and the new bifunctional
catalysts were evaluated as catalysts for the unreported
enantioselective conjugate addition of N,N′-diphenylbarbituric
acid to β-nitrostyrene (Table 1). Among the catalysts
Table 1. Evaluation of Catalysts and Other Reaction
Conditions
Figure 2. Synthesis of bifunctional thiosquaramides via the vinylogous
butyl ester.
butyl ester−amide 2 with 1 equiv of Lawesson’s reagent gave
the easily isolated dithionation product 3, which is moderately
stable at room temperature.17 Carrying out these steps on the
corresponding methyl ester gave little or no product, depending
on the substrate. Coupling of 3 with a chiral diamine provided
bifunctional catalysts A−E, which were purified by trituration to
give yellow to amber, bench-stable solids. As expected, unlike
their widely used oxo-counterparts, which are at best sparingly
soluble in common organic solvents, thiosquaramides are
significantly more soluble in a range of solvents. At room
temperature, squaramide F has a solubility of <0.1 mg/mL
in toluene, whereas thiosquaramide E has a solubility of
>3 mg/mL. We have also determined the pKa of select chiral
squaramides and thiosquaramides using various methods
(computational, NMR titration, and Bordwell) and have
found thiosquaramides to be 4−5 pKa units more acidic than
the corresponding oxosquaramides.18,19 We expect this
increased acidity to confer greater hydrogen bonding capability
to the thiosquaramide N−H bonds.
a
b
c
entry
catalyst
mol%
solvent
time, h
conv,
%
ee, %
1
A
B
C
D
E
F
E
E
E
E
E
E
E
E
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.1
0.05
0.02
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
MeOH
acetone
CHCl3
EtOAc
CH2Cl2
PhMe
PhMe
PhMe
0.5
0.5
0.5
0.5
0.5
0.5
6
>98
>98
>98
>98
>98
>98
>98
>98
>98
>98
>98
>98
>98
83
54
45
88
91
97
95
38
87
91
92
94
97
96
72
2
3
4
To gain insight on the structural changes imparted upon
substitution of the two oxygens with sulfurs, we secured the
X-ray crystal structure of bifunctional thiosquaramide A
(Figure 3). Two rotameric forms of the compound are
5
6
7
8
1.5
0.5
0.5
0.5
2
9
10
11
12
13
14
10
10
a
Reactions were carried out using 0.2 mmol of 5a and 0.22 mmol
b
Figure 3. X-ray crystal structure of a bifunctional thiosquaramide.
of 4a. Conversion was determined by 1H NMR spectroscopy.
c
Enantiomeric excess measured after halogenation (see Supporting
observed in the structure, of which the one with the dimethyl-
amino group pointing forward is shown. The planar geometry
about the two squarate nitrogens is consistent with sp2
hybridization expected at these atoms, and the anti/anti
conformation, with the N−H bonds syn to each other, is as
observed for most squaramides.7a,9 In the two rotameric forms
Information).
possessing the N,N-dimethylated cyclohexanediamine unit,
reduction in steric bulk on the distal thiosquaramide nitrogen
corresponded with higher ee for the Michael addition product
(entries 1−3). Of the piperidine containing thiosquaramides
B
DOI: 10.1021/jacs.7b01115
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
Chart 1. Conjugate Addition of Barbituric Acids to
Nitroolefins
Figure 4. X-ray crystal structure of a chlorinated barbiturate.
no effect on ee. Even at a catalyst loading of 0.05 mol%, the
reaction proceeded smoothly, going to full conversion within
10 h, with essentially no diminution in ee. The reaction worked
even when the catalyst level was reduced to 0.02 mol%, but gave
the product in 72% ee. The conjugate addition can also be
carried out on gram-scale, affording 1.65 g of the product in 96%
yield and 96.5% ee. Importantly, nearly all of these catalyzed
reactions, as well as those shown Chart 1, were carried out
without special precautions, under an air atmosphere and using
reagent grade solvents right out of a bottle.24
The scope of this thiosquaramide catalyzed conjugate
addition of barbiturates was examined next. Different
combinations of nitroolefins and N,N′-disubstituted barbituric
acids were reacted in the presence of 0.5 mol% of catalyst E
(Chart 1). The reactions gave high yields and high enantio-
selectivities for most of the reactants examined.25 Brominated
nitrostyrenes gave excellent results, although the rate of the
reaction was considerably slower for the substrate giving 6d,
presumably due to the steric hindrance caused by the ortho-
substituent, necessitating higher catalyst loading (5 mol%).
