Integrative Theory/Experiment-Driven Exploration of a Multicomponent Reaction towards Imidazoline-2-(thi)ones

Article abstract of DOI:10.1002/ejoc.201700941

Predicting reactivity in multicomponent reactions (MCRs) is extremely difficult. These reactions proceed by multiple pathways and are inherently associated with a potentially large variation of reactants and functional groups. To date, theoretical chemist

Full text of DOI:10.1002/ejoc.201700941

DOI: 10.1002/ejoc.201700941
Full Paper
Integrative Theory/Experiment | Very Important Paper |
Integrative Theory/Experiment-Driven Exploration of a
Multicomponent Reaction towards Imidazoline-2-(thi)ones
Art Kruithof,[a] Jos R. Mulder,[a,b] J. M. Ruiz,[b] Elwin Janssen,[a] M. Mooijman,[a]
Eelco Ruijter,[a] Célia Fonseca Guerra,[b,c] F. Matthias Bickelhaupt*[b,d] and
Romano V. A. Orru*[a]
Abstract: Predicting reactivity in multicomponent reactions pinpointing the most relevant parameter(s) in the reactivity,
(MCRs) is extremely difficult. These reactions proceed by multi- thus focusing experimental efforts. Herein, we discuss a study
ple pathways and are inherently associated with a potentially that truly integrates theoretical and synthetic chemistry to un-
large variation of reactants and functional groups. To date, ravel in full detail the complex and intricate reaction character-
theoretical chemistry has been used in hindsight to verify ex- istics of the novel versatile MCR of α-acidic iso(thio)cyanates,
perimental observations. However, its use in the early stages of amines and aldehydes to access densely functionalized imidaz-
the development of a (multicomponent) reaction process can oline-2-(thi)ones.
prevent laborious and time-consuming optimization studies by
Introduction
thetic chemist to reduce the number of experiments to further
explore desired reactivity or avoid non-desired reactivity. The
acquired experimental data in turn serve as input for additional
detailed computational clarification of reaction pathways and
reaction outcomes.
We herein describe an approach that combines an initial
thorough computational analysis of the reaction mechanism of
a novel multicomponent reaction (MCR) with experimental
benchmarking of a combinatorial set of reaction inputs (Fig-
ure 1). This should, on the one hand, confirm (or reject) the
hypothesis on overall reactivity, but also provide information
on additional or alternative (rate-)limiting factors. Then, in the
Computational chemistry has developed from a niche between
physics and chemistry to an explanatory tool for any chemist.
By exploring reaction channels on the multidimensional poten-
tial energy surface (PES), a computational chemist is able to
elucidate the reaction path(s) of any given reaction. Especially
in the past decade, computational chemistry tools have ad-
vanced exponentially and are now at a highly sophisticated
level.[1] The maturity of such computational tools should en-
courage synthetic chemists to routinely seek collaborations or
employ these tools themselves as an integral part of rational
reaction development.
We feel that a pragmatic approach making use of iterative
theory/experiment cycles is needed to facilitate computational
chemists to better aid synthetic chemists (and vice versa). In
this way, the computational chemist may indeed identify a
problematic part in a reaction pathway, thus helping the syn-
[a] Department of Chemistry & Pharmaceutical Sciences and Amsterdam
Institute for Molecules, Medicines & Systems (AIMMS), Vrije Universiteit
Amsterdam,
De Boelelaan 1108, 1081 HZ Amsterdam, The Netherlands
E-mail: r.v.a.orru@vu.nl
http://www.syborch.com
[b] Department of Theoretical Chemistry and Amsterdam Center for Multiscale
Modeling (ACMM), Vrije Universiteit Amsterdam,
De Boelelaan 1083, 1081 HV Amsterdam, The Netherlands
E-mail: f.m.bickelhaupt@vu.nl
http://www.chem.vu.nl/~bickel/
[c] Leiden Institute of Chemistry, Gorlaeus Laboratories, Leiden University,
P. O. Box 9502, 2300 RA Leiden, The Netherlands
[d] Institute for Molecules and Materials (IMM), Radboud University,
Heyendaalseweg 135, 6525 AJ Nijmegen, The Netherlands
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under https://doi.org/10.1002/ejoc.201700941.
Figure 1. Our integrative methodology for iterative theory/experiment-driven
multicomponent reaction exploration.
Eur. J. Org. Chem. 0000, 0–0
1
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
envisioned iterative process, the computational model system MCR and then replacement of one reactant with a different
is improved to the next level of accuracy, guiding follow-up reactant displaying a similar reactivity mode required for the
laboratory exploration of reaction scope.
multicomponent condensation.[8] Considering that only the
electron-withdrawing and electrophilic properties of the iso-
cyanide functional group are exploited in the 3-CR towards 2-
imidazolines, it may well be replaced by an iso(thio)cyanate to
access imidazolidine-2-(thi)ones 1 instead.
Several (asymmetric) synthetic methods employing α-acidic
isothiocyanates[9] for the synthesis of imidazoline-2-thiones
have been reported; however, none employ the in situ forma-
tion of imines, thus leaving the advantages associated with
MCRs unutilized. Furthermore, the known reports describe the
employment of either harsh activation[10] or activated imines,[11]
which narrow the potential scope of this reaction.
MCRs offer a versatile platform for the combinatorial explora-
tion of chemical space. Consequently, MCRs have developed
into popular synthetic tools for medicinal chemists to efficiently
access libraries of low-molecular-weight, drug-like com-
pounds.[2]
The computational mechanistic analysis of the model system
should disclose all intermediate steps of the reaction. Then, to-
gether with preliminary experimental results, a sound hypothe-
sis for the (rate-)limiting step is developed. Subsequently,
parametrization is used to account for any substituent effects,
thereby creating a complete overall picture of the reaction char-
acteristics. Although computational parametrization is a vibrant
field with an increasing amount of predicting power,[3] the stud-
ies reported herein are focused on pragmatic methodology,
which could be efficiently tailored to a particular reaction of
choice.
Finally, a one-step approach starting from readily available
inputs (Figure 2) would be a significant improvement compared
with our earlier multistep procedures to access imidazoline-2-
(thi)ones 1.[12]
To demonstrate our integrative theory/experiment-driven
approach to reaction development, we focus here on a new
MCR towards imidazoline-2-(thi)ones. These heterocycles repre-
Results and Discussion
sent important synthetic targets. For example, they have been Initially, we used readily available p-chlorobenzaldehyde (2a),
recognized as kinase inhibitors,[4] protease inhibitors[5] and are n-butylamine (3a), and the iso(thio)cyanates 4 derived from p-
used as precursors for N-heterocyclic carbenes.[6] Relevant to chlorophenylglycine. Conveniently, compounds 4 can be pre-
this work is our previously reported three-component reaction pared in one step starting from the corresponding amines by
(3-CR) to access 2-imidazolines, a widely applied condensation using (thio)phosgene and sodium carbonate.[13,14] The one-pot
of aldehydes/ketones, primary amines and isocyanides bearing 3-CR of 2, 3 and 4a indeed gave the expected imidazoline-2-
an electron-withdrawing group at the α-position.[7] By employ- thione 1a, which could be isolated in an excellent 93 % yield
ing empirical design principles based on literature and experi- (Scheme 1). The pre-formation of the imine 5a proved neces-
mental data, we envisioned a single-reactant replacement (SRR) sary to prevent side-product formation (6a and 7a), and the
to arrive at a novel MCR to access imidazoline-2-(thi)ones of addition of an external base, that is, pyridine, turned out to
type 1 (Figure 2).
be unnecessary.[15] However, under these reaction conditions
isocyanate 4b failed to react with the pre-formed imine, and
formation of the desired 1b was not observed.
Scheme 1. Optimized reaction conditions and observed side-products. Ar =
p-chlorophenyl.
The formation of 6a and 7a in the non-optimized reaction
indicates that the 3-CR proceeds in a stepwise fashion, starting
with the formation of the imine 5a followed by (cyclo)addition
of the isothiocyanate 4a. The addition of an external base had
Figure 2. Design of a new MCR to access imidazoline-2-(thi)ones.
This SRR strategy involves systematic assessment of the no influence on the outcome of the reaction. Further, the
mechanistic or functional role of each component in a known (rate-)limiting step of this reaction lies before any irreversible
Eur. J. Org. Chem. 0000, 0–0
www.eurjoc.org
2
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
step at an early stage of the reaction pathway, as the use of
isocyanate 4b (X = O) did not result in product formation and
only starting material was recovered.
After imine formation, the formal cycloaddition to give the
imidazoline-2-(thi)one scaffold involves both carbon–carbon
(C–C) and nitrogen–carbon (N–C) bond formation. Three path-
ways are conceivable: (1) first C–C and then N–C bond forma-
tion, (2) first N–C and then C–C bond formation and (3) simulta-
neous C–C and N–C bond formation.
In this respect, some of our earlier mechanistic findings on
the cyclization reactions of imines 5 by using either α-acidic
isocyanides 8 or nitrilium triflates 9 are relevant (Scheme 2). In
the 3-CR towards 2-imidazolines, that is, the reaction of an im-
ine with an α-acidic isocyanide, C–C bond formation precedes
C–N bond formation.[7b,16] The deprotonated α-carbon atom of
the isocyanide was postulated as the initial nucleophile. Later,
we demonstrated that the reactions of imines and nitrilium tri-
flates to access 2-arylimidazolines occur with an opposite order
of events. DFT calculations showed here that the imine is more
likely to attack the nitrilium ion.[17]
Scheme 3. Disqualification of N–C bond formation as the initial reaction step.
the in situ formed imine (Figure 3, green line) is sufficiently
basic, resulting in ion pair A1 (X = S). This initial proton transfer
proves to be rate-limiting (17.4 kcal/mol). Activation of the im-
ine to the iminium ion results in a relatively small barrier for
the subsequent C–C bond formation. The nucleophilic attack of
the α-carbanion on the iminium ion then gives the linear
rotamers B1α and B1ꢀ as the next intermediates in the pathway.
Next, the rotamers B1α+ꢀ have to undergo C–C bond rotation
providing B1γ–ꢁ. After that, ring closure results in zwitterionic
species C1. Deprotonation of cis isomers C1α+ꢀ by a second
imine molecule leads in a concerted fashion to product 1a-cis.
However, in the case of the trans isomer, a distinct ion pair
D1 is formed, which undergoes (partial) ion separation (TS6)
followed by recombination to furnish product 1a-trans (Fig-
ure 3).
Finally, the fact that the imine is needed to deprotonate the
isothiocyanate disqualifies simultaneous C–C and N–C bond for-
mations, as this is only possible with a neutral imine and a
deprotonated α-carbon atom.[22]
Scheme 2. Initial considerations from analogous imidazoline formations.
With the complete reaction pathway for the model reaction
Taking the above into account, the addition/cyclization reac- charted (Figure 3, green line; for a complete overview see also
tion of N-methylethanimine (5b) and methyl 2-isothiocyanato- the Supporting Information), we then turned to investigate the
2-phenylacetate (4e) was chosen as the model reaction for the combination of isocyanate 4b and 5b (Figure 3, red line). Again,
initial DFT calculations in our current study. The fairly simple deprotonation of the α-carbon atom by the imine is the rate-
starting imine 5b was chosen to reduce the number of atoms determining step (20.6 kcal/mol). From the intermediate com-
and degrees of freedom, therefore limiting the required compu- plex A2, the computations show that nucleophilic attack by
tational resources. Additionally, this model system reduced the the α-carbanion of 4b on the iminium carbon yields either the
number of possible conformers, and thus conformer space rotamers B2α+ꢀ or proceeds directly towards zwitterionic C2
could be covered efficiently (see the Supporting Information for through a concerted ring closure. Although the transition vec-
all geometries). All the calculations were performed by using tors of the involved transition states TS2 do not suggest imme-
the Amsterdam Density Functional package[18] with the OLYP diate ring closure, the asynchronous ring closure proceeds in
functional and a TZ2P basis set. Transition-state optimizations a consecutive fashion, as became evident from the attempted
were performed by using QUILD,[19] solvent effects were taken geometry optimization of B2γ–ꢁ, which only results in C2.
into account by using the COSMO (DCM) model[20] and relativis- Finally, according to the computational model, the imine-
tic effects were taken into account explicitly by using the ZORA facilitated proton shift results in products 1b. Unlike the model
approach (see Computational Details).
Compared with the isocyanides in the related MCRs towards
2-imidazolines, iso(thio)cyanates 4 are more electrophilic. The
pathway towards imidazoline-2-thiones 1a, both 1b-cis and 1b-
trans can only be formed via separate ion pairs (TS6).
The computations revealed the full reaction profiles using
nucleophilic attack of the imine nitrogen atom of 5b on the isothiocyanate 4a or isocyanate 4b. The initial ion-pair forma-
isothiocyanate carbon atom in 4e could be a possible first step; tion (A) seems the limiting factor for this reaction and forms
however, this event leading to P needs 21.8 kcal/mol to proceed the kinetic barrier. In the model system using isocyanate 4b,
(Scheme 3). Furthermore, the follow-up step in this path is a this prevents the reaction from proceeding as here the kinetic
1,2-unimolecular proton shift[21] leading to the endothermic barrier is significantly higher in energy compared with the case
formation of intermediate Q (27.3 kcal/mol), which disqualifies for 4a. In other words, if the first barrier is overcome, C–C bond
this as a likely pathway for our reaction.
Next, we turned to a C–C bond formation as the initial step
in which the α-carbon atom of the isothiocyanate acts as a
formation should occur and the reaction proceeds to form 1a
or 1b.
Clearly, the height of the first barrier also depends on the
nucleophile. This can only occur after an initial α-deproton- nature of the imine employed and thus on the substituent
ation. For this, no external base proved necessary, apparently groups R1 and R2 on the amine and aldehyde used. The initial
Eur. J. Org. Chem. 0000, 0–0
www.eurjoc.org
3
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
Figure 3. Reaction profile for the reaction between N-methylethanimine (5b) and phenylglycine-derived iso(thio)cyanates 4 (top) and specific routes for the
various conformers and diastereoisomers (bottom).
kinetic barrier is determined mainly by the acidity of the α- tive thermodynamic stability of the separate ions will not ex-
proton in the iso(thio)cyanate and the basicity of the imine. The actly correspond to the kinetic barrier of the proton transfer.
proton affinity (PA), which is defined as the change in enthalpy Consequently, the steric effects of the substituents, which could
of removing a proton from its conjugated acid, has been used be of importance for the kinetics of the initial proton transfer
to computationally establish the acidity of a given system.[23] and also for the stabilization of the resulting ion pair, were not
As such, the difference in proton affinity (ΔPA) between the two
reaction partners used in our model may well serve to quantify
the ability to form these acid/base ion pairs.
By using this approach only the ΔPA between either the iso-
thiocyanate or the isocyanate on one hand and the imine on
taken into account. However, by using substituents of similar
steric bulk, the effect becomes comparable for all computed
ion pairs and we can in these cases neglect steric considera-
tions. For the combination of imine 5a with iso(thio)cyanates
4a and 4b, we performed these calculations and compared the
the other needs to be determined, thus avoiding the computa- results with the experimental outcome. The results depicted in
tionally much more expensive transition state and bimolecular Table 1 show that indeed the ΔPA seems to be a reliable param-
geometry optimizations. In such an approach, indeed the rela- eter to predict product formation.
Eur. J. Org. Chem. 0000, 0–0
www.eurjoc.org
4
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
Table 1. ΔPAs [kcal/mol] of the inputs for the optimization study and of 9H-
fluorenyl-substituted iso(thio)cyanates, namely 5a with 4a–d.
cyanate 4d showed no conversion. After calculating the ΔPA
values, this reactivity can again be explained by the (in)ability
to form the initial ion pair (Table 1).
To map the influence of the imine, we picked nine different
imines (5c–5k) derived from three representative amines and
aldehydes (Table 2). In addition to 4c and 4d, we employed 4e
and 4f, which are the phenyl analogues of 4a and 4b, respec-
tively. Subsequently, the actual reactions for a selected sub-set
of possible combinations were performed in the laboratory.[24]
Conveniently, it proved unnecessary to perform all 36 possible
reactions, because the computational results had already al-
lowed us to establish the reactivity profile and identify border-
line cases for expected reactivity. This additionally demon-
strates the explanatory power of our approach. From Table 2,
two observations stand out. First, input combinations 4e–5e
Next, we extended the test set of iso(thio)cyanates to 4c and and 4e–5g with a ΔPA of over 20 kcal/mol show product forma-
4d bearing the highly electron-withdrawing 9H-fluorenyl group. tion. Secondly, input combinations 4d–5c and 4c–5f (and 4c–
This functional group was also employed in our earlier studies 5h), with a significantly lower ΔPA, do not show any conversion.
on 3-CRs towards 2-imidazolines.[7a] Experimentally, only the Additionally, the reactions that show some conversion indeed
use of isothiocyanate 4c led to product formation, whereas iso- gave (partly) the expected imidazoline-2-thione product, which
Table 2. Computed ΔPA values [kcal/mol, green < 20 < red) and experimentally determined reactivity.[25]
Figure 4. Extended hypothesis.
Eur. J. Org. Chem. 0000, 0–0
www.eurjoc.org
5
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
1s2s2p3s3p for fourth period, 1s2s2p3s3p3d4s4p for fifth period
and 1s2s2p3s3p3d4s4p4d for sixth period) were treated by using
the frozen core approximation.[18c] An auxiliary set of s, p, d, f, and
g STOs was used to fit the molecular density and to represent the
coulomb and exchange potentials accurately in each self-consistent
field (SCF) cycle. Scalar relativistic corrections were included self-
consistently by using the zeroth-order regular approximation
(ZORA).[28] By using the OLYP density functional, energies, geome-
tries and vibrational frequencies were calculated by using the local
density approximation (LDA; Slater exchange[29] and VWN correla-
indicates that no additional significant barriers are encountered
along the reaction coordinates. Consequently, in the reaction
profile established above (Figure 3), this means that in addition
to the ΔPA, the initial C–C bond formation must in some cases
be involved as a rate-limiting step. Both experimental observa-
tions and our model system indicate that after this irreversible
C–C bond formation, the reaction proceeds to the product with-
out additional high kinetic barriers.
These observations led to a refined hypothesis accounting
for the progress of our new 3-CR: in addition to the initial ion-
pair formation, the C–C bond formation must also be involved
as a possible rate-limiting step. As depicted in Figure 4a, when
the reaction leads to the desired imidazoline-2-thione products,
ion-pair formation is viable, and the carbon–carbon bond for-
mation is sufficiently favoured for the reaction to proceed. In
the case of a high ΔPA (Figure 4b), the reaction does not pro-
ceed, irrespective of the height of the second barrier. In the
third scenario (Figure 4c), ion-pair formation is viable; however,
the second barrier is too high in comparison with the proton
transfer, and the reaction does not proceed.
tion[30]
) with the gradient corrections of Handy–Cohen (ex-
change)[31] and Lee–Yang–Parr (correlation)[32] added self-consist-
ently. The OLYP density functional is known as the best functional
for the accuracy of geometries and the second best GGA functional
for the energy barrier for SN2 reactions.[23b] Solvent effects were
taken into account in all calculations by using the COSMO model,[20]
used explicitly both for solving the SCF equations and for geometry
optimization. The solvent radius (Rs) for DCM was determined from
experimental data for the macroscopic density (r) and molecular
mass (M) with the formula Rs3 = 2.6752 · Mm/ρ leading to an Rs
value of 2.94 Å for DCM; a value of 78.4 was used for the dielectric
constant of water, and 8.9 was used for the dielectric constant of
DCM. Atomic radii were taken from the MM3 van der Waals radii,[33]
which are available for almost the whole periodic system, and
scaled by 0.8333 (the MM3 radii are 20 % larger than the normal
van der Waals radii due to the specific form of the van der Waals
energy within the MM3 force field). The surface charges at the GE-
POL93 solvent-excluding surface were corrected for outlying char-
ges.[34] This setup provides a “non-empirical” approach to including
solvent effects with a dielectric continuum, and works well for solv-
ation processes.[7a] The non-electrostatic term in the ADF 2009 im-
plementation of COSMO was set to zero, because this term is un-
physical and also leads to unphysical binding at large distances. In
the present version of the ADF program, this term has been re-
moved. Geometries were optimized by using analytical gradient
techniques until the maximum gradient component was less than
1.0 × 10–4 atomic units. All structures were verified by vibrational
analyses to be minima structures (zero imaginary frequencies) or
transition states (one imaginary frequency). Vibrational frequencies
were obtained through numerical differentiation of the analytical
gradients,[30] for which the GEPOL93 surface was recreated for all
of the systems at each displaced geometry. For most systems, these
standard settings resulted in too many imaginary frequencies (in
the range of 0 to –200 cm–1), which, however, proved to have posi-
tive values (of around 0–200 cm–1) in the more accurate (automatic)
scanfreq performed afterwards. The force constants of the imagi-
nary frequencies were recalculated in scanfreq by numerical differ-
entiation of the gradient at six points along the respective frequen-
cies normal mode. The character of the normal mode associated
with the imaginary frequency of a transition state (i.e., the transition
vector) was analysed to ensure that the correct transition state was
found. Vibrational energy effects (in particular, zero-point vibra-
tional energy) and entropy effects were not considered in the calcu-
lations, because they have only a small influence on the energies
obtained. Coordinates of all geometries can be found in the Sup-
porting Information. Additionally, the Supporting Information con-
tains a comprehensive illustration containing the structures of all
investigated routes.
Conclusions
We have reported an efficient and pragmatic methodology that
integrates computational and experimental organic chemistry
tools in an iterative fashion to drive multicomponent reaction
exploration. We could efficiently study and predict the reaction
mechanism as well as chart the scope and limitations of a new
MCR towards imidazoline-2-(thi)ones. We observed a lack of re-
activity for isocyanates in this reaction. Clarification of the reac-
tion profile of a model system led to the extraction of a limiting
parameter, that is, the difference in proton affinity (ΔPA) be-
tween the imine and the iso(thio)cyanate. This parameter was
then used to computationally determine the scope and limita-
tions and thus the performance of the reaction for a larger
combinatorial set of possible inputs. Differences between the
theoretical and experimental trends led to refinement of the
reaction profile (C–C bond formation as a second decisive pa-
rameter). In general, we believe that using this integrative itera-
tive theory/experiment methodology for reaction development
leads to the fast elucidation of relevant reaction pathways, and
a more effective charting of the scope and limitations of a novel
reaction.
Experimental Section
Computational Details: All calculations were performed with the
Amsterdam Density Functional (ADF) program developed by Baer-
ends et al.[18] For transition-state optimizations the Quantum-re-
gions Interconnected by Local Descriptions (QUILD) program was
used.[19,26] The QUILD program is a wrapper around ADF (and other
programs), which is used for its superior geometry optimizer, which
is based on adapted delocalized coordinates. Molecular orbitals
(MOs) were expanded by using the TZ2P basis set, which is an
uncontracted set of Slater-type orbitals (STOs).[27] The TZ2P basis
set is of triple-ꢀ quality, augmented by two sets of polarization
functions (d and f on heavy atoms; 2p and 3d sets on hydrogen).
