31P NMR Spectroscopically Quantified Hydrogen-Bonding Strength of Thioureas and Their Catalytic Activity in Diels-Alder Reactions

Article abstract of DOI:10.1002/ejoc.201402871

The hydrogen-bonding strength of a variety of commonly employed thiourea catalysts was quantified by using a trialkylphosphine oxide as a ³¹P NMR probe. Simple diarylthioureas and more complex bifunctional amine- and hydroxy-substituted thiourea derivatives were examined. Their catalytic activity was determined in a Diels-Alder reaction, and the obtained pseudo-first-order rate constants were correlated with the ³¹P NMR chemical shifts. A linear correlation between both variables was observed throughout the functionalized thioureas. The ³¹P NMR probe correlation fared better in comparison to a pK _a correlation. Accordingly, the quantification presented herein by using a ³¹P NMR probe offers an elegant way to estimate the catalytic activity of thiourea catalysts in hydrogen-bond-activated reactions such as the Diels-Alder reaction. The correlation of ³¹P NMR shift values [Δδ(³¹P)] for the determination of hydrogen-bond strengths of thiourea derivatives with kinetic data [ln (k _rel)]of thiourea-catalyzed Diels-Alder reactions is evaluated. A Hammett-type plot provides a more reliable correlation than the correlation of kinetic data with the pK _a values of the thiourea derivatives.

Full text of DOI:10.1002/ejoc.201402871

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201402871
31P NMR Spectroscopically Quantified Hydrogen-Bonding Strength of
Thioureas and Their Catalytic Activity in Diels–Alder Reactions
Alexander R. Nödling,[a] Gergely Jakab,[b] Peter R. Schreiner,[b] and Gerhard Hilt*[a]
Keywords: Hydrogen bonds / Cycloaddition / Kinetics / NMR spectroscopy / Lewis acids / Thioureas
The hydrogen-bonding strength of a variety of commonly
employed thiourea catalysts was quantified by using a trialk-
ylphosphine oxide as a 31P NMR probe. Simple diarylthio-
ureas and more complex bifunctional amine- and hydroxy-
between both variables was observed throughout the func-
tionalized thioureas. The 31P NMR probe correlation fared
better in comparison to a pKa correlation. Accordingly, the
quantification presented herein by using a 31P NMR probe
substituted thiourea derivatives were examined. Their cata- offers an elegant way to estimate the catalytic activity of thio-
lytic activity was determined in a Diels–Alder reaction, and
the obtained pseudo-first-order rate constants were corre-
lated with the 31P NMR chemical shifts. A linear correlation
urea catalysts in hydrogen-bond-activated reactions such as
the Diels–Alder reaction.
transfer hydrogenations,[10] have shown no correlation be-
tween pKa values and thiourea catalyst reactivity. As a con-
sequence, the Brønsted acidity of thioureas cannot be ac-
counted as a sole measure of their catalytic activity.
Introduction
Hydrogen-bond-donor catalysis in asymmetric organic
synthesis has been a flourishing field over the last dec-
ades.[1,2] Amongst numerous catalysts applied, thioureas
have distinguished themselves because of their straightfor-
ward, flexible preparation as well as their diverse reaction
scope. They have found application as mild organic “Lewis
acids”,[3] as bifunctional amine catalysts capable of dual
substrate activation,[4] and as co-catalysts in complex multi-
catalytic reactions.[5] Many efforts have been made to ex-
plore further catalyst structures, reactivities, and related
mechanisms. On the contrary, only few systematic attempts
have been made to probe the influence of fundamental
properties, such as steric and electronic substituent effects,
on the reactivity of thioureas.[6] A seemingly logical param-
eter affecting their reactivity are their pKa values. Hence,
pKa scales for thioureas have been established and a link
between the pKa values and the catalytic activities has been
proposed.[7,8]
Figure 1. Classes of thioureas investigated by Cheng regarding a
structure–activity relationship between their catalytic activity in
Michael reactions and their pKa values.[8]
In previous work, we examined possible correlations be-
tween quantified strengths of Lewis acids by using NMR
probes 4 and 5 (Figure 2) and their catalytic activity.[11,12]
Furthermore, structure–activity relationships between
the pKa values of three classes of tertiary amine–thioureas
and their activity in Michael additions have been found
(Figure 1).[8] The studies were limited to these classes of
thioureas and more acidic, non-bifunctional thioureas such
as Schreiner’s catalyst remain unexamined. In contrast,
some reactions, for example, Diels–Alder reactions[9] and
Figure 2. Nitrogen-donor-based 2H NMR probes 4 and 5 for the
quantification of metal halide and silicon based Lewis acids.[11,12]
Given that the activation mode of carbonyl functionali-
ties by thioureas has been proposed to be similar to that of
common Lewis acids,[3] we became interested in employing
our approach for the quantification of thiourea efficacy.
During our first experiments on this topic, Kozlowski et al.
published an intriguing article, in which they pursued a sim-
ilar strategy on the correlation between the catalytic activity
[a] Fachbereich Chemie, Philipps-Universität Marburg,
Hans-Meerwein-Strasse, 35043 Marburg, Germany
E-mail: Hilt@chemie.uni-marburg.de
http://www.uni-marburg.de/fb15/ag-hilt/
[b] Institut für Organische Chemie der Justus-Liebig-Universität,
Heinrich-Buff-Ring 58, 35392 Giessen, Germany
E-mail: prs@uni-giessen.de
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201402871.
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Eur. J. Org. Chem. 2014, 6394–6398

Hydrogen-Bonding Strength of Thioureas
of a few simple hydrogen-bonding donors and the blueshifts
in the UV/Vis spectra inflicted by them upon coordinating
a colorimetric sensor.[9] The colorimetric sensor used in this
study was previously employed to quantify the strength of
Lewis acids,[13] which encouraged us to use NMR probes to
quantify the hydrogen-bonding strength of thioureas.
Results and Discussion
Upon Lewis acid complexation, previously used deuter-
2
ium-labeled nitrogen-donor H NMR probes 4 and 5 show
2
a distinct H NMR downfield shift, Δδ(2H), that is consid-
ered as a measure of the strength of the respective Lewis
acid. As N–H··N hydrogen bonds are rather weak, probes
4 and 5 seemed less suitable to quantify the hydrogen-bond-
ing strength of thiourea catalysts, and we shifted our focus
on more Lewis basic probes. Phosphine oxides were intro-
duced by Gutmann as Lewis acidity probes[14] and were re-
seized by Beckett to quantify mild boron-based Lewis
acids;[15] furthermore, they are more Lewis basic than both
4 and 5, resemble carbonyl groups, which are often targeted
by thioureas, and offer an easy and fast application as a
probe through 31P NMR shift quantification.[16]
Therefore, we selected tri-n-butylphosphine oxide (6) as
a
31P NMR probe. Upon hydrogen-bond formation be-
tween the oxygen atom of 6 and the acidic thiourea
hydrogen atoms an electron density shift towards the thio-
urea is expected.[16] This should result in a downfield shift
in the 31P NMR signal for 6a (Scheme 1).
Figure 3. Thioureas 7–11 and thiophosphoramide 12 used in the
present study.
Scheme 1. Working model for the quantification of thiourea
hydrogen-bonding strength by 31P NMR shifts.
In our initial attempt, we employed thioureas 7a, 8c, 7c,
and 10 in titration experiments with phosphine oxide 6.
These thioureas were expected to exhibit different
hydrogen-bonding strengths, as a varying number of elec-
tron-withdrawing CF3 groups[7b] and aryl substituents and
a second thiourea subunit in proximity to the first are in-
stalled (Figure 3). All three features are known to lower the
pKa value of thiourea derivatives.[7] Phosphine oxide 6 was
titrated by successively increasing the amount of thiourea
by adding a thiourea stock solution and monitoring the
31P NMR shift of the adduct of type 6a. Indeed, the four
thioureas inflicted varyingly strong 31P NMR downfield
shifts to yield the order 7aϾ8cϾ7cϾ10 (Figure 4). In each
case, saturation of the shift was observed, but the smaller
Figure 4. Plot of the 31P NMR shift change Δδ(31P) of phosphine
oxide 6 upon titration with four different thioureas. 6: δ(31P,
CH2Cl2) = 47.23 ppm.