A similar effect on rate was observed with other hindered
substrates, and with alkenyl and alkyl substituted nitroalkenes.
For comparison purposes, the corresponding squaramide (F)
was employed for the catalysis of two additional reactions,
under otherwise identical conditions (6e and 6h, enantiomeric
excess given in parentheses). The absolute stereochemistry of
6f, and by analogy all other conjugate addition products, was
determined by X-ray crystallography of its chlorination product
7f (Figure 4).
In conclusion, we have developed a general method for the
synthesis of chiral thiosquaramides, a class of bifunctional
catalysts not previously described in the literature. Thiosquar-
amides can be prepared in only three steps from commercially
available materials, and they are more acidic and significantly
more soluble in nonpolar solvents than their “oxo”-squaramide
counterparts. Thiosquaramides are excellent catalysts for the
unreported, enantioselective conjugate addition reaction of
the barbituric acid pharmacaphore to nitroalkenes, delivering
the chiral barbiturate derivatives in high yields and high enan-
tioselectivities, even with catalyst loadings as low as 0.05 mol%.
All reactions were carried out using 0.22 mmol of nitroolefin and
0.2 mmol of barbituric acid, and yields given are of isolated products.
Enantiomeric excess was determined after chlorination, and the
absolute stereochemistry shown is tentative, based on the crystal
structure of 7f (see Figure 4 and Supporting Information, including
a
the Crystallographic Information File, for further details). Enantio-
meric excesses in parentheses correspond to reactions carried out with
b
squaramide catalyst F. 5 mol% of the catalyst was used.
examined, the benzyl-substituted catalyst performed better
than the one possessing a phenethyl unit (entries 4 and 5).
Catalyst F, the oxo-analogue of E, was also effective, but gave
lower enantioselectivity (entries 5 and 6). The seemingly small
difference in ee observed with catalysts E and F (97% vs 95%)
corresponds to selectivity ratios of 70:1 and 40:1, respectively.23
Further screening of conditions showed thiosquaramide E
to afford excellent yields and high enantioselectivities in all
solvents examined except methanol, and the optimal solvent
was found to be toluene. No reaction took place in the absence
of a catalyst. Further reduction of catalyst loading to 0.1 mol%
increased the reaction time only slightly, from 0.5 to 2 h, with
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.7b01115.
■
S
X-ray crystallographic data for thiosquaramide A (CIF)
X-ray crystallographic data for 7f (CIF)
Experimental procedures and detailed characterization
data of all new compounds (PDF)
C
DOI: 10.1021/jacs.7b01115
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
(11) Studies on pKa values of thioureas and squaramides:
(a) Bordwell, F. G. Acc. Chem. Res. 1988, 21, 456. (b) Bordwell, F.
G.; Algrim, D. J.; Harrelson, J. A. J. Am. Chem. Soc. 1988, 110, 5903.
(c) Bordwell, F. G.; Ji, G. Z. J. Am. Chem. Soc. 1991, 113, 8398. (d) Li,
X.; Deng, H.; Zhang, B.; Li, J.; Zhang, L.; Luo, S.; Cheng, J. − P. Chem.
- Eur. J. 2010, 16, 450. (e) Jakab, G.; Tancon, C.; Zhang, Z.; Lippert,
K. M.; Schreiner, P. R. Org. Lett. 2012, 14, 1724. (f) Ni, X.; Li, X.;
Wang, Z.; Cheng, J. − P. Org. Lett. 2014, 16, 1786. (g) See also ref 7..
(12) Increased acidity of a catalyst has been found to correlate with
increased activity and capability. See, inter alia: (a) Wittkopp, A.;
Schreiner, P. R. Chem. - Eur. J. 2003, 9, 407. (b) Jensen, K. H.; Sigman,
M. S. Angew. Chem., Int. Ed. 2007, 46, 4748. (c) Jensen, K. H.; Sigman,
M. S. J. Org. Chem. 2010, 75, 7194. (d) Parmar, D.; Sugiono, E.; Raja,
S.; Rueping, M. Chem. Rev. 2014, 114, 9047.
