Electrostatically Enhanced Thioureas

Article abstract of DOI:10.1021/acs.orglett.5b03213

A new class of readily prepared thiourea catalysts with one or more positively charged centers and no new hydrogen-bonding sites are exploited in several bond-forming reactions and are orders of magnitude more reactive than Schreiner's thiourea. These fin

Full text of DOI:10.1021/acs.orglett.5b03213

Letter
pubs.acs.org/OrgLett
Electrostatically Enhanced Thioureas
Yang Fan and Steven R. Kass*
Department of Chemistry, University of Minnesota, 207 Pleasant Street, SE, Minneapolis, Minnesota 55455, United States
S
* Supporting Information
ABSTRACT: A new class of readily prepared thiourea
catalysts with one or more positively charged centers and no
new hydrogen-bonding sites are exploited in several bond-
forming reactions and are orders of magnitude more reactive
than Schreiner’s thiourea. These findings provide the basis for
a new strategy for activating hydrogen-bond catalysts.
mall molecule metal-free hydrogen-bond catalysis has
Sbecome an active and vibrant research area over the past
two decades.1 Numerous classes of compounds have been
explored including binols,2 silane diols,3 squaramides,1e,4 and
α,α,α,α-tetraaryl-1,3-dioxolane-4,5-dimethanols (TADDOLs)5
among others, but no species have received more attention
than thioureas.6 Of these, N,N′-bis(3,5-bis(trifluoromethyl)-
phenyl)thiourea [(3,5-(CF3)2C6H3NH)2CS], also known as
Schreiner’s thiourea,7 occupies a privileged position because it
is an especially effective catalyst leading to relatively rapid
transformations. This has been attributed to its enhanced
acidity due to the four electron-withdrawing trifluoromethyl
groups8 and weak C−H···S hydrogen bonds that are thought to
play a factor in stabilizing the reactive Z,Z-conformer.7b,c
Cationic hydrogen bond donors such as amidinium,9
ammonium,10 guanidinium,11 pyridinium,12 and quinolinium13
ions also have been extensively explored.14 These species
correspond to protonated neutral bases and consequently are
more acidic than their corresponding conjugate bases. This may
account for their enhanced reactivities, but conformational
rigidity, changes in the binding site, and the potential use of an
additional hydrogen bond are also important contributing
effects. A different strategy for increasing the reactivity of
neutral hydrogen bond catalysts, especially in nonpolar solvents
where organic transformations of this sort are typically carried
out, is to incorporate a charged center without introducing a
new hydrogen bond site. A recent report by Berkessel et al.
exploiting this novel approach to develop Coulombic anion-
binding catalysts15 and our observation that the catalytic ability
of a phenol can be enhanced by orders of magnitude by the
presence of a charged site16 suggests that electrostatic
enhancement of hydrogen-bond catalysts is a new general
design strategy.17
and are found to be orders of magnitude more reactive in
nonpolar solvents.18
Figure 1. Thiourea catalysts employed in this work.
Mono- and di-N-methylpyridinium ions 3 and 4 were readily
synthesized starting with commercially available 3-amino-
pyridine (5) as illustrated in Figure 2. Thiophosgene was
used to convert this amine into its isothiocyanate,19 and this
product was subsequently alkylated with methyl iodide to afford
the corresponding pyridinium ion 7. This key intermediate was
reacted with aniline to afford the iodide salt of 3 (3I).
To explore this hypothesis, thioureas with one and two N-
methylpyridinium ion centers were prepared, and their
reactivities in several different types of transformations were
examined. These new catalysts were compared to N,N′-
diphenylthiourea (1) and Schreiner’s thiourea (2) (Figure 1)
Figure 2. Synthetic routes for thioureas 3 and 4.
Received: November 6, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b03213
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Alternatively, methylation of 3-aminopyridine occurs at the
more nucleophilic ring nitrogen atom,20 and the resulting
pyridinium iodide 8 was reacted with 7 to yield the doubly
charged thiourea derivative of 4 (4I). Both iodide salts have
limited solubilities in weakly polar solvents and presumably
form deactivating NH···I− hydrogen bonds so they were
converted to their tetrakis(3,5-bis(trifluoromethyl)phenyl)-
borate (BArF ) salts 3 and 4. These metathesis reactions were
4
readily accomplished by stirring 3I or 4I with NaBArF in
4
CH2Cl2.
To evaluate the catalytic activity of electrostatically enhanced
thioureas 3 and 4, the Friedel−Crafts alkylation of trans-β-
nitrostyrene with N-methylindole was examined in CDCl3 at
room temperature (eq 1). This transformation was chosen
Figure 3. Linear least-squares fit of the second-order Friedel−Crafts
rate constants vs (cat. %)2; k = 0.46(cat. %)2 − 0.70, r2 = 0.999; Table
1, entries 5−8.
Carrying out the Friedel−Crafts alkylation in a few different