Experimental Details: All reactions were carried out under atmos-
pheric conditions, unless stated otherwise. 1H and 13C NMR spectra
were recorded with a Bruker Avance 250 (250.13 MHz for 1H and
62.90 MHz for 13C), Bruker Avance 400 (400.13 MHz for 1H and
1
Core electrons (e.g., 1s for second period, 1s2s2p for third period, 100.62 MHz for 13C) or Bruker Avance 500 (500.23 MHz for H and
Eur. J. Org. Chem. 0000, 0–0
www.eurjoc.org
6
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
125.70 MHz for 13C) spectrometer with chemical shifts (δ) reported
in ppm and internally referenced to residual solvent resonances of
CDCl3 (1H: δ = 7.26 ppm; 13C{1H}: δ = 77.0 ppm). Coupling constants
General Procedure 2: The amine (2.0 equiv.) and aldehyde
(2.2 equiv.) were added to a flame-dried Schlenk flask charged with
crushed molecular sieves (4.0 Å) and freshly distilled DCM (4.0 mL)
(J) are reported in Hz, and all diastereoisomeric ratios (dr) were at room temperature. The mixture was stirred overnight after which
determined from crude spectra. IR spectra were obtained from neat
samples utilizing a Shimadzu FTIR-8400s spectrophotometer. Elec-
trospray ionization (ESI) MS was carried out with a micrOTOF-Q
spectrometer in positive ion mode unless stated otherwise. Chro-
the iso(thio)cyanate (1.0 equiv.) was added. The progress of the
reaction was monitored by TLC and MS, and after completion, the
mixture was filtered through Celite and concentrated in vacuo. The
residue was purified on silica gel, eluting with EtOAc/cHex (9:1 →
matographic purification refers to flash chromatography using the 1:1). For all reactions in which an aromatic amine was employed,
indicated solvent (mixture) and Baker 7024-02 silica gel (40 μ, 60 Å).
TLC was performed by using silica plates from Merck (Kieselgel 60
F254 on aluminium with fluorescence indicator), and compounds
were visualized by UV detection and I2 staining unless stated other-
wise. DCM was dried and freshly distilled from CaH2 prior to use.
All other commercial reagents, namely amines, aldehydes, pyridine,
sodium carbonate and 9-isocyanato-9H-fluorene, were used with-
out further purification. All iso(thio)cyanates failed to ionize on ESI-
HRMS, both in positive and negative mode, and were therefore only
6.6 equiv. of aldehyde were used.
Methyl 1-Butyl-5-(4-chlorophenyl)-4-phenyl-2-thioxoimidazol-
idine-4-carboxylate (4a5a): According to general procedure 2, the
reaction between n-butylamine (146 mg; 2.00 mmol), 4-chloroben-
zaldehyde (309 mg; 2.20 mmol) and methyl 2-(4-chlorophenyl)-2-
isothiocyanatoacetate (4a; 242 mg; 1.00 mmol) afforded 4a5a as a
1
yellow foam (407 mg, 93 %, dr =47:53). H NMR (250 MHz, CDCl3):
δ = 7.60 (d, J = 10.0 Hz, 2 H), 7.42 (d, J = 7.5 Hz, 2 H), 7.38 (d, J =
7.5 Hz, 2 H), 7.22 (d, J = 10.0 Hz, 2 H), 7.12–7.08 (m, 4 H), 7.03–6.99
(m, 2 H), 6.84–6.78 (m, 2 H), 6.50 (s, 1 H), 5.68 (s, 1 H), 4.9 (s, 1 H),
4.22–4.12 (m,1 H), 4.10–3.99 (m, 1 H), 3.82 (s, 3 H), 3.37 (s, 3 H),
2.79–2.69 (m, 1 H), 2.68–2.58 (m, 1 H), 1.57–1.42 (m, 2 H), 1.35–1.18
(m, 4 H), 1.12–0.97 (m, 2 H), 0.90 (t, J = 7.5 Hz, 3 H), 0.75 (t, J = 7.5 Hz,
3 H) ppm. The 1H NMR spectrum matches that of the compound
synthesized by another route reported by us earlier.[12a]
1
analysed by H and 13C NMR and IR spectroscopy.
General Procedure 1: Either a solution of phosgene (1.0
M in tolu-
ene) or neat thiophosgene (1.3 equiv.) was added to a stirred solu-
tion of organic ammonium chloride (1.0 equiv.) and Na2CO3
(4 equiv.) in freshly distilled DCM at 0 °C. The resulting reaction
mixture was warmed to room temperature and subsequently stirred
for 7 d, filtered through Celite and concentrated in vacuo.
1′-Butyl-5′-(4-chlorophenyl)spiro[fluorene-9,4′-imidazolidine]-
2′-thione (4c5a): According to general procedure 2, the reaction
between n-butylamine (99 μL, 1.00 mmol), p-chlorobenzaldehyde
(121 mg, 1.10 mmol) and 9-isothiocyanato-9H-fluorene (4c; 112 mg,
0.50 mmol) afforded 4c5a as a white solid (153 mg, 73 %). M.p.
Methyl 2-(4-Chlorophenyl)-2-isothiocyanatoacetate (4a): Ac-
cording to general procedure 1, the reaction between 4-chloro-
phenylglycine methyl ester hydrochloride (12.6 g; 53.2 mmol), CSCl2
(5.32 mL; 69.2 mmol) and Na2CO3 (22.6 g; 213 mmol) afforded 4a
as a yellow-brown oil (12.8 g, 100 %). 1H NMR (250 MHz, CDCl3): δ =
7.35 (s, 4 H), 5.06 (s, 1 H), 3.78 (s, 3 H) ppm. 13C NMR (63 MHz,
CDCl3): δ = 170.1 (C), 135.0 (C), 133.8 (C), 132.3 (C), 129.2 (CH),
128.1 (CH), 62.0 (CH), 53.5 (CH3) ppm (NCS carbon signal was not
1
159.5–160.5 °C. H NMR (500 MHz, CDCl3): δ = 7.64 (d, J = 7.5 Hz, 1
H), 7.60 (d, J = 7.5 Hz, 1 H), 7.49 (d, J = 7.5 Hz, 1 H), 7.44 (t, J =
7.5 Hz, 1 H), 7.37 (t, J = 7.5 Hz, 1 H), 7.23 (t, J = 7.5 Hz, 1 H), 7.14
(d, J = 8.5 Hz, 2 H), 6.95 (t, J = 7.5 Hz, 1 H), 6.75 (d, J = 7.0 Hz, 2 H),
6.68 (d, J = 8 Hz, 1 H), 5.96 (s, 1 H), 5.10 (s, 1 H), 4.42 (ddd, J = 13.5,
10.0, 6.5 Hz, 1 H), 2.96 (ddd, J = 13.5, 10.0, 5.0 Hz, 1 H), 1.71–1.68
(m, 1 H), 1.58–1.52 (m, 1 H), 1.41–1.29 (m, 2 H), 0.92 (t, J = 7.0 Hz,
3 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 185.1 (C), 147.6 (C), 141.4
(C), 140.2 (C), 139.3 (C), 134.6 (C), 132.8 (C), 130.0 (CH), 129.7 (CH),
129.0 (CH), 128.7 (2 CH), 127.5 (CH), 126.2 (CH), 125.3 (CH), 123.3
(CH), 120.4 (CH), 120.2 (CH), 120.1 (CH), 72.9 (C), 72.7 (CH), 45.44
observed). IR (neat): νmax = 2948, 2048, 2044, 1999, 1756, 1490,
˜
1434, 1337, 1307, 1285, 1247, 1015 cm–1
.
Methyl 2-(4-Chlorophenyl)-2-isocyanatoacetate (4b): According
to general procedure 1, the reaction between 4-chlorophenyl-
glycine methyl ester hydrochloride (2.36 g, 10.0 mmol), COCl2
(1.29 mL, 13.0 mmol) and Na2CO3 (5.68 g, 40.0 mmol) afforded 4b
as a yellow-brown oil (1.19 g, 100 %). 1H NMR (250 MHz, CDCl3): δ =
7.39–7.31 (m, 4 H), 5.06 (s, 1 H), 3.73 (s, 3 H) ppm. 13C NMR (63 MHz,
CDCl3): δ = 167.6 (C), 135.5 (C), 132.4 (C), 129.3 (CH), 128.2 (CH),
62.2 (CH), 53.7 (CH3) ppm (NCO carbon signal was not observed).
(CH2), 28.9 (CH2), 20.3 (CH2), 13.9 (CH3) ppm. IR (neat): νmax
=
˜
3138, 2926, 1489, 1458, 1448, 1281, 1190, 1144, 1090, 1011, 764,
733 cm–1. HRMS (ESI): calcd. for C25H24ClN2S+ 419.1343; found
419.1361.
9-Isothiocyanato-9H-fluorene (4c): According to general proce-
dure 1, the reaction between 9H-fluoren-9-amonium chloride
(2.177 g, 10.0 mmol), CSCl2 (1.0 mL, 13.0 mmol) and Na2CO3 (5.68 g,
40.0 mmol) afforded 4c as a yellow-brown oil (2.23 g, 100 %). 1H
NMR (250 MHz, CDCl3): δ = 7.71 (d, J = 7.5 Hz, 2 H), 7.66 (d, J =
7.5 Hz, 2 H), 7.46 (t, J = 7.5 Hz, 2 H), 7.38 (t, J = 7.5 Hz, 2 H), 5.73 (s,
1 H) ppm. 13C NMR (63 MHz, CDCl3): δ = 140.9 (C), 140.1 (C) 129.7 (2
CH), 128.2 (2 CH), 124.9 (2 CH), 120.4 (2 CH), 59.9 (CH) ppm. IR (neat):
1′-Butyl-5′-(4-methoxyphenyl)spiro[fluorene-9,4′-imidazol-
idine]-2′-thione (4c5c): According to general procedure 2, the reac-
tion between n-butylamine (73 mg, 1.00 mmol), p-methoxybenz-
aldehyde (151 mg, 1.10 mmol) and 9-isothiocyanato-9H-fluorene
(4c; 112 mg, 0.50 mmol) afforded imidazolidine-2-thione 4c5c as a
yellow foam (166 mg, 80 %). 1H NMR (500 MHz, CDCl3): δ = 7.63 (d,
J = 7.5 Hz, 1 H), 7.58 (d, J = 7.5 Hz, 1 H), 7.47 (d, J = 7.5 Hz, 1 H),
7.41 (t, J = 7.5 Hz, 1 H), 7.34 (t, J = 7.5 Hz, 1 H), 7.20 (t, J = 7.5 Hz,
1 H), 6.91 (t, J = 7.5 Hz, 1 H), 6.76–6.71 (m, 2 H), 6.67 (t, J = 8.5 Hz,
1 H), 6.01 (s, 1 H), 5.07 (s, 1 H), 4.43–4.36 (m, 1 H), 3.72 (s, 3 H),
2.99–2.94 (m, 1 H), 1.74–1.64 (m, 1 H), 1.60–1.49 (m, 1 H), 1.43–1.28
νmax = 3065, 3043, 3020, 2179, 2152, 2083, 1607, 1475, 1450, 1288,
˜
1180, 1150, 1105, 1072, 1018, 943, 874, 841, 789, 733 cm–1.
Methyl 2-Isothiocyanato-2-phenylacetate (4e): According to gen-
eral procedure 1, the reaction between (+)-(S)-2-phenylglycine
methyl ester (2.14 g, 10.6 mmol), CSCl2 (1.06 mL, 13.8 mmol) and (m, 2 H), 0.92 (t, J = 7.0 Hz, 3 H) ppm. 13C NMR (125 MHz): δ = 184.6
Na2CO3 (4.49 g, 42.4 mmol) afforded 4e as a dark-red oil (2.18 g, (C), 159.6 (C), 147.8 (C), 141.5 (C), 140.0 (C), 139.0 (C), 129.5 (CH),
1
100 %). H NMR (500 MHz, CDCl3): δ = 7.43–7.40 (m, 5 H), 5.29 (s, 1
129.2 (CH), 128.7 (CH), 128.4 (CH), 127.1 (CH), 126.2 (CH), 126.0 (C),
123.0 (CH), 120.0 (CH), 119.6 (CH), 113.6 (CH), 72.8 (C), 72.7 (CH),
H), 3.78 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 168.0 (C),
139.9 (C), 134.0 (C), 129.5 (CH), 129.3 (2 CH), 126.9 (2 CH) 62.9, (CH), 55.1 (CH3), 45.1 (CH2), 28.9 (CH2), 20.1 (CH2), 13.7 (CH3) ppm. IR:
53.7 (CH3) ppm. IR (neat): νmax = 2023, 1747, 1454, 1435, 1246, 1207, νmax = 3067, 3009, 2957, 2930, 2837, 2735, 1682, 1597, 1578, 1510,
˜
˜
1169, 984, 721, 692 cm–1
.
1448, 1425, 1302, 1248, 1215, 1192, 1177, 1159, 1109, 1026, 833,
Eur. J. Org. Chem. 0000, 0–0
www.eurjoc.org
7
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
766, 733 cm–1. HRMS (ESI): calcd. for C26H27N2OS+ 415.1844; found
415.1809.
Diastereomer 1: M.p. 128.8–130.7 °C. 1H NMR (500 MHz, CDCl3):
δ = 7.10–7.08 (m, 3 H), 7.06–7.04 (m, 2 H), 6.83–6.69 (m, 2 H), 6.57
(d, J = 7.5 Hz, 2 H), 6.47 (s, 1 H), 5.67 (s, 1 H), 4.14 (ddd, J = 13.5,
8.0, 8.0 Hz, 1 H), 3.79 (s, 3 H), 3.66 (s, 3 H), 2.75 (ddd, J = 14.5, 7.5,
5.5 Hz, 1 H), 1.54–1.50 (m, 2 H), 1.32–1.23 (m, 2 H), 0.89 (t, J = 7.5 Hz,
3 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 182.7 (C), 172.0 (C), 159.6
(C), 134.5 (C), 128.5 (n CH), 128.5 (n CH), 125.9 (n CH), 125.4 (C),
113.7 (n CH), 73.0 (C), 70.1 (CH), 55.3 (CH3), 53.7 (CH3), 45.0 (CH2),
1′,5′-Dibutylspiro[fluorene-9,4′-imidazolidine]-2′-thione (4c5d):
According to general procedure 2, the reaction between n-butyl-
amine (99 μL, 1.00 mmol), valeraldehyde (117 μL, 1.10 mmol) and
9-isothiocyanato-9H-fluorene (4c; 112 mg, 0.50 mmol) afforded
1
4c5d as a white solid (53 mg, 23 %). M.p. 125.1–125.6 °C. H NMR
(500 MHz, CDCl3): δ = 7.64 (t, J = 8.0 Hz, 2 H), 7.55 (d, J = 7.5 Hz, 1
H), 7.47 (d, J = 7.5 Hz, 1 H), 7.43–7.40 (m, 2 H), 7.34 (td, J = 7.5,
0.5 Hz, 1 H), 7.28 (td, J = 7.0, 0.5 Hz, 1 H), 5.74 (s, 1 H), 4.25 (dd, J =
10.5, 4.0 Hz, 1 H), 4.04 (ddd, J = 14.5, 9.5, 6.5 Hz, 1 H), 3.50 (ddd,
J = 12.5, 9.5, 7.0 Hz, 1 H), 1.69–1.61 (m, 2 H), 1.47–1.43 (m, 2 H),
1.34–1.28 (m, 1 H), 1.01 (t, J = 7.0 Hz, 3 H), 0.93–0.81 (m, 3 H), 0.65–
0.57 (m, 1 H), 0.45 (t, J = 7.5 Hz, 3 H), 0.44–0.38 (m, 1 H) ppm. 13C
NMR (125 MHz, CDCl3): δ = 183.9 (C), 145.7 (C), 143.3 (C), 140.5 (C),
140.1 (C), 130.0 (CH), 129.9 (CH), 128.4 (CH), 128.2 (CH), 125.6 (CH),
124.5 (CH), 120.5 (CH), 120.3 (CH), 72.2 (C), 68.2 (CH), 44.9 (CH2),
29.3 (CH2), 28.5 (CH2), 26.8 (CH2), 22.2 (CH2), 20.4 (CH2), 14.1 (CH3),
29.1 (CH2), 19.9 (CH2), 13.9 (CH3) ppm. IR (neat): νmax = 3175, 2959,
˜
1730, 1608, 1508, 1448, 1231, 1205, 1038, 932, 827, 692 cm–1. HRMS
(ESI): calcd. for C22H27N2O3S+ 399.1737; found 399.1729.