AUTHOR INFORMATION
■
Corresponding Author
*vrawal@uchicago.edu
ORCID
Michael Rombola: 0000-0002-4402-5619
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Science Foundation (NSF-1566402) for
financial support of this work. We thank Prof. J.-P. Cheng,
Tsinghua University, for helpful guidance on pKa measurement
techniques.
(13) For a computation study, see: Lu, T.; Wheeler, S. E. Chem. - Eur.
J. 2013, 19, 15141.
(14) (a) Gulliya, K. S. Anti-Cancer Uses for Barbituric Acid Analogs.
U.S. Patent 5674870A, Oct 7, 1997. (b) Gulliya, K. S. Uses for
Barbituric Acid Analogs. U.S. Patent 5869494A, Feb 9, 1999. (c) Kaur,
M.; Verma, P.; Singh, P. Bioorg. Med. Chem. Lett. 2009, 19, 3054.
(d) Dhorajiya, B. D.; Ibrahim, A. S.; Badria, F. A.; Dholakiya, B. Z.
Med. Chem. Res. 2014, 23, 839. (e) Penthala, N. R.; Ketkar, A.; Sekhar,
K. R.; Freeman, M. L.; Eoff, R. L.; Balusu, R.; Crooks, P. A. Bioorg.
Med. Chem. 2015, 23, 7226.
(15) To the best of our knowledge, the only use of barbituric acids as
nucleophiles in asymmetric catalysis has been in palladium-catalyzed
allylation reactions: (a) Brunner, H.; Deml, I.; Dirnberger, W.; Nuber,
B.; Reißer, W. Eur. J. Inorg. Chem. 1998, 1998, 43. (b) Brunner, H.;
Deml, I.; Dirnberger, W.; Ittner, K.-P.; Reißer, W.; Zimmermann, M.
Eur. J. Inorg. Chem. 1999, 1999, 51. (c) Trost, B. M.; Schroeder, G. M.
J. Org. Chem. 2000, 65, 1569.
REFERENCES
■
(1) For selected pioneering examples of enantioselective hydrogen-
bond donor catalysis, see: (a) Sigman, M. S.; Jacobsen, E. N. J. Am.
Chem. Soc. 1998, 120, 4901. (b) Wenzel, A. G.; Jacobsen, E. N. J. Am.
Chem. Soc. 2002, 124, 12964. (c) Huang, Y.; Unni, A. K.; Thadani, A.
N.; Rawal, V. H. Nature 2003, 424, 146. (d) Nugent, B. M.; Yoder, R.
A.; Johnston, J. N. J. Am. Chem. Soc. 2004, 126, 3418.
(2) For reviews of hydrogen-bond donor catalysis, see: (a) Doyle, A.
G.; Jacobsen, E. N. Chem. Rev. 2007, 107, 5713. (b) Hydrogen Bonding
in Organic Synthesis; Pihko, P. M., Ed.; Wiley-VCH: Weinheim, 2009.
(c) Turkmen, Y. E.; Zhu, Y.; Rawal, V. H. Brønsted Acids In
̈
Comprehensive Enantioselective Organocatalysis; Dalko, P. I., Ed.; Wiley-
VCH: Weinheim, 2013; Vol. 2, Chapter 10.
(3) For reviews of bifunctional thiourea catalysis, see: (a) Takemoto,
Y. Chem. Pharm. Bull. 2010, 58, 593. (b) Siau, W.-Y.; Wang, J. Catal.
Sci. Technol. 2011, 1, 1298.
(4) For early examples of thiourea-based bifunctional catalysis, see:
(a) Okino, T.; Hoashi, Y.; Takemoto, Y. J. Am. Chem. Soc. 2003, 125,
12672. (b) Yoon, T.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2005, 44,
466.
(5) For the first applications of squaramides as asymmetric
organocatalysts, see: (a) Malerich, J. P.; Hagihara, K.; Rawal, V. H. J.
Am. Chem. Soc. 2008, 130, 14416. (b) Lee, J. W.; Ryu, T. H.; Oh, J. S.;
Bae, H. Y.; Jang, H. B.; Song, C. E. Chem. Commun. 2009, 7224.
(c) Zhu, Y.; Malerich, J. P.; Rawal, V. H. Angew. Chem., Int. Ed. 2010,
49, 153.