Whereas the order of 7a, 7c, and 10 was expected from
the maximum shift value was the more equivalents of the an empirical point of view as well as from the correspond-
thiourea were necessary to reach saturation. Such findings ing pKa values (Table 1), 8c Ͼ 7c is surprising, as 7c was
have been reported for simple metal halide Lewis acids[11] found to possess a lower pKa value than 8c.[7] This compari-
as well as for hydrogen-bond donors.[9]
son already showed a first discrepancy between the quanti-
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6395

A. R. Nödling, G. Jakab, P. R. Schreiner, G. Hilt
SHORT COMMUNICATION
fied Lewis acidity and the pKa values of hydrogen-bond- expectations based on the electron-withdrawing ability of
donor catalysts, which is in accordance with Kozlowski’s the exchanged substituents. Inconsistent results were ob-
observations.[9]
tained for thiourea classes 8 and 9. Whereas only a small
influence of the different backbones on the Δδ(31P) values
was found for the pairs 8b/9b (6.10/5.52 ppm) and 8c/9c
(7.05/7.36 ppm), a large discrepancy was found for 8a/9a
(4.56/5.99 ppm).
Table 1. Δδ(31P) NMR shift values upon coordination of the em-
ployed hydrogen-bond donors to 6, kobs values for the examined
Diels–Alder reaction, Scheme 2, and pKa values.
[c]
Catalyst
Δδ(31P) / ppm[a]
kobs / 10–2 min–1[b]
pKa
To probe the predictive power of the quantified thiourea
Lewis acidities, a potential correlation between the latter
and the catalytic activity of the thiourea catalysts was inves-
tigated. We chose the Diels–Alder reaction between cyclo-
pentadiene (13) and methyl vinyl ketone (14) to determine
rate constants (Scheme 2). Rate accelerations by Lewis
acids in Diels–Alder reactions of α,β-unsaturated carbonyls
are based on the LUMO-lowering effect of electron-de-
ficient Lewis acids[21] and, accordingly, the amount of rate
acceleration is directly linked to the strength of a Lewis
acid.[22] In that line, a correlation between the Δδ(31P) val-
ues and the Diels–Alder reaction rate constants should be
observed.
none
7a
7b
7c
7d
8a
8b
8c
8d
9a
9b
9c
10
11
12
0
1.733Ϯ0.077
3.947Ϯ0.046
2.831Ϯ0.045
2.061Ϯ0.127
1.809Ϯ0.033
1.746Ϯ0.079
1.865Ϯ0.067
2.821Ϯ0.016
1.691Ϯ0.049
1.912Ϯ0.020
1.837Ϯ0.011
3.182Ϯ0.059
1.766Ϯ0.024
2.370Ϯ0.133
4.278Ϯ0.217
–
7.95
7.51
6.71
6.01
4.56
6.10
7.05
1.75
5.99
5.52
7.36
5.33
9.00
9.17
8.5
≈9.7[d]
10.9
12.1
≈13.4[d]
–
11.98
≈18.0[d]
≈13.4[d]
–
≈12.0[d]
12.39
12.98
–
[a] Conditions according to GP1: 6 (2.29 μmol), catalyst (up to
175 equiv.), absolute CH2Cl2, 2.0 mL final volume, see the Support-
ing Information for detailed information. [b] Reaction conditions
according to GP2: 1.0 m 13, 0.1 m 14, 0.01 m catalyst, absolute
CDCl3, 0.7 mL total volume, NMR tube, 300 K, see the Support-
ing Information for detailed information. [c] Taken from ref.[7]
[d] Estimation based on ref.[7]
Scheme 2. Investigated Diels–Alder reaction to determine the cata-
lytic activity of the thioureas and thiophosphoramide 12.