solvents was also examined. Little impact was noted by
switching from CDCl3 to toluene-d8, but a 5-fold increase was
observed when the reaction was carried out in CD2Cl2. All
three of these solvents have dielectric constants of less than 10,
but the most polar one of these leads to the fastest
transformation. This may be a reflection of the aggregation
state of 4 in these solvents. In any case, the doubly charged
thiourea salt is soluble in nonpolar media and displays excellent
performance characteristics.
because the reaction rate has been observed to correlate with
the acidity of hydrogen bond catalysts, whereas acetic acid does
not promote this process.21,22 Second-order rate constants were
determined by monitoring the reaction via H NMR spectros-
copy, and the data are summarized in Table 1. Diphenylth-
1
We next turned our attention to the Diels−Alder reaction
between cyclopentadiene and methyl vinyl ketone (eq 2), in
Table 1. Kinetic Data for the Room-Temperature Friedel−
Crafts Reaction of trans-β-Nitrostyrene with N-Methylindole
entry cat. mol %
1
solvent
k (M−1 h−1
)
t1/2 (h)
1100
krel
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
C6D5CD3
CD2Cl2
2.8 × 10−3
3.9 × 10−3
1.1 × 10−1
7.1 × 10−1
45
2
1
2
3
4
4
4
4
4
4
10
10
10
10
5
820
0.035
1.0
3
29
part because Schreiner’s thiourea previously has been reported
to catalyze this transformation.7b At room temperature in
CDCl3 with 1 mol % of the catalyst, 2 accelerates this
cycloaddition by less than a factor of 1.5 relative to the
uncatalyzed process (Table 2). In contrast, the charge
4
4.5
6.5
5
0.071 (4.3 m)
0.29 (17 m)
3.5
410
6
11
7
2.5
9.1 × 10−1
1.6 × 10−2
14
8
1
5
5
200
9
0.23 (14 m)
0.058 (3.5 m)
Table 2. Diels−Alder Kinetic Data
10
55
a
entry
cat.
k (M−1 h−1
)
t1/2
krel
endo/exo
iourea 1 is a poor catalyst in that it only speeds up the
uncatalyzed process by a factor of 1.4, and more than a month
is needed for half of the starting material to be converted to
product. Schreiner’s thiourea is 28 times more effective than 1,
but this transformation is still slow and has a half-life of 29 h. N-
Methylpyridinium ion containing thioureas 3 and 4 are much
more active than 2 and have half-lives of 5 h and 4 min,
respectively. An acidic impurity in 3 or 4 acting as the active
catalyst was discounted since 1 mol % of p-toluenesulfonic acid
1
2
3
4
0.72
1.0
7.3
28
2.2 h
1.6 h
13 m
3.5 m
71:29
81:19
88:12
88:12
2
3
4
1.0
24
97
a
Corrected for the rate of the uncatalyzed reaction.
containing thioureas 3 and 4 enhance the background-corrected
rates by one and 2 orders of magnitude, respectively. The half-
life for the latter transformation is also under 4 min. As for the
selectivity, the major product is the endo isomer in each
instance as expected. Its relative contribution, however,
increases from 71% for the uncatalyzed process to 81% with
Schreiner’s thiourea and 88% when either 3 or 4 is used.
Lastly, the ring-opening aminolysis of styrene oxide with
aniline was explored under solvent free conditions (SFC, eq 3).
1
(p-TsOH) did not afford any observable product by H NMR
over 20 h. These results indicate that the one charged center in
3 is more effective than the four CF3 groups in 2 by a factor of
7, and that the presence of two cationic sites affords an even
more active catalyst that is 400 times more reactive.
Catalyst loading was explored for 4 (Table 1, entries 5−8),
and as expected the Friedel−Crafts reaction rate increases with
the amount of added catalyst. A linear dependence was not
observed, but a straight line was obtained from a plot of the
second-order rate constants versus the square of the catalyst
concentrations (Figure 3). This suggests that the dimer of 4 is
the active catalyst in this transformation, which is consistent
with a previous report on thiourea catalysts.23
B
DOI: 10.1021/acs.orglett.5b03213
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Product formation was monitored for each transformation and
zero and first-order processes were found to fit the data
depending upon which catalyst, if any, was used. Consequently,
qualitative results are reported (Table 3), but it is apparent that
ACKNOWLEDGMENTS
■
Generous support from the National Science Foundation is
gratefully acknowledged.
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■
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.5b03213.
Experimental procedures, NMR spectra, and reaction
data (PDF)
AUTHOR INFORMATION
Corresponding Author
■
(14) Bolm, C.; Rantanen, T.; Schiffers, I.; Zani, L. Angew. Chem., Int.
Ed. 2005, 44, 1758.
*E-mail: kass@umn.edu.
Notes
(15) Berkessel, A.; Das, S.; Pekel, D.; Neudorfl, J.-M. Angew. Chem.,
̈
The authors declare no competing financial interest.
Int. Ed. 2014, 53, 11660.
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DOI: 10.1021/acs.orglett.5b03213
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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DOI: 10.1021/acs.orglett.5b03213
Org. Lett. XXXX, XXX, XXX−XXX