1
Diastereomer 2: H NMR (500 MHz, CDCl3): δ = 7.64 (d, J = 7.5 Hz,
2 H), 7.45–7.38 (m, 3 H), 7.21 (d, J = 8.5 Hz, 2 H), 6.90 (d, J = 8.5 Hz,
2 H), 6.76 (s, 1 H), 4.98 (s, 1 H), 4.05 (ddd, J = 14.0, 8.0, 8.0 Hz, 1 H),
3.82 (s, 3 H), 3.33 (s, 3 H), 2.67 (ddd, J = 13.5, 8.0, 6.0 Hz, 1 H), 1.34–
1.25 (m, 2 H), 1.05–1.01 (m, 2 H), 0.73 (t, J = 7.0 Hz, 3 H) ppm. 13C
NMR (125 MHz, CDCl3): δ = 181.6 (C), 168.6 (C), 160.3 (C), 140.1 (C),
129.1 (n CH), 129.0 (n CH), 127.0 (C), 125.5 (n CH), 114.3 (n CH), 74.7
(CH), 72.8 (C), 55.4 (CH3), 52.8 (CH3), 44.3 (CH2), 29.3 (CH2), 19.6
13.4 (CH3) ppm. IR (neat): νmax = 3163, 2954, 2925, 2858, 1489, 1448,
˜
1191, 732 cm–1. HRMS (ESI): calcd. for C23H29N2S+ 365.2046; found
365.2028.
(CH2), 13.7 (CH3) ppm. IR (neatνmax = 3190, 2955, 1742, 1610, 1512,
˜
1445, 1246, 1177, 1030, 733, 696 cm–1. HRMS (ESI): calcd. for
C22H27N2O3S+ 399.1737; found 399.1729.
4-(1′-Butyl-2′-thioxospiro[fluorene-9,4′-imidazolidin]-5′-yl)-
benzonitrile (4c5e): According to general procedure 2, the reaction
between n-butylamine (99 μL, 1.00 mmol), p-cyanobenzaldehyde
(144 mg, 1.10 mmol) and 9-isothiocyanato-9H-fluorene (4c; 112 mg,
0.50 mmol) afforded 4c5e as a white solid [20 mg, 10 %; yield based
Methyl 1,5-Dibutyl-4-phenyl-2-thioxoimidazolidine-4-carboxyl-
ate (4e5d): According to general procedure 2, the reaction between
n-butylamine (99 μL, 1.00 mmol), valeraldehyde (117 μL, 1.10 mmol)
and methyl 2-isothiocyanato-2-phenylacetate (4e; 104 mg,
0.50 mmol) afforded 4e5d as a yellow oil (66 mg, 38 %) as a 1:1
1
on H NMR relative to the doublet at δ = 7.97 ppm (4-cyanobenz-
aldehyde, 2 H)]. M.p. 161.3–162.6 °C. 1H NMR (500 MHz, CDCl3): δ =
7.64 (d, J = 7.5 Hz, 1 H), 7.59 (d, J = 7.5 Hz, 1 H), 7.48–7.43 (m, 4 H),
7.22 (t, J = 7.5 Hz, 2 H), 6.93–6.91 (m, 3 H), 6.63 (d, J = 8.0 Hz, 1 H),
6.07 (s, 1 H), 5.17 (s, 1 H), 4.44 (ddd, J = 14.0, 10.0, 6.5 Hz, 1 H), 2.94
(ddd, J = 14.0, 9.5, 5.0 Hz, 1 H), 1.71–1.67 (m, 1 H), 1.55–1.51 (m, 1
H), 1.41–1.31 (m, 2 H), 0.92 (t, J = 7.0 Hz, 3 H) ppm. 13C NMR
(125 MHz, CDCl3): δ = 185.4 (C), 147.2 (C), 141.1 (C), 140.1 (C), 139.8
(C), 139.2 (C), 132.3 (2 CH), 130.2 (CH), 130.0 (CH), 130.0 (CH), 128.8
(CH), 128.3 (CH), 127.5 (CH), 125.9 (CH), 123.3 (CH), 120.5 (CH), 120.3
(CH), 118.4 (C), 112.6 (C), 72.8 (C), 72.8 (CH), 45.6 (CH2), 29.8, 28.8
1
mixture of diastereomers. H NMR (500 MHz, CDCl3): δ = 7.53–7.52
(m, 1 H + 1 H), 7.39–7.34 (m, 4 H + 4 H), 6.62 (s, 1 H), 6.38 (s, 1 H),
4.70–4.68 (m, 1 H), 4.20 (ddd, J = 14.5, 8.5, 7.0 Hz, 1 H), 4.12–4.07
(m, 1 H), 3.75 (s, 3 H), 3.74 (s, 3 H), 3.04 (ddd, J = 14.0, 8.5, 5.0 Hz,
1 H), 2.93 (ddd, J = 14.0, 8.0, 5.0 Hz, 1 H), 2.09–2.06 (m, 1 H), 1.82–
1.77 (m, 1 H), 1.64–1.55 (m, 2 H), 1.01–0.77 (m, 7 H), 0.72 (t, J =
7.0 Hz, 3 H), 0.58 (t, J = 7.5 Hz, 3 H) ppm. 13C NMR (125 MHz, CDCl3):
δ = 182.2 (C), 180.9 (C), 172.4 (C), 169.1 (C), 140.4 (C), 134.1 (C),
129.1 (n CH), 129.1 (n CH), 128.9 (n CH), 126.3 (n CH), 125.1 (n CH),
72.4 (C), 70.6 (CH), 70.3 (C), 65.0 (CH), 53.7 (CH3), 53.1 (CH3), 44.8
(CH2), 44.0 (CH2), 29.4 (CH2), 29.2 (CH2), 29.0 (CH2), 28.1 (CH2), 26.0
(CH2), 25.7 (CH2), 23.0 (CH2), 22.5 (CH2), 20.0 (CH2), 19.5 (CH2), 14.0
(CH2), 20.2 (CH2), 13.9 (CH3) ppm. IR (neat): νmax = 3151, 2230, 1448,
˜
1281, 1188, 1143, 879, 731, 590, 551 cm–1. HRMS (ESI): calcd. for
C26H24N3S+ 410.1685; found 410.1680.
(CH3), 14.0 (CH3), 13.7 (CH3), 13.6 (CH3) ppm. IR (neat): νmax = 2955,
˜
2926, 2856, 1736, 1487, 1431, 1234, 1204, 731, 698 cm–1. HRMS
(ESI): calcd. for C19H29N2O2S+ 349.1944; found 349.1950.
1′,5′-Bis(4-methoxyphenyl)spiro[fluorene-9,4′-imidazolidine]-
2′-thione (4c5f): According to general procedure 2, the reaction
between p-anisidine (123 mg, 1.0 mmol), 4-methoxybenzaldehyde
(828 μL, 6.6 mmol) and 9-isothiocyanato-9H-fluorene (4c; 112 mg,
0.5 mmol) afforded imidazolidine-2-thione 4c5f in trace amounts.
HRMS (ESI): calcd. for C29H24N2NaO2S 487.1451; found 487.1462.