After having identified a suitable NMR probe in phos-
phine oxide 6, we examined a broader range of thioureas,
including thiourea classes such as those introduced by
The reactions were performed under identical conditions
Schreiner, 7a;[1h,3] Soós, 10;[17] and Ricci, 11,[18] which con- by using 10 equivalents of cyclopentadiene (13) and 10 mol-
tain various structural elements and chiral scaffolds (Fig- % of the thiourea catalysts to obtain pseudo-first-order ki-
ure 3, Table 1). Thiophosphoramide 12 has been shown to netics with respect to 14. The reaction progress was moni-
be even more reactive than 7a in Diels–Alder reactions,[19] tored by 1H NMR spectroscopy by integration of the
and it was subsequently included to add another strong methyl group of substrate 14 and the methyl groups of exo-
hydrogen-bonding catalyst with a similar structure and 15 and endo-15 (see the Supporting Information). Indeed,
binding motif. The shifts were determined by adding mul- an exponential decrease in [14] was observed, which is in-
tiple equivalents of hydrogen-bond-donors 7–12 to probe 6 dicative of pseudo-first-order kinetics. Only 8b showed
until no further shifts in the 31P NMR signals were ob- slight deviations. In that case, reversible formation of an
served. Additionally, the influence of a trace amount of enamine between 8b and 14 or 15 might be possible through
water was found to have a negligible effect on the Δδ(31P) the primary amine functionality of 8b; however, similar be-
values (see the Supporting Information), by the addition of havior was not observed for 9b. Taking this into account,
1 μL of deionized water after the final measurement. Fi- rate constants were calculated for all catalysts (up to 80%
nally, the expected 1:1 complex stoichiometry between conversion), and very good R2 values of at least 0.9999 were
probe 6 and the thioureas, shown in Scheme 1, was verified obtained. At least three runs were conducted for every cata-
by using Job’s method[20] for some exemplary thioureas (see lyst, and the mean values of the reaction rates are given
the Supporting Information).
in Table 1. In agreement with the NMR experiments, the
The trend observed for the initially examined thioureas influence of a trace amount of water was found to have
was continued for the new set of thioureas. Larger a minor influence on the reaction rate constants (see the
31P NMR downfield shifts were found for thioureas bearing Supporting Information). The observed reactivities of the
more electron-withdrawing substituents. This is easily seen thiourea catalysts are rather small compared to those of
in the series of diphenylthiourea derivatives 7a–d. An in- common Lewis acids but nonetheless cover a broad range.
creased number of CF3 substituents resulted in increased For example, dialkylthiourea 8d does not catalyze the reac-
Δδ(31P) values, analogous to their pKa values.[7] Another tion, whereas thiophosphoramide 12 yields a significant
example of substituent effects on the Δδ(31P) values is no- rate acceleration.
ticeable in switching from 8d [Δδ(31P) = 1.75 ppm] over 8a
Having data of both the quantified hydrogen-bonding
[Δδ(31P) = 4.56 ppm] to 8c [Δδ(31P) = 7.05 ppm], and ending strength and the catalytic activity in hand, we set out to
with 7a [Δδ(31P) = 7.95 ppm]. This order matches well with determine a possible connection. A Hammett-type plot of
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Eur. J. Org. Chem. 2014, 6394–6398

Hydrogen-Bonding Strength of Thioureas
Figure 6. Overlay of plots of the ln(krel) values of the Diels–Alder
reaction between 13 and 14 and the 31P NMR shifts (diamonds) as
well as pKa values (squares, Table 1). Dashed line: fit of Δδ(31P)
values, R2 = 0.72315, including 11. Dotted line: fit of pKa values,
R2 = 0.30673.
Figure 5. Hammett-type plot of the ln(krel) values of the Diels–
Alder reaction versus the thiourea-induced 31P NMR shifts. Com-
pounds 11 and 12 were excluded from the linear fit. For calculation
of the ln(krel) values, see the Supporting Information.
Conclusions
the measured rate constants versus the 31P NMR shifts is
given in Figure 5.
With the results presented herein we were able to identify
a phosphine oxide based NMR probe that was able to qual-
itatively predict the reactivity of a broad range of structur-
ally diverse thioureas by utilizing a simple and robust pro-
cedure. We obtained a satisfying correlation between
hydrogen-bonding strength in terms of Δδ(31P) values, de-
termined with the NMR probe, and the ln(krel) values of a
Diels–Alder reaction. Our findings are in line with and ex-
pand on those of Kozlowski et al., namely, that at least for
transformations such as Diels–Alder reactions that are gov-
erned by the LUMO-lowering strength of a thiourea,
probes originating from Lewis acid quantification studies
are more accurate than simple pKa values. Additional func-
tional groups, other than amines, such as a hydroxy group
in 11 have a distinct effect on the reactivity of such thio-
urea-based catalysts and deviate for the amine-modified
thioureas. Whether or not these conclusions hold true for
other reactions as well will be the focus of ongoing studies
in our groups.
Overall, a good linear correlation between both variables
ln(krel) and Δδ(31P) was observed. Accordingly, a higher
Δδ(31P) value translates into a higher reaction rate and,
hence, catalytic activity. Two outliers, 11 and 12, were ob-
served; their catalytic activities are smaller than the Δδ(31P)
values would suggest. A reason for this could be the effect
of a possible threefold hydrogen bond, at least in the case
of catalyst 12. Despite this exception, the approach of using
phosphine oxide 6 as a probe for the catalytic activity of
structurally diverse thioureas seems valid. Yet, it should be
noted that this correlation has to be seen as qualitative, con-
sidering the good but not excellent R2 value.
As mentioned above, pKa values are often used as refer-
ences for the activity of thiourea catalysts. Therefore, a
comparison between correlations of both Δδ(31P) as well as
pKa values with the ln(krel) values was evoked (Table 1).
The overlay of both plots is shown in Figure 6. The y axis
for the Δδ(31P) values is inverted to match the pKa scale.
The comparison shows a better correlation of the ln(krel)
values with the Δδ(31P) values (R2 = 0.723, in this case in-
cluding the value for 11 for accurate comparison) than with
the pKa values (R2 = 0.307). Apparently, the 31P NMR ap-
proach is more suitable for the evaluation of the catalytic
activity of thioureas than the pKa values. This finding is in
line with reports by Schreiner[7] and Kozlowski,[9] in which
it was concluded that pKa values can be misleading and are
only an incomplete measure for predicting catalytic efficacy.
A possible reason may be the activation mode, as the Diels–
Alder reaction examined by Kozlowski[9] and us is domi-
nated by Lewis acid like behavior, whereas studies by
Cheng[8] focused on reactions in need of an additional
amine functionality to act as a Brønsted base in dual acti-
vation processes.
Experimental Section
Supporting Information (see footnote on the first page of this arti-
cle): Experimental procedures for the NMR quantification and ki-
netic experiments, NMR spectra of previously unknown com-
pounds, additional data and models for the calculation of reaction
rate constants, and Job plots.
Acknowledgments
G. H. thanks the Deutsche Forschungsgemeinschaft (DFG) for fin-
ancial support. The authors thank Dr. Hon Man Yau for construc-
tive comments on this work.
Eur. J. Org. Chem. 2014, 6394–6398
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A. R. Nödling, G. Jakab, P. R. Schreiner, G. Hilt
SHORT COMMUNICATION
study of the privileged 3,5-bis(trifluoromethyl)phenyl group,
see: K. M. Lippert, K. Hof, D. Gerbig, D. Ley, H. Hausmann,
S. Guenther, P. R. Schreiner, Eur. J. Org. Chem. 2012, 5919–
5927.