(6) For selected recent applications of squaramides, see: (a) Albrecht,
L.; Dickmeiss, G.; Acosta, F. C.; Rodríguez-Escrich, C.; Davis, R. L.;
Jørgensen, K. A. J. Am. Chem. Soc. 2012, 134, 2543. (b) Yang, K. S.;
(16) For reports of thionation of squaric acid derivatives, see:
(a) Eggerding, D.; West, R. J. Org. Chem. 1976, 41, 3904.
(b) Frauenhoff, G. R.; Takusagawa, F.; Busch, D. H. Inorg. Chem.
1992, 31, 4002. (c) Muller, M.; Heileman, M. J.; Moore, H. W.;
̈
Schaumann, E.; Adiwidjaja, G. Synthesis 1997, 1997, 50.
(17) Monothiosquarate can be prepared by limiting the amount of
the thionating agent. Studies on the synthesis and catalyst properties of
monothiosquaramides will be reported in due course.
(18) Using the method of overlapping indicators (Bordwell’s
method), the pKa of dithiosquaramide A was determined to be
13.96, whereas that for the corresponding dioxosquaramide was 18.88.
(19) Please see Supporting Information for a summary of our
extensive studies on pKa determination of numerous squaramides and
thiosquaramides.
(20) Okino, T.; Hoashi, Y.; Furukawa, T.; Xu, X. N.; Takemoto, Y. J.
Am. Chem. Soc. 2005, 127, 119.
(21) Calculated for a single molecule in vacuum: Spartan ‘08,
Wavefunction, Inc., Irvine, CA.
(22) Similar to the situation with thioureas, in the absence of other
hydrogen bond acceptors, thiosquaramides crystallize in a head-to-tail
arrangement with each thiosquaramide unit perpendicular to the next
unit. See: Custelcean, R. Chem. Commun. 2008, 295.
(23) Please see Supporting Information for a comparison with
relevant thioureas and squaramides.
Nibbs, A. E.; Turkmen, Y. E.; Rawal, V. H. J. Am. Chem. Soc. 2013, 135,
̈
16050. (c) Manoni, F.; Connon, S. J. Angew. Chem., Int. Ed. 2014, 53,
2628.
(7) (a) Aciro, C.; Jones, L. H.; Storer, R. I. Chem. Soc. Rev. 2011, 40,
́
2330. (b) Aleman, J.; Parra, A.; Jiang, H.; Jørgensen, K. A. Chem. - Eur.
J. 2011, 17, 6890. (c) Auvil, T. J.; Schafer, A. G.; Mattson, A. E. Eur. J.
Org. Chem. 2014, 2014, 2633. (d) Chauhan, P.; Mahajan, S.; Kaya, U.;
Hack, D.; Enders, D. Adv. Synth. Catal. 2015, 357, 253.
(8) (a) Portell, A.; Barbas, R.; Braga, D.; Polito, M.; Puigjaner, C.;
Prohens, R. CrystEngComm 2009, 11, 52. (b) Prohens, R.; Portell, A.;
(24) Please see Supporting Information for a complete optimization
table.
Alcobe,
Bardia, M.; Bauza,
2014, 14, 2578. (d) Portell, A.; Bardia-Font, M.; Bauza,
A.; Prohens, R. CrystEngComm 2016, 18, 6437.
́
X. Cryst. Growth Des. 2012, 12, 4548. (c) Portell, A.; Font-
A.; Frontera, A.; Prohens, R. Cryst. Growth Des.
A.; Frontera,
(25) The conjugate addition products have long retention times and
broad peaks when examined by chiral HPLC, presumably a result of
their high acidity and the presence of significant enol content. The
chloro and bromo derivatives of the products (cf., 7f) form in
quantitative yield upon treatment with NCS or NBS, elute quickly, and
give sharper peaks.
́
́
(9) Ladder arrangement was also observed for the chiral, bifunctional
squaramide we had examined (see ref 5a). A reconstructed image from
the CIF file (Cambridge Structural Database Refcode: NOLRIQ;
CCDC No. 712821) from ref 5a is included in the Supporting
Information.
(10) The synthesis of achiral thiosquaramides was reported recently:
Busschaert, N.; Elmes, R. B. P.; Czech, D. D.; Wu, X.; Kirby, I. L.;
Peck, E. M.; Hendzel, K. D.; Shaw, S. K.; Chan, B.; Smith, B. D.;
Jolliffe, K. A.; Gale, P. A. Chem. Sci. 2014, 5, 3617.
D
DOI: 10.1021/jacs.7b01115
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX