New architectures in hydrogen bond catalysis

Article abstract of DOI:10.1016/j.tetlet.2009.09.129

New achiral sulfamide, phosphoric triamide, and thiophosphoric triamide compounds have been synthesized. Their activity as hydrogen bond catalysts for the Friedel-Crafts and Baylis-Hillman reactions compares favorably with that of a known and an active th

Full text of DOI:10.1016/j.tetlet.2009.09.129

Tetrahedron Letters 50 (2009) 6830–6833
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
New architectures in hydrogen bond catalysis
*
Andrew A. Rodriguez, Hoseong Yoo, Joseph W. Ziller, Kenneth J. Shea
Department of Chemistry, University of California, Irvine, Irvine, CA 92697-2025, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 8 July 2009
Revised 19 September 2009
Accepted 21 September 2009
Available online 25 September 2009
New achiral sulfamide, phosphoric triamide, and thiophosphoric triamide compounds have been synthe-
sized. Their activity as hydrogen bond catalysts for the Friedel–Crafts and Baylis–Hillman reactions com-
pares favorably with that of a known and an active thiourea catalyst. The new compounds were also
studied by X-ray crystallography and their solid state structures are described.
Ó 2009 Elsevier Ltd. All rights reserved.
Hydrogen bonding is a ubiquitous force in nature. Not until rel-
atively recently have chemists begun to implement this force in
catalysis, but already with extraordinary success.1 The majority
of hydrogen bonding (HB) catalysts incorporate the thiourea func-
tional group.2 Advantages of the thiourea include air and water sta-
bility, ease of synthesis and modification, and activity toward a
wide range of substrates.
S
O
P
S
P
O
O
Ar
Ar
Ar
Ar
Ar
S
Ar
Ar
Ar
N
H
N
H
N
H
N
H
N
H
N
H
N
H
N
H
Ar
Ar
N
N
H
H
thiourea
sulfamide
phosphoric
triamide
thiophosphoric
triamide
Figure 1. The sulfamide, phosphoric triamide, and thiophosphoric triamide
Despite their success, thiourea catalysts suffer from some sig-
nificant disadvantages. First, they have relatively weak activity,
frequently necessitating high catalyst loading and/or long reaction
times to achieve a satisfactory yield. A more active HB catalyst
would be desirable. The second concern for the thiourea function-
ality is its sensitivity to heat. At elevated temperatures (>75 °C),
some thiourea catalysts have been reported to decompose.3
Although the majority of HB-catalyzed reactions are run at or be-
low room temperature, a more thermally robust catalyst could al-
low for a more versatile catalyst system.
Several non-thiourea HB catalysts have been developed as po-
tential alternatives. These can be categorized into neutral and pro-
tonated catalysts. Notable examples of the neutral compounds
include those based on squaramide,4 sulfonamide,5 and urea-N-
sulfoxide6 structures. Protonated catalysts include those based on
guanidinium,7 quinolinium thioamide,8 and ammonium9 struc-
tures. While the latter catalysts tend to activate electrophiles more
strongly than the former, due to their increased acidity, they are
incompatible with basic functionality. This serves to limit sub-
strate scope and places restrictions on the catalyst design. Based
on this consideration, we focused on improved neutral thiourea
alternatives. Our aim was to develop new neutral molecular de-
signs that display improved catalytic activity over the thiourea mo-
tif. We focus in this Letter on the relative catalytic efficiency of
these structural motifs.
structures.
CF3
CF3
CSCl2, NEt3
S
CH2Cl2
F3C
N
H
N
H
CF3
65%
1
CF3
CF3
SO2Cl2, NEt3
O
O
CH2Cl2
S
F3C
N
N
H
CF3
CF3
H
35%
2
CF3
CF3
F3C
NH2
CF3
CF3
O
POCl3, NEt3
P
N
H
100 oC, neat
F3C
N
N
H
H
49%
3
CF3
CF3
CF3
CF3
CF3
S
PSCl3, NEt3
P
N
H
F3C
N
H
N
100 ºC, neat
H
72%
4
CF3
* Corresponding author. Tel.: +1 949 824 5844; fax: +1 949 824 2210.
E-mail address: kjshea@uci.edu (K.J. Shea).
Scheme 1. Synthesis of sulfamide 2, phosphoric triamide 3, and thiophosphoric
triamide 4.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.09.129

A. A. Rodriguez et al. / Tetrahedron Letters 50 (2009) 6830–6833
6831
We identified three motifs as the promising candidates: (i)
sulfamides, (ii) phosphoric triamides, and (iii) thiophosphoric
triamides. All the structures, like thioureas, join two or more
amide-like groups to a single electron-withdrawing atom (Fig. 1).
As such, they were expected to exhibit a similar mode of activity
toward common substrates. Replacement of the thiocarbonyl
group with sulfone, phosphorus oxide, or phosphorus sulfide teth-
ers however was anticipated to give these compounds modified,
perhaps improved, binding properties. In addition, the phosphoric
triamide and thiophosphoric triamide would hold a potential ki-
netic binding advantage as a consequence of the third active
hydrogen bond. All three structures exhibit exceptional hydrogen
bonding ability in the solid state,10 yet to our knowledge none have
been utilized as HB catalysts.
For this study, the thiourea catalyst 1 designed by Schrein-
er2a was used for comparison purposes. This catalyst represents
one of the most active and versatile thiourea catalysts known.
The corresponding sulfamide 2, phosphoric triamide 3, and thio-
phosphoric triamide 4 were synthesized as shown in Scheme 1.
Sulfamide 2 was prepared using a procedure developed for thio-
urea 1, in which sulfuryl chloride was treated with 3,5-bis(tri-
fluoromethyl)aniline in the presence of triethylamine.
A
modified procedure, with elevated temperature in the absence
of solvent, was necessary to synthesize phosphoric triamide 3
and thiophosphoric triamide 4. The three new structures 2–4
would allow a direct comparison between the thiourea, sulfam-
ide, phosphoric triamide, and thiophosphoric triamide groups as
HB catalysts.
Figure 2. Solid state structures of compounds 1, 2, 3, and 4. Packing behavior and hydrogen bonding networks are shown with selected bond distances and angles
highlighted.

6832
A. A. Rodriguez et al. / Tetrahedron Letters 50 (2009) 6830–6833
O
The target molecules 2–4 were isolated as crystalline solids, and
CHO
O
OH
Ph
cat. (10 mol%)
X-ray crystal structures were solved for each one (see Fig. 2). The
solid state structure of thiourea 1 has been previously solved,11
and was used for comparison. In all cases, the compounds formed
three-dimensional hydrogen bonding networks. Thiourea 1 exists
almost completely flat in the solid state, forming linear hydrogen
bonding chains that involves double hydrogen bonding typical of
ureas and thioureas.12 Hydrogen bonds were 2.54 Å in length, mea-
sured from the hydrogen atom to the acceptor atom, with a 158°
NHS angle. In contrast to the thiourea’s flat structure, sulfamide
2 adopted a folded configuration in the crystal. It formed linear
intermolecular hydrogen-bonded chains with two 2.05 Å hydrogen
bonds between each pair of neighboring molecules, each of which
had an NHO angle of 172°. Phosphoric triamide 3 adopted a par-
tially folded conformation, with two parallel N–H bonds. It also
formed linear chains, but with only one 1.96 Å hydrogen bond be-
tween each pair of neighboring molecules with an NHO angle of
175°. Thiophosphoric triamide 4 adopted a similar conformation
as that of 3, but its extended crystal structure consisted of isolated,
loosely associated dimers with weaker 2.60 Å hydrogen bonds at
NHS angles of 165°. Compared to thiourea 1, each of the new com-
pounds 2–4 displayed a similar ability to donate organized and
directional hydrogen bonds, suggesting a potential for catalytic
activity.
A study to assess catalytic activity was next initiated. The Fri-
edel–Crafts reaction between N-methyl indole and b-nitrostyrene
was chosen as the first test reaction to compare the catalytic activ-
ity of compounds 1–4. Thioureas have previously been shown to be
competent catalysts for this transformation.13 With a threefold ex-
cess of indole starting material, pseudo-first order kinetics were
observed, and the relative rate constants were measured for each
catalyst. The results are summarized in Scheme 2. All the new com-
pounds 2–4 exhibited some catalytic activity for the chosen reac-
tion, placing them in the category of HB catalysts for the first
time. Furthermore, thiophosphoric triamide 4 displayed a 2.6-fold
increase in activity compared to thiourea 1.
MeO
MeO
DABCO, neat
rt
(10 equiv.)
cat.
krel
% conv. (48 h)
none
0.5
1.0
1.5
1.1
1.3
32%
58%
73%
59%
67%
1
2
3
4
Scheme 3. Catalyst comparison for the Baylis–Hillman reaction of methyl acrylate
with benzaldehyde.
In summary, the three new compounds 2–4 were synthesized
as candidates for HB catalysts. The compounds exhibit extensive
hydrogen bonding in the solid state. Each of the three compound
types showed activity as HB catalysts. Furthermore, modest
improvements (1.5–2.6-fold) were observed for selected Friedel–
Crafts and Baylis–Hillman reactions when compared to the corre-
sponding thiourea catalyst. In consideration of the relatively slow
rates for many known HB catalysts, the modest rate enhancements
exhibited by the sulfamides, phosphoric triamides, and thiophos-
phoric triamides represent fertile territory for the development
of new, more efficient HB catalyst designs.
Future work will involve asymmetric catalyst development. The
fact that catalysts 2–4 adopt three-dimensional structures as
opposed to the thiourea’s preferred flat structure is expected to
aid in creating compounds with unique chiral space. In the case
of phosphoric triamides and thiophosphoric triamides, the phos-
phorus atom itself can serve as a chiral center. Work in this project
is ongoing.
Acknowledgments
The Baylis–Hillman reaction between methyl acrylate and
benzaldehyde was also examined with catalysts 1–4. As in the pre-
vious reaction, thioureas have been used successfully to catalyze
this transformation.14 Following the literature protocol,15 the reac-
tions were carried out neat at room temperature with 1,4-diazabi-
cyclo[2.2.2]octane (DABCO) as a co-catalyst (Scheme 3). With a 10-
fold excess of methyl acrylate compared to benzaldehyde, this
reaction also exhibited pseudo-first order behavior, so relative rate
constants were calculated. As in the first example, all catalysts 2–4
showed activity, but this time all were equal to or slightly more
effective than the reference catalyst 1. Interestingly, sulfamide 2
catalyzed the reaction at the fastest rate, 50% faster than thiourea
1.
This work was supported by a grant from the NIH. H.Y. is grate-
ful for the support from the University Research Opportunities
Program.
Supplementary data
Supplementary data (experimental methods and selected 1H
and 13C NMR data) associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.09.129.
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with b-nitrostyrene.

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