Methyl 1-Butyl-5-(4-cyanophenyl)-4-phenyl-2-thioxoimidazol-
idine-4-carboxylate (4e5e): According to general procedure 2, the
reaction between n-butylamine (99 μL, 1.00 mmol), p-cyanobenz-
aldehyde (144 mg, 1.10 mmol) and methyl (S)-2-isothiocyanato-2-
phenylacetate (4e; 104 mg, 0.50 mmol) afforded 4e5e as a 2:1 mix-
ture of diastereoisomers of which only the minor isomer was fully
5′-Butyl-1′-(4-methoxyphenyl)spiro[fluorene-9,4′-imidazol-
idine]-2′-thione (4c5g): According to general procedure 2, the re-
action between p-anisidine (123 mg, 1.00 mmol), valeraldehyde
(351 μL, 3.30 mmol) and 9-isothiocyanato-9H-fluorene (4c; 112 mg,
0.50 mmol) afforded 4c5g as a yellow oil [41 mg, 20 %; yield based
1
isolated as a red solid (45 mg, 23 %). M.p. 154.6–158.1 °C. H NMR
(500 MHz, CDCl3): δ = 7.36 (d, J = 8.5 Hz, 2 H), 7.12–7.10 (m, 3 H),
7.03–7.02 (m, 4 H), 6.58 (s, 1 H), 5.77 (m, 1 H), 4.21 (ddd, J = 14.0,
8.0, 8.0 Hz, 1 H), 3.82 (s, 3 H), 2.72 (ddd, J = 14.0, 8.0, 6.0 Hz, 1 H),
1.54–1.50 (m, 2 H), 1.31–1.25 (m, 2 H), 0.90 (t, J = 7.5 Hz, 3 H) ppm.
13C NMR (125 MHz, CDCl3): δ = 183.3 (C), 171.4 (C), 139.3 (C), 133.6
(C), 132.1 (CH), 129.5 (CH), 128.8 (2 CH), 125.7 (2 CH), 118.3 (C),
117.9 (CH), 112.5 (C), 73.0 (C), 69.8 (CH), 54.0 (CH3), 45.3 (CH2), 29.1
1
1
on H NMR relative to the doublet at δ = 6.08 ppm (2 H)]. H NMR
(500 MHz, CDCl3): δ = 4.60 (dd, J = 9.5, 4.5 Hz, 1 H) ppm. IR (neat):
νmax = 2926, 1508, 1448, 1437, 1244, 1028, 737 cm–1. HRMS (ESI):
˜
calcd. for C26H27N2OS+ 415.1839; found 415.1825.
Methyl 1-Butyl-5-(4-methoxyphenyl)-4-phenyl-2-thioxoimid-
azolidine-4-carboxylate (4e5c): According to general procedure 2,
the reaction between n-butylamine (99 μL, 1.00 mmol), p-methoxy-
benzaldehyde (144 mg, 1.10 mmol) and methyl (S)-2-isothio-
cyanato-2-phenylacetate (4e; 104 mg, 0.50 mmol) afforded 4e5c as
a yellow solid (diastereomer 1, 68 mg) and a yellow oil (diastereo-
mer 2, 78 mg) (total yield 37 %, dr = 47:53).
(CH2), 19.9 (CH2), 13.9 (CH3) ppm. IR (neat): νmax = 3136, 2955, 2231,
˜
1737, 1481, 1244, 1148, 1059, 842, 689, 550 cm–1. HRMS (ESI): calcd.
for C22H24N3O2S+ 394.1584; found 394.1587.
Methyl 5-Butyl-1-(4-methoxyphenyl)-4-phenyl-2-thioxoimid-
azolidine-4-carboxylate (4e5g): According to general procedure 2,
the reaction between p-anisidine (123 mg, 1.00 mmol), valeralde-
Eur. J. Org. Chem. 0000, 0–0
www.eurjoc.org
8
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
[12] a) R. S. Bon, N. E. Sprenkels, M. M. Koningstein, R. F. Schmitz, F. J. J.
de Kanter, A. Domling, M. B. Groen, R. V. A. Orru, Org. Biomol. Chem.
2008, 6, 130–137; b) M. Mooijman, R. S. Bon, N. E. Sprenkels, H. N.
van Oosterhout, F. J. J. de Kanter, M. B. Groen, E. Ruijter, R. V. A. Orru,
Synlett 2012, 23, 80–84.
hyde (702 μL, 6.60 mmol) and methyl 2-isothiocyanato-2-phenyl-
acetate (4e; 104 mg, 0.50 mmol) afforded 4e5g in trace amounts.
HRMS (ESI): calcd. for C22H27N2O3S+ 399.1737; found 399.1727.
[13] J. S. Nowick, N. A. Powell, T. M. Nguyen, G. Noronha, J. Org. Chem. 1992,
57, 7364–7366.
Acknowledgments
[14] Instead of a homogeneous base, Na2CO3 was employed.
[15] For the optimization table, see the Supporting Information.
[16] R. S. Bon, C. G. Hong, M. J. Bouma, R. F. Schmitz, F. J. J. de Kanter, M.
Lutz, A. L. Spek, R. V. A. Orru, Org. Lett. 2003, 5, 3759–3762.
[17] G. V. Janssen, P. Slobbe, M. Mooijman, A. Kruithof, A. W. Ehlers, C. F.
Guerra, F. M. Bickelhaupt, J. C. Slootweg, E. Ruijter, K. Lammertsma,
R. V. A. Orru, J. Org. Chem. 2014, 79, 5219–5226.
F. J. J. de Kanter and A. W. Ehlers are kindly acknowledged for
maintaining the NMR facilities. The Ministerio de Ciencia e Inno-
vacion (MICINN), the Fundacion Española para la Ciencia y la
Tecnologıa (FECYT), the National Research School of Combina-
tion – Catalysis (NRSC-C), the Netherlands Organization for Sci-
entific Research (NWO-CW, NWO-NCF, NWO-EW) and the Dutch
Astrochemistry Network (DAN) supported by NWO are all ac-
knowledged for funding.
[18] a) E. J. Baerends, T. Ziegler, J. Autschbach, D. Bashford, A. Bérces, F. M.
Bickelhaupt, C. Bo, P. M. Boerrigter, L. Cavallo, D. P. Chong, L. Deng, R. M.
Dickson, D. E. Ellis, M. van Faassen, L. Fan, T. H. Fischer, C. Fonseca Guerra,
M. Franchini, A. Ghysels, A. Giammona, S. J. A. van Gisbergen, A. W. Götz,
J. A. Groeneveld, O. V. Gritsenko, M. Grüning, S. Gusarov, F. E. Harris, P.
van den Hoek, C. R. Jacob, H. Jacobsen, L. Jensen, J. W. Kaminski, G.
van Kessel, F. Kootstra, A. Kovalenko, M. V. Krykunov, E. van Lenthe, D. A.
McCormack, A. Michalak, M. Mitoraj, S. M. Morton, J. Neugebauer, V. P.
Nicu, L. Noodleman, V. P. Osinga, S. Patchkovskii, M. Pavanello, P. H. T.
Philipsen, D. Post, C. C. Pye, W. Ravenek, J. I. Rodríguez, P. Ros, P. R. T.
Schipper, H. van Schoot, G. Schreckenbach, J. S. Seldenthuis, M. Seth,
J. G. Snijders, M. Solà, M. Swart, D. Swerhone, G. te Velde, P. Vernooijs, L.
Versluis, L. Visscher, O. Visser, F. Wang, T. A. Wesolowski, E. M. van Wezen-
beek, G. Wiesenekker, S. K. Wolff, T. K. Woo, A. L. Yakovlev, ADF2014,
SCM, Theoretical Chemistry, Vrije Universiteit, Amsterdam, http://
www.scm.com; b) C. Fonseca Guerra, J. G. Snijders, G. te Velde, E. J. Baer-
ends, Theor. Chem. Acc. 1998, 99, 391–403; c) G. te Velde, F. M. Bickel-
haupt, E. J. Baerends, C. Fonseca Guerra, S. J. A. van Gisbergen, J. G.
Snijders, T. Ziegler, J. Comput. Chem. 2001, 22, 931–967.
[19] M. Swart, F. M. Bickelhaupt, J. Comput. Chem. 2008, 29, 724–734.
[20] a) A. Klamt, G. Schuurmann, J. Chem. Soc. Perkin Trans. 2 1993, 799–805;
b) C. C. Pye, T. Ziegler, Theor. Chem. Acc. 1999, 101, 396–408.