[1] Selected, early examples of hydrogen-bond-donor catalysis: a)
H. Hiemstra, H. Wynberg, J. Am. Chem. Soc. 1981, 103, 417–
429; b) J.-I. Oku, S. Inoue, J. Chem. Soc., Chem. Commun.
1981, 229–230; c) U.-H. Dolling, P. Davis, E. J. J. Grabowski,
J. Am. Chem. Soc. 1984, 106, 446–447; d) J. Hine, S.-M. Lin-
den, V. M. Kanagasabapathy, J. Am. Chem. Soc. 1985, 107,
1082–1083; e) T. R. Kelly, P. Meehani, V. S. Ekkundi, Tetrahe-
dron Lett. 1990, 31, 3381–3884; f) D. P. Curran, L. H. Kuo, J.
Org. Chem. 1994, 59, 3259–3261; g) M. S. Sigman, E. N. Ja-
cobsen, J. Am. Chem. Soc. 1998, 120, 4901–4902; h) A.
Wittkopp, P. R. Schreiner, Diels–Alder Reactions in Water and
in Hydrogen-Bonding Environments, in: The Chemistry of Dienes
and Polyenes (Ed.: Z. Rappoport), Wiley, Chichester, UK,
2000, vol. 2, p. 1029–1088.
[2] Recent reviews of hydrogen-bond-donor catalysis: a) P. R.
Schreiner, Chem. Soc. Rev. 2003, 32, 289–296; b) A. G. Doyle,
E. N. Jacobsen, Chem. Rev. 2007, 107, 5713–5743; c) Z. Zhang,
P. R. Schreiner, Chem. Soc. Rev. 2009, 38, 1187–1198; d) J.
Alemán, A. Parra, H. Jiang, K. A. Jørgensen, Chem. Eur. J.
2011, 17, 6890–6899; e) K. M. Lippert, K. Hof, P. R. Schreiner,
Hydrogen-Bonding Catalysis: (Thio)urea Catalysis, in: Science
of Synthesis (Eds.: K. Maruoka, B. List), Thieme, Stuttgart,
Germany, 2012, p. 297–412; f) R. C. Wende, P. R. Schreiner,
Green Chem. 2012, 14, 1821–1849; g) O. V. Serdyuk, C. M.
Heckel, S. B. Tsogoeva, Org. Biomol. Chem. 2013, 11, 7051–
7071.
[3] a) P. R. Schreiner, A. Wittkopp, Org. Lett. 2002, 4, 217–220; b)
A. Wittkopp, P. R. Schreiner, Chem. Eur. J. 2003, 9, 407–414.
[4] First example: T. Okino, Y. Hoashi, Y. Takemoto, J. Am. Chem.
Soc. 2003, 125, 12672–12673; for other examples, see ref.[2]
[5] For selected recent examples, see: a) S. Lin, L. Deiana, G.-L.
Zhao, J. Sun, A. Córdova, Angew. Chem. Int. Ed. 2011, 50,
7624–7630; Angew. Chem. 2011, 123, 7766–7772; b) H. Y. Kim,
K. Oh, Org. Lett. 2011, 13, 1306–1309; c) N. Z. Burns, M. R.
Witten, E. N. Jacobsen, J. Am. Chem. Soc. 2011, 133, 14578–
14581; d) Y. Wang, T.-Y. Yu, H.-B. Zhang, Y.-C. Luo, P.-F. Xu,
Angew. Chem. Int. Ed. 2012, 51, 12339–12342; Angew. Chem.
2012, 124, 12505–12508.
[8] pKa values and structure–activity relationship: X. Li, H. Deng,
B. Zhang, J. Li, L. Zhang, S. Luo, J.-P. Cheng, Chem. Eur. J.
2010, 16, 450–455.
[9] P. N. H. Huynh, R. R. Walvoord, M. C. Kozlowski, J. Am.
Chem. Soc. 2012, 134, 15621–15623.
[10] N. J. A. Martin, L. Ozores, B. List, J. Am. Chem. Soc. 2007,
129, 8976–8977.
[11] G. Hilt, F. Pünner, J. Möbus, V. Naseri, M. A. Bohn, Eur. J.
Org. Chem. 2011, 5962–5966.
[12] a) G. Hilt, A. Nödling, Eur. J. Org. Chem. 2011, 7071–7075; b)
A. R. Nödling, K. Müther, V. H. G. Rohde, G. Hilt, M. Oest-
reich, Organometallics 2014, 33, 302–308.
[13] a) S. Fukuzumi, K. Ohkubo, Chem. Eur. J. 2000, 6, 4532–4535;
b) K. Okhubo, T. Suenobu, H. Imohori, A. Orita, J. Otera,
S. Fukuzumi, Chem. Lett. 2001, 978–979; c) S. Fukuzumi, K.
Ohkubo, J. Am. Chem. Soc. 2002, 124, 10270–10271.
[14]
U. Mayer, V. Gutmann, W. Gerger, Monatsh. Chem. 1975, 106,
1235–1257.
M. A. Beckett, G. C. Strickland, J. R. Holland, K. S. Varma,
Polymer 1996, 37, 4629–4631.
[15]
[16] For recent examples with the use of the Gutmann–Beckett
method, see: a) G. J. P. Britovsek, J. Ugolotti, A. J. P. White,
Organometallics 2005, 24, 1685–1691; b) G. C. Welch, L. Cab-
rera, P. A. Chase, E. Hollink, J. D. Masuda, P. Wei, D. W. Ste-
phan, Dalton Trans. 2007, 3407–3414; c) A. E. Ashley, T. J.
Herrington, G. G. Wildgoose, H. Zaher, A. L. Thompson,
N. H. Rees, T. Krämer, D. O’Hare, J. Am. Chem. Soc. 2011,
133, 14727–14740; d) M. Mewald, R. Fröhlich, M. Oestreich,
Chem. Eur. J. 2011, 17, 9406–9414; e) A. Schnurr, M. Bolte,
H.-W. Lerner, M. Wagner, Eur. J. Inorg. Chem. 2012, 112–120.
[17] B. Vakulya, S. Varga, A. Csámpai, T. Soós, Org. Lett. 2005, 7,
1967–1969.
[18] R. P. Herrera, V. Sgarzani, L. Bernardi, A. Ricci, Angew. Chem.
Int. Ed. 2005, 44, 6576–6579; Angew. Chem. 2005, 117, 6734–
6737.
[6] Physical-organic studies on the reactivity of hydrogen-bond-
donor catalysts: a) K. H. Jensen, M. S. Sigman, Angew. Chem.
[19] A. A. Rodriguez, H. Yoo, J. W. Ziller, K. J. Shea, Tetrahedron
Lett. 2009, 50, 6830–6833.
Int. Ed. 2007, 46, 4748–4750; Angew. Chem. 2007, 119, 4832– [20] a) P. Job, Compt. Rend. 1925, 180, 928–930; b) P. Job, Ann.
4834; b) J. Du, Z. Li, D.-M. Du, J. Xu, ARKIVOC 2008, xvii,
145–156; c) K. H. Jensen, M. S. Sigman, J. Org. Chem. 2010,
75, 7194–7201; d) K. C. Harper, M. S. Sigman, J. Org. Chem.
2013, 78, 2813–2818; see also ref.[7–9] for studies focusing on
thioureas.
Chim. Appl. 1928, 9, 113–203.
[21] K. N. Houk, R. W. Strozier, J. Am. Chem. Soc. 1973, 95, 4094–
4096.
[22] P. Laszlo, M. Teston-Henry, Tetrahedron Lett. 1991, 32, 3837–
3838.
[7] a) pKa values: G. Jakab, C. Tancon, Z. Zhang, K. M. Lippert,
P. R. Schreiner, Org. Lett. 2012, 14, 1724–1727; b) for a detailed
Received: July 7, 2014
Published Online: September 10, 2014
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Eur. J. Org. Chem. 2014, 6394–6398