Thiosemicarbazone organocatalysis: Tetrahydropyranylation and 2-deoxygalactosylation reactions and kinetics-based mechanistic investigation

Article abstract of DOI:10.1039/c7sc03366d

The first use of thiosemicarbazone-based organocatalysis was demonstrated on both tetrahydropyranylation and 2-deoxygalactosylation reactions. The organocatalysts were optimised using kinetics-based selection. The best catalyst outperformed previously reported thiourea catalysts for tetrahydropyranylation by 50-fold. Hammett investigations of both the organocatalyst and the substrate indicate an oxyanion hole-like reaction mechanism.

Full text of DOI:10.1039/c7sc03366d

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Thiosemicarbazone organocatalysis:
tetrahydropyranylation and 2-
Cite this: DOI: 10.1039/c7sc03366d
deoxygalactosylation reactions and kinetics-based
mechanistic investigation†
Dennis Larsen, ‡ Line M. Langhorn,
Olivia M. Akselsen, Bjarne E. Nielsen
*
and Michael Pittelkow
The first use of thiosemicarbazone-based organocatalysis was demonstrated on both
tetrahydropyranylation and 2-deoxygalactosylation reactions. The organocatalysts were optimised using
kinetics-based selection. The best catalyst outperformed previously reported thiourea catalysts for
tetrahydropyranylation by 50-fold. Hammett investigations of both the organocatalyst and the substrate
indicate an oxyanion hole-like reaction mechanism.
Received 2nd August 2017
Accepted 27th September 2017
DOI: 10.1039/c7sc03366d
rsc.li/chemical-science
Dual hydrogen-bonding organocatalysts have gained signicant
Inspired by the thiourea catalysts developed by Schreiner
popularity recently, particularly the use of (thio)urea catalysts.1 and co-workers,7 catalyst 1b (Fig. 2) was synthesised and used
Ever since Jacobsen's serendipitous 1998 landmark discovery of (10 mol%) to develop conditions for a kinetics-based catalyst
the thiourea-catalysed asymmetric Strecker reaction,2 building screening. While 1b was able to afford turnover in several non-
on pioneering urea work by Curran and others,3 chemists have polar solvents (1 : 1 DHP/solvent), CH2Cl2 proved to be most
been looking for new double hydrogen-bonding motifs to suitable (see Table S1 in the ESI†). Addition of benzoic acid co-
exploit for organocatalytic purposes.
catalyst further improved reactivity, allowing for full conversion
Corey introduced guanidinium-based dual hydrogen bond within hours under relatively dilute conditions (10 eq. of DHP).
donor catalysts as early as 1999,4 while Rawal demonstrated
squaramide-based organocatalysis in 2008.5 Based on our
recent development of the squaramide-related croconamide
organocatalysts and our concurrent work with thiourea-like
thiosemicarbazones,6 we became interested in developing
organocatalysts structurally related to thioureas as well.
In this proof-of-principle study, we establish thio-
semicarbazones (Fig. 1a) as a new class of organocatalysts that
act as unique catalysts for the tetrahydropyranylation of alco-
hols under mild conditions, and we perform a double Hammett
investigation of the reaction mechanism using a range of
catalysts and a range of phenol substrates (Fig. 1b). The
resulting double Hammett plot (Fig. 1c) gives experimentally-
based insights into the electronic requirements of both the
catalyst and phenol substrates in the transition state, and
allows us to propose a mechanism of the reaction based solely
on experimentally-gathered evidence.
Department of Chemistry, University of Copenhagen, Universitetsparken 5, DK-2100
Copenhagen, Denmark. E-mail: pittel@chem.ku.dk
† Electronic supplementary information (ESI) available: Experimental procedures,
supplementary data, tables, gures, mechanistic discussions, and crystal
structures. CCDC 1473889–1473891 and 1473916. For ESI and crystallographic
data in CIF or other electronic format see DOI: 10.1039/c7sc03366d
‡ Current address: Department of Chemistry, Technical University of Denmark,
Kemitorvet, DK-2800 Kongens Lyngby, Denmark.
Fig. 1 (a) Thiosemicarbazone organocatalyst scaffold used in this
study. (b) Optimised conditions for Hammett investigations of the
thiosemicarbazone-catalysed tetrahydropyranylation of phenols. (c)
Hammett plot for catalyst ( ) and substrate ( ).
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thiosemicarbazones used in this study function in a similar
manner to thiourea catalysts, e.g. via dual hydrogen-bonding
from the two NH-groups.7b
The data presented in Table 1 indicate that EWGs on the
imine C-phenyl are better able to afford turnover than EWGs on
the thiourea N-phenyl. Thus, there is a modest rate increase
going from 3a-catalysis to 1a-catalysis (3.7-fold), while a larger
improvement is seen when going from 3a to 3b (6.8-fold). A
possible explanation for this phenomenon might be inferred
from the X-ray crystal structure of 1b (Fig. 3a and b). Due to the
steric demand of the thiocarbonyl, the N-phenyl cannot be in
the same plane as the central thiosemicarbazone moiety. The C-
phenyl, on the other hand, forms a planar, fully conjugated
system with the thiosemicarbazone moiety. Therefore, the
EWGs on the C-phenyl withdraw electron-density via both
inductive and mesomeric pathways, while the EWGs on the N-
phenyl can only exert electron-withdrawing effects by way of
induction.
Fig. 2 Catalysts 1a–h, 3a–b, and 4.
Despite having an additional EWG, the catalytic efficacy of
1d was found to be inferior to 1c. This is in contradiction to the
hypothesis that more EWGs lead to higher catalytic effect, but as
is evident from the X-ray crystal structures, the additional nitro
group on 1d forces the imine C-phenyl out of the plane of the
thiosemicarbazone moiety (Fig. 3c and d). It appears that the
added electron-withdrawal from the additional nitro group is
overcome by this perturbation of the conjugated system.
The C6F5-substituted catalyst 1e performs almost as well as
1c, while the 2-pyridinyl derivative 1f failed to give useable
conversion. In accordance with the observed trend, catalyst 1g,
with the strongly electron-donating dimethylamino group,
failed to give appreciable turnover.
All but the slowest of the working thiosemicarbazone cata-
lysts give higher k2's than previously reported thiourea 4. While
4 remains one of the most efficient organocatalysts reported
under high reagent concentration conditions (as low as
0.001 mol% catalyst loading in neat DHP),7b the best thio-
semicarbazone (1c) gives a 50-fold increase of k2 compared to
thiourea 4 under the more dilute conditions in this study.
The transient nature of the intermediates in non-covalent
hydrogen bond-catalysed reactions makes mechanistic investi-
gations of reactions involving non-covalent organocatalysts
difficult.9,10 The lack of tangible evidence of unique reaction
intermediates to substantiate and validate mechanistic
proposals has made indirect methods the main source of
mechanistic insight, e.g. computational methods that account
for solvent using continuum models.11 In spite of tremendous
effort and great improvements, identifying the mechanistic
pathway in organocatalytic reactions remains a difficult task,12
and reports of experimental methods to gain mechanistic
insight into non-covalent organocatalysis are relatively few and
relatively far between.9 Many rely on inferring catalytic proper-
ties from catalyst–substrate complexes identied by e.g. spec-
troscopy,13 while other methods rely on relatively cumbersome
physico-chemical analyses of the catalysts.14
Though benzoic acid gave a sizeable 1.5-fold rate increase in
the presence of catalyst 1b (Fig. S1 and Table S2 in the ESI for
details†), benzoic acid itself, i.e. without catalyst, did not afford
any turnover, underscoring the positive catalytic effect of the
thiosemicarbazone. Use of 2-(4-nitrophenyl)ethanol, 2, ensured
simple reaction monitoring by HPLC-UV (290 nm). Kinetics
studies conrmed rst-order dependence with respect to both
DHP and alcohol concentrations, and the overall second-order
rate constant, k2, was determined by non-linear regression
(see ESI for details†) for a range of thiosemicarbazones, 1a–h
and 3a–b (Fig. 2). The best previously reported thiourea catalyst
for this reaction, 4,7b was used for comparison.
Thiosemicarbazone catalysts are highly tuneable, and there
is an apparent trend favouring catalysts that have electron-
withdrawing groups (EWGs) (Table 1). This is in accordance
with results described by the Schreiner lab, who found that
EWGs improve the efficacy of thiourea catalysts, with 4 being
the most prominent example.8 This indirectly suggests that the
Table 1 Second-order rate constants, k2, from catalyst screeninga
Catalyst
k2 (10ꢀ6 Mꢀ1 sꢀ1
b
)
Catalyst
k2 (10ꢀ6 Mꢀ1 sꢀ1
b
)
(None)
1a
1b
1c
1d
No conversion
6.8 ꢁ 0.2
37.7 ꢁ 1.1
129 ꢁ 5
1f
Conv. too low
Conv. too low
Solubility too low
1.83 ꢁ 0.05
1g
1h
3a
3b
4
53 ꢁ 2
12.38 ꢁ 0.07
1e
101 ꢁ 3
2.55 ꢁ 0.03
A Hammett analysis gives experimental insight into the
nature of the transition state of a chemical reaction by deter-
mining the linear free energy relationship between the
a
Obtained by non-linear regression (see ESI). b Standard errors on best
t.
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Fig. 3 Crystal structures of selected catalysts, C: grey, H: white, F: green, N: blue, O: red, S: yellow. (a) Front and (b) top view of 1b (ethanol). (c) 1c
(CH2Cl2/methanol). (d) 1d (ethanol, disorder of CF3 groups omitted for clarity).
logarithm of relative reaction rate constants and Hammett's s 11.1, DMSO),18 which itself does not promote the reaction, this
values.15 In spite of the widespread use of organocatalysts and type of mechanism was rejected.
the demand for insight into the way in which they operate, there
1H NMR titrations in CDCl3 revealed that 1c forms a 1 : 1
are very few examples of Hammett analyses performed with adduct with 4-methoxyphenol with a low binding constant, Ka,
focus on the organocatalyst, and none of these investigations of 1.71 ꢁ 0.03 mꢀ1, while DHP was found to have a signicantly
were expanded to also include a Hammett analysis of the weaker interaction with 1c (Ka below the detection limit affor-
substrate.16
ded by 1H NMR titrations) (details in ESI†). This suggests
To gain mechanistic insight on this new class of organo- a mechanism in which DHP does not interact with the catalyst
catalysts, we exploited the ease of derivatisation of thio- itself, but rather with a catalyst–substrate adduct.
semicarbazones. A range of thiosemicarbazone catalysts all
Based on a thorough evaluation of the available data, plau-
bearing different substituents in the p-position on the imine C- sible mechanistic pathways (see further details in the ESI†), and
phenyl were used to determine k2's for the tetrahydropyr- comparison to similar reactions,7b we suggest a mechanism in
anylation of 4-methoxyphenol (i.e. different X's in Fig. 1b). In which the catalyst–phenol complex reacts with DHP to form the
parallel, a range of p-substituted phenols were selected as product via a not fully synchronous cyclic proton transfer,
substrates and tetrahydropyranylated using 1c (i.e. different Y's which in its entirety results in the same product that would be
in Fig. 1b). This allowed us to perform a double Hammett formed via a formally forbidden [2 + 2] cycloaddition mecha-
analysis: one Hammett plot to investigate the effect of electron- nism. Aer initial build-up of negative charge on the phenol
withdrawing and electron-donating substituents on the catalyst oxygen, stabilised by double H-bonding from the organocatalyst
and one Hammett plot to investigate the effect of the substit- (pre-TS, Fig. 4) in the so-called “oxyanion hole”,1b,7b,11a the
uents on phenol substrates (Fig. 1c).
partial negative charge on the phenol oxygen is lost in the
For the catalysts, Hammett's sp values were used to obtain ensuing transition state (TS, Fig. 4). This is in agreement with
a plot with good linear correlation ( , Fig. 1c).17 The positive
slope (r ¼ 1.48) is in agreement with the previous notion that
EWGs on the catalyst leads to faster reactions.
For the phenols, a similar plot was made against the Ham-
mett spꢀ values to obtain a plot with good linear correlation ( ,
Fig. 1c).17 The negative slope (r ¼ ꢀ0.57) reveals a decrease in
electron-density (build-up of positive charge or loss of negative
charge) on the phenol in the transition state.
Based on these double Hammett investigations, several
possible reaction pathways were considered. Traditional
Brønsted acid-catalysed tetrahydropyranylation via an oxo-
carbenium ion formed by protonation of DHP by the thio-
semicarbazone catalyst was ruled out. The best catalyst (1c) was
found to have a pKa value of 11.5 ꢁ 0.1 (DMSO) (see ESI for
Fig. 4 Proposed catalytic cycle for the thiosemicarbazone-catalysed
details†), and since this is less acidic than benzoic acid (pKa tetrahydropyranylation of phenols.
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the Hammett analysis of the phenol substrates, which supports
In summary, we have illustrated the rst use of thio-
a mechanism going via a loss of (partial) negative charge on the semicarbazones as organocatalysts. Guided by kinetics, an
phenol in the transition state. optimised catalyst structure, 1c, was identied. A double
The best catalysts are the strongest hydrogen bond donors, Hammett analysis, along with NMR and pKa data, allowed us to
since they most efficiently afford preorganisation of the reactants suggest an asynchronous cyclic transition state. The fact that
to form the pre-TS and stabilisation of the transition state, TS, in thiosemicarbazones function in a similar manner to the well-
accordance with the oxyanion stabilisation concept.1b,7b,11a proven thiourea catalysts gives rise to optimism regarding the
Further 1H NMR investigations revealed a 1 : 1 interaction (Ka ¼ future use of thiosemicarbazone catalysts in other reactions.
46 ꢁ 4 mꢀ1) as well as chemical shi changes consistent with an
electrophilic interaction upon titration of 1c with benzoic acid.
Such an interaction results in a more electron-decient catalyst
Conflicts of interest
and thus can seemingly explain the slight increase in reaction There are no conicts to declare.
rate (1.5-fold with 1b and 2-(4-nitrophenyl)ethanol, Table S2,
ESI†) seen with addition of benzoic acid.
Acknowledgements
This mechanistic proposal runs parallel to the previously
proposed mechanism for thiourea-catalysed tetrahydropyr- The authors acknowledge support from the Lundbeck Foun-
anylations by Kotke and Schreiner, who, based on computa- dation (Young Group Leader Fellowship), the Danish Council
tional results, identied a mechanism going via a cyclic for Independent Research (Sapere Aude – DFF 4181-00206), and
transition state, though they emphasised that the overall addi- the Department of Chemistry, University of Copenhagen.
tion must be “highly asynchronous” since a thermal [2 + 2]
cycloaddition is formally forbidden.7b The study presented in
this report represents the rst kinetics-based experimental
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