[21] Attempts to quantify this proton shift by means of a TS analysis were
unsuccessful.
[22] The barrier of this hypothetical concerted reaction was calculated and
gave a relative barrier of 39.7 kcal/mol, see the overview in the Support-
ing Information for more information.
Keywords: Multicomponent reactions · Computer
chemistry · Synthesis design · Density functional
calculations · Nitrogen heterocycles
[1] a) G. O. Jones, X. Li, A. E. Hayden, K. N. Houk, S. J. Danishefsky, Org. Lett.
2008, 10, 4093–4096; b) J. Mancebo-Aracil, C. Nájera, L. M. Castelló, J. M.
Sansano, O. Larrañaga, A. de Cózar, F. P. Cossío, Tetrahedron 2015, 71,
9645–9661; c) L. P. Wolters, F. M. Bickelhaupt, WIREs Comput. Mol. Sci.
2015, 5, 324–343.
[2] a) R. C. Cioc, E. Ruijter, R. V. A. Orru, Green Chem. 2014, 16, 2958–2975;
b) A. Dömling, W. Wang, K. Wang, Chem. Rev. 2012, 112, 3083–3135; c)
J. Zhu, H. Bienaymé, Multicomponent Reactions, Wiley-VCH, Weinheim,
2005; d) J. E. Biggs-Houck, A. Younai, J. T. Shaw, Curr. Opin. Chem. Biol.
2010, 14, 371–382.
[3] For recent examples, see: a) A. Milo, A. J. Neel, F. D. Toste, M. S. Sigman,
Science 2015, 347, 737–743; b) Z. L. Niemeyer, A. Milo, D. P. Hickey, M. S.
Sigman, Nat. Chem. 2016, 8, 610–617; c) R. P. Orenha, R. T. Santiago,
R. L. A. Haiduke, S. E. Galembeck, J. Comput. Chem. 2017, 38, 883–981.
[4] I. W.-S. Lin, C.-N. Lok, K. Yan, C.-M. Che, Chem. Commun. 2013, 49, 3297–
3299.
[5] P. Y. Lam, P. K. Jadhav, C. J. Eyermann, C. N. Hodge, Y. Ru, L. T. Bacheler,
J. L. Meek, M. J. Otto, M. M. Rayner, Y. N. Wong, C.-H. Chang, P. Weber,
D. A. Jackson, T. R. Sharpe, S. Erickson-Viitanen, Science 1994, 263, 380–
384.
[6] a) M. K. Denk, A. Thadani, K. Hatano, A. J. Lough, Angew. Chem. Int. Ed.
Engl. 1997, 36, 2607–2609; Angew. Chem. 1997, 109, 2719; b) N. Kuhn, T.
Kratz, Synthesis 1993, 561–562.
[7] a) R. S. Bon, B. van Vliet, N. E. Sprenkels, R. F. Schmitz, F. J. J. de Kanter,
C. V. Stevens, M. Swart, F. M. Bickelhaupt, M. B. Groen, R. V. A. Orru, J. Org.
Chem. 2005, 70, 3542–3553; b) N. Elders, R. F. Schmitz, F. J. J. de Kanter,
E. Ruijter, M. B. Groen, R. V. A. Orru, J. Org. Chem. 2007, 72, 6135–6142;
c) N. Elders, D. van der Born, L. J. D. Hendrickx, B. J. J. Timmer, A. Krause,
E. Janssen, F. J. J. de Kanter, E. Ruijter, R. V. A. Orru, Angew. Chem. Int. Ed.
2009, 48, 5856–5859; Angew. Chem. 2009, 121, 5970.
[23] a) P. W. Atkins, Physical Chemistry, 8th ed., Freeman, New York, 2006; b)
M. Swart, E. Rösler, F. M. Bickelhaupt, Eur. J. Inorg. Chem. 2007, 3646–
3654.
[24] For all anilines, 6 equiv. of aldehyde were employed to exclude urea
formation caused by incomplete imine formation.
[25] The color scheme is derived from the reactivity/ΔPA relation in the two
above-mentioned sets of experiments, and is meant to highlight the
observations discussed hereafter.
[26] M. Swart, F. M. Bickelhaupt, Computer Code QUILD (QUantum regions
Interconnected by Local Description), Vrije Universiteit, Amsterdam,
2006.
[27] E. van Lenthe, E. J. Baerends, J. Comput. Chem. 2003, 24, 1142–1156.
[28] E. van Lenthe, E. J. Baerends, J. G. Snijders, J. Chem. Phys. 1993, 99, 4597–
4610.
[8] a) B. Ganem, Acc. Chem. Res. 2009, 42, 463–472; b) E. Ruijter, R. Scheffe-
laar, R. V. A. Orru, Angew. Chem. Int. Ed. 2011, 50, 6234–6246; Angew.
Chem. 2011, 123, 6358.
[9] W. Y. Han, J. Q. Zhao, J. Zuo, X. Y. Xu, X. M. Zhang, W. C. Yuan, Adv. Synth.
Catal. 2015, 357, 3007–3031.
[10] a) R. A. Volkmann, J. T. Davis, C. N. Meltz, J. Am. Chem. Soc. 1983, 105,
5946–5948; b) C. N. Meltz, R. A. Volkmann, Tetrahedron Lett. 1983, 24,
4503–4506.
[11] a) H.-W. Zhao, B. Li, T. Tian, X.-Q. Song, H.-L. Pang, X.-Q. Chen, Z. Yang,
W. Meng, RSC Adv. 2016, 6, 27690–27695; b) Y.-Y. Han, W.-B. Chen, W.-Y.
Han, Z.-J. Wu, X.-M. Zhang, W.-C. Yuan, Org. Lett. 2012, 14, 490–493; c)
H. Cai, Y. Zhou, D. Zhang, J. Xu, H. Liu, Chem. Commun. 2014, 50, 14771–
14774.
[29] J. C. Slater, Phys. Rev. 1951, 81, 385–390.
[30] S. H. Vosko, L. Wilk, M. Nusair, Can. J. Phys. 1980, 58, 1200–1211.
[31] N. C. Handy, A. J. Cohen, Mol. Phys. 2001, 99, 403–412.
[32] a) B. G. Johnson, P. M. W. Gill, J. A. Pople, J. Chem. Phys. 1993, 98, 5612–
5626; b) C. Lee, W. Yang, R. G. Parr, Phys. Rev. B 1988, 37, 785–789; c)
T. V. Russo, R. L. Martin, P. J. Hay, J. Chem. Phys. 1994, 101, 7729–7737.
[33] N. L. Allinger, X. Zhou, J. Bergsma, J. Mol. Struct. 1994, 312, 69–83.
[34] a) J. L. Pascual-Ahuir, E. Silla, J. Comput. Chem. 1990, 11, 1047–1060; b)
J. L. Pascual-Ahuir, E. Silla, I. Tuñon, J. Comput. Chem. 1994, 15, 1127–
1138; c) E. Silla, I. Tuñón, J. L. Pascual-Ahuir, J. Comput. Chem. 1991, 12,
1077–1088.
Received: July 4, 2017
Eur. J. Org. Chem. 0000, 0–0
www.eurjoc.org
9
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
Integrative Theory/Experiment
We have exploited the strengths of
both synthetic and computational dis-
ciplines to explore the reactivity of a
three-component reaction involving
iso(thio)cyanates, amines and alde-
hydes to access multifunctionalized
imidazoline-2-(thi)ones. We explore
the predictive ability of the approach
with a view to applying it to the devel-
opment of new reactions.
A. Kruithof, J. R. Mulder, J. M. Ruiz,
E. Janssen, M. Mooijman, E. Ruijter,
C. Fonseca Guerra, F. M. Bickelhaupt,*
R. V. A. Orru* .................................... 1–10
Integrative
Theory/Experiment-
Driven Exploration of a Multicompo-
nent Reaction towards Imidazoline-
2-(thi)ones
DOI: 10.1002/ejoc.201700941
Eur. J. Org. Chem. 0000, 0–0
www.eurjoc.org
10
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim