Design and synthesis of novel indoline-(thio)urea hybrids

Article abstract of DOI:10.1080/00397911.2019.1675706

A series of novel indoline-(thio)urea were designed and prepared using indoline(s) as a new platform and tested as organocatalysts in the Michael and Morita–Baylis–Hillman reactions. Most of the compounds were found to be very active catalysts although they did not promote the enantioselectivity. As agents for the conversion of thiocarbonyl compounds into carbonyl compounds, potentials of PIFA and DDQ were also displayed. Furthermore, DFT calculations rationalized the experimentally observed non-enantioselectivity of the catalysts.

Full text of DOI:10.1080/00397911.2019.1675706

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: https://www.tandfonline.com/loi/lsyc20
Design and synthesis of novel indoline-(thio)urea
hybrids
Ferruh Lafzi, Haydar Kilic, Gamze Tanriver, Öyküm Naz Avcı, Saron Catak &
Nurullah Saracoglu
To cite this article: Ferruh Lafzi, Haydar Kilic, Gamze Tanriver, Öyküm Naz Avcı, Saron Catak
& Nurullah Saracoglu (2019): Design and synthesis of novel indoline-(thio)urea hybrids, Synthetic
Communications, DOI: 10.1080/00397911.2019.1675706
To link to this article: https://doi.org/10.1080/00397911.2019.1675706
View supplementary material
Published online: 21 Oct 2019.
Submit your article to this journal
View related articles
View Crossmark data
Full Terms & Conditions of access and use can be found at
https://www.tandfonline.com/action/journalInformation?journalCode=lsyc20

R
SYNTHETIC COMMUNICATIONSV
https://doi.org/10.1080/00397911.2019.1675706
Design and synthesis of novel indoline-(thio)urea hybrids
c
Ferruh Lafzia , Haydar Kilica,b , Gamze Tanriverc , Oykum Naz Avcı
,
€
€
Saron Catakc , and Nurullah Saracoglua
a
b
€
Department of Chemistry Faculty of Sciences, Ataturk University, Erzurum, Turkey; Oltu Vocational
c
€
Training School, Ataturk University, Erzurum, Turkey; Department of Chemistry, Bogazici University
Bebek, Istanbul, Turkey
ABSTRACT
ARTICLE HISTORY
Received 29 August 2019
A series of novel indoline-(thio)urea were designed and prepared using
indoline(s) as a new platform and tested as organocatalysts in the
Michael and Morita–Baylis–Hillman reactions. Most of the compounds
were found to be very active catalysts although they did not promote
the enantioselectivity. As agents for the conversion of thiocarbonyl
compounds into carbonyl compounds, potentials of PIFA and DDQ
were also displayed. Furthermore, DFT calculations rationalized the
experimentally observed non-enantioselectivity of the catalysts.
KEYWORDS
Conjugate addition; density
functional calculations;
Morita–Baylis–Hillman;
organocatalyst; thio-
urea; urea
GRAPHICAL ABSTRACT
Introduction
Organocatalysis refers to the use of small organic molecules to catalyze organic transfor-
mations and has become a highly dynamic area in chemical research.[1,2] Metal-free cat-
alysts or organocatalysts have been growing interest in the field of asymmetric catalysis
over the past decades due to their notable advantages such as their affordability, safety,
environmentally friendly or green chemistry, nontoxic nature, low cost, usually ease of
use, water- and air-tolerant, and the easy structural modifications.[2] Because of the
absence of transition metals, organocatalysts provide the advantage of environmentally
friendly chemistry or green chemistry, which is an essential criterion for scientific and
industrial studies.[3] The asymmetric synthesis of natural products and chiral drugs has
become an important focus for synthetic organic chemists and industrial chemists.[4]
CONTACT Saron Catak
34342, Turkey; Nurullah Saracoglu
University, Erzurum 25240, Turkey.
saron.catak@boun.edu.tr
Department of Chemistry, Bogazici University Bebek, Istanbul
€
Department of Chemistry Faculty of Sciences, Ataturk
nsarac@atauni.edu.tr
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/lsyc.
Supplemental data for this article is available online at on the publisher’s website.
ß 2019 Taylor & Francis Group, LLC

2
F. LAFZI ET AL.
Figure 1. Some proline, pyrrolidine-type and indoline-type organocatalysts.
The efficiency and the scope of organocatalysis have been broadly increased since the
rediscovery of proline-catalyzed aldol reactions.[5] Frequently, organocatalysts are classi-
fied according to their binding capacity with the substrate through a covalent bond or
noncovalent interactions such as hydrogen bonding and electrostatic cooperation.[6]
Various types of small organic molecules such as phosphoric acids,[7] proline and its
derivatives,[8] cinchona derivatives,[9] sulfones,[10] (thio)urease,[11] N-oxides,[12] and
amino acids[13] have been employed as hydrogen bonding organocatalysts in various
chemical reactions. In general, chiral (thio)urea-based molecules have found frequent
applications as organocatalysts through hydrogen-bonding interactions to coordinate
and activate H-bond accepting substrates in modern synthetic organic chemistry.[11]
Cooperative catalysis with chiral bifunctional (thio)ureas for asymmetric organocatal-
ysis has recently been a new and exciting strategy.[11] Since (thio)ureas are a stronger
H-bond donor, we were interested in exploring whether indoline-(thio)urea organocata-
lysts would perform or even better. Generally, many proline and pyrrolidine derivatives
are well-known, versatile catalysts in organic synthesis (Fig. 1),[8,11] but only scattered
examples of chiral indolines as organocatalysts are known. Indeed, only two indoline-
carboxylic acids and a few of their derivatives have been used as organocatalyst until
now.[14] This encouraged us to synthesize and evaluate the new-type indoline-(thio)ur-
eas as potential organocatalyst for the Michael addition and Morita–Baylis–Hillman
reactions. We designed that appropriate combinations of (thio)urea and indoline in a
chiral scaffold could result in a potential mono- and bifunctional organocatalysts. In
this paper, we report the preliminary results of our investigations.
Results and discussions
Initially, indoline (8) and (S)-1-phenylethyl isocyanate (9a) were employed for the syn-
thesis of indoline-urea 10a by a known method (Scheme 1).[15] Subsequent treatment of

R
SYNTHETIC COMMUNICATIONSV
3
Scheme 1. Synthesis of 11a/b from indoline (8).
10a with manganese dioxide gave indole-urea 11a in 91% yield. For the synthesis of
thiourea analog, (S)-1-phenylethyl isothiocyanate (9b) reacted with 8 to afford thiourea
10b as shown in Scheme 1. Attempt to prepare indole-thiourea derivative 11b from 10b
via a one-pot procedure involving the radical cascade and the manganese(IV) oxide
(MnO2) oxidation resulted in the formation of indole-urea 11a as an unexpected prod-
uct. The presented spectra explicitly confirm the structure of the synthesized urea 11a.
In point of fact, chiral HPLC chromatogram of compound 11a shows that the optical
purity and optical rotation were not compromised during the synthetic sequences.
Because of unexpected oxidation of thiourea to urea during dehydrogenation of indoline
to indole ring, we surveyed corresponding literature. According to this literature, a sim-
ple and efficient procedure for the mild conversion of thio-enolizable thioureas, thioa-
mides end thiolactams to ureas, amides and lactams in good yields using active
manganese dioxide were described.[16] For this reaction, Sharma et alet al. suggested a
probable mechanism involving the initial formation of carbodiimide, whereas Bhalerao
et alet al. explained a mechanism via the participation of labile hydroxyl radicals to
yield probably a cyclic intermediate that can undergo sulfur extrusion. Next, a variety of
oxidants, phenyliodine bis(trifluoroacetate) (PIFA), and 2,3-dichloro-5,6-dicyano-1,4-
benzoquinone (DDQ) were screened in the reaction. The attempt to dehydrogenate
indoline in thiourea 10b using a stoichiometric amount of DDQ gave an unexpected
urea derivative 11a as a sole product instead of thiourea 11b. Indoline-urea 10a was
oxidized with DDQ to afford the corresponding urea 11a. Also, the use of 1.1 equiv. of
PIFA as an oxidant afforded urea 10a in 82% yield. When the reaction of 10a and
PIFA under the conditions was carried out, only a trace amount of 11a was detected.
After all unsuccessful efforts, the synthesis of thiourea 11b could be achieved by direct
thionation of urea 11a with Lawesson’s reagent (LR) (reflux in toluene, 12 h; 78%)
(Scheme 1).
Next, our attention was focused on the synthesis of indoline-(enantiomers 12 and 13)
and indole-(thio)ureas 14a/b in which there can potentially behave as a bifunctional cata-
lyst (Fig. 2). To provide a cheaper synthesis cost, all test reactions were first carried out
starting from a racemic compound 15. To access the diastereoisomers (dia-12/13) of enan-
tiomers 12 and 13, esterification of indoline-2-carboxylic acid (rac-15) in the presence of
thionyl chloride and methanol led to methyl ester rac-16 in 83% yield (Scheme 2).[17]

4
F. LAFZI ET AL.
Figure 2. Structures of another type-target indoline/indole-based chiral catalyst candidates.
Scheme 2. Attempts to synthesize rac-23/24.
In next step, the methyl ester rac-16 could be converted to its amide rac-17 by treat-
ing with ammonia gas in methanol.[18] Unfortunately, all attempts to reduce the corre-
sponding amine rac-17 to amide rac-18 met with failure. We, therefore, changed our
strategy and reached to the target molecules in seven steps involving reduction, N-tert-
butoxycarbonyl (Boc) protection, tosylation, azidation, deprotection of Boc, addition,
and reduction (Scheme 2). The enantiopure synthesis of the target (thio)ureas 12 was
performed in seven steps (Scheme 3). As highlighted in Scheme 3, a lithium aluminum
hydride reduction of (S)-(-)-indoline-2-carboxylic acid (S-15) delivered the desired alco-
hol (S)-19 in 85% yield.[19] Later, alcohol (S)-19 reacted with di-tert-butyl dicarbonate
(Boc2O) in acetonitrile to give the corresponding N-Boc protected derivative (S)-20
with good yields. N-Boc indoline (S)-20 bearing alcohol was then converted into tosyl-
ate (S)-21 using tosyl chloride. Displacement of the tosylate of (S)-21 with sodium azide
in dimethyl sulfoxide (DMSO) at 64 ꢀC gave the azide (S)-22 which was then subjected
to deprotection of N-Boc with TFA to give the indoline (S)-23. The subsequent free
amine (S)-23 reacted with (S)-1-phenylethyl isocyanate (9a) in methylene chloride
under reflux to form urea (S,S)-24a. An identical procedure provided thiourea (S,S)-
24b upon treatment with a free amine (S)-23 and (S)-1-phenylethyl isothiocyanate (9b)
in refluxing 1,2-dichloroethane. The preparation of amine (S,S)-12a from the azide
(S,S)-24a was conveniently achieved by Pd/C-catalyzed hydrogenation, whereas the
reduction attempts of thiourea-azide (S,S)-24b using the same approach resulted in the
poison of catalyst system. On the other hand, the reduction of azide moiety of (S,S)-
24b to the amine (S,S)-12b was accomplished using Zn/NH4Cl as reducing agent in

R
SYNTHETIC COMMUNICATIONSV
5
Scheme 3. Synthesis of (S,S)-12a/b.
EtOH/water (3:1).[20] The synthesis of (R,R)-13a/b was also achieved following the
same protocols as explained earlier in Scheme 2.
The attempts to oxidize were performed using diastereoisomeric compounds dia-
12a and dia-24a (Scheme 4). However, the reaction of dia-12a with MnO2 (10
equiv.) in methylene chloride (CH2Cl2) gave only the unexpected fragmentation
product (S)-N-(1-phenylethyl)-1H-indole-1-carboxamide (11a) in 78% yield
(Scheme 4).
To our surprise, the treatment of dia-24a with manganese dioxide (10 equiv.) in
methylene chloride at room temperature (rt) led to the unexpected formation of the
fragmentation product 11a in nearly quantitative yield. A plausible mechanism to
account for the outcome of the reaction is proposed in Scheme 4. The corresponding
amine dia-12a (or azide dia-24a) may be initially oxidized by MnO2 to generate nitro
compound (S)-25. Retro-aldol condensation followed by allylic oxidation to give 26
may then lead to the formation of 11a. Attempts on oxidation of dia-12a with 1 equiv.
of DDQ in methylene chloride resulted in a complex mixture along with the formation
of Michael adduct dia-27 in 10% yield (Scheme 4). The structure of dia-27 was espe-
cially confirmed by high-resolution mass spectrometry (HRMS), as well as nuclear mag-
netic resonance (NMR) spectroscopy (see Supporting Information). Unfortunately,
when the azide dia-24a was treated with 1 equiv. of PIFA or DDQ, the desired

6
F. LAFZI ET AL.
Scheme 4. Attempts to synthesize (S)-13a/14a and a proposed mechanism for the formation of 11a.
oxidation product (S)-28 could be isolated in only 3.5–4% yield, along with substantial
quantities of recovered starting material (88–90%) (Scheme 4). Since many oxidation
attempts upon both dia-12a and dia-24a did not succeed to provide desired com-
pounds, the synthesis of 14a/b was not achieved.
We also aimed the preparation of the new urea and thiourea derivatives 29–31 to deter-
mine their organocatalyst behaviors (Fig. 3). N-Boc-protected chiral amine 32 played a key
role in synthesis. The organocatalyst 29a/b and 30a/b were readily synthesized by the reac-
tions of indoline N-Boc-protected chiral amine 32 with the corresponding isocyanates and
isothiocyanates 9a/b and 34a/b followed by deprotection step using TFA with high yields
(Scheme 5).
Symmetrical urea and thiourea 31a/b were synthesized in high yields via the reactions
of 1,1-carbonyldiimidazole (37) and carbon disulfide with primary amine 36, which was
obtained from deprotection of N-Boc group in 32, without incident, respectively
(Scheme 6).[21]
With a collection of all possible catalysts in hand after the synthesis, we also eval-
uated the catalytic effect of organocatalysts regarding reactivity and enantioselectivity.
The catalytic performances were initially examined in the Michael addition of indole
(38) to trans-b-nitrostyrene (39) as the model reaction. Reactions were performed using
10 mol% of 10, 11, 12, 13, and 29–31 in toluene at 25 and 50 ꢀC for 12–48 h (Table 1,
Entries 2–15). As shown in Table 1, the reactions of 38–39 were efficient but generated
nearly racemic product (82–93% conversion, almost 1:1 enantiomeric ratio (er)).

R
SYNTHETIC COMMUNICATIONSV
7
Figure 3. Structures of target indoline-based chiral catalyst candidates.
Scheme 5. Synthesis of 29a/b and 30a/b.
Scheme 6. Synthesis of 31a/b.
Structurally modified versions 10, 11, 12 and 13 were less efficient than 29–31, and
all catalysts under study were ineffective in generating 40[22] with significant enantiose-
lectivity. Screening of the solvents and temperatures for catalysts 10a and 12a did not
give expected positive results. We also examined the scope of the Michael acceptors and
donors concerning the above reaction. The reaction using 2-methylindole as a Michael
donor with catalyst 31a (20 mol%) in toluene at room temperature afforded the adduct

8
F. LAFZI ET AL.
Table 1. Catalyst screening for the asymmetric Michael addition of indole (38) to
b-nitrostyrene (39).a
Entry
Catalyst
Temperature (oC)
Time (h)
Yield (%)b
er (%)c
1
2
3
4
5
6
7
8
–
50
50
50
50
50
50
50
50
50
25
25
25
25
25
25
12
12
12
12
12
12
12
12
12
48
48
48
48
48
48
NR
NR
82
NR
NR
85
NR
81
NR
93
91
89
91
90
91
–
–
10a
10b
11a
11b
12a
12b
13a
13b
29a
29b
30a
30b
31a
31b
50.7:49.3
–
–
49.5:50.5
–
49.6:50.4
–
50.1:49.9
50.5:49.5
50.2:49.8
50.4:49.6
50.7:49.3
50.2:49.8
9
10
11
12
13
14
15
aThe reactions were performed with 0.1 mmol of 38, 0.1 mmol of 39, 10 mol% of catalyst in 1 mL of toluene.
bIsolated yield after thin-layer chromatography on silica gel.
cDetermined using HPLC on chiral OD-H column.
NR: no reaction.
Figure 4. Structures of Michael adducts 41–42.
41 in 85% yield and in a racemic form (Fig. 4).[23] The use of diethyl malonate for 48 h
in toluene at both room temperature and 60 ꢀC did not lead to product (cycloadduct
42) formation with these catalysts (Fig. 4).[24] The treatments with Michael acceptors
such as 2-cyclohexen-1-one, trans-chalcone, methyl trans-cinnamate and crotonaldehyde
with indole and indoline in the presence of catalysts (20 mol%) in toluene did not result
in any detectable reactions. Newly designed catalysts gave racemic products although
with at least the same level of reactivity as catalysts reported in the literature.
Additive effects on asymmetric catalysis are reported very well.[25] Therefore, we
expected that the resulting enantiomeric ratio (er) would be higher using chiral and
achiral Brønsted acids such as L-proline, benzoic acid, and TFA. The Michael additions
of indole (38) to trans-b-nitrostyrene (39) were also examined using 10 mol% of 10, 12,
29, and 31 as a catalyst in toluene at 25 ꢀC for 48 h for 48 h in the presence of

R
SYNTHETIC COMMUNICATIONSV
9
Table 2. Catalyst screening for the asymmetric Morita–Baylis–Hillman (MBH) reaction of 2-
cyclohexen-1-one (43) with benzaldehydes (44 and 45).a
Entry
Catalyst
BA
Yield (%)b
er (%)c
Entry
BA
Yield (%)b
er (%)c
1
2
3
4
5
6
7
8
9
–
43
NR
NR
NR
90
91
93
94
95
95
–
–
–
10
11
12
13
14
15
16
17
18
44
NR
85
83
87
88
90
90
96
94
–
10a
10b
11a
11b
12a
12b
13a
13b
50.3:49.7
50.8:49.2
51.3:48.7
52.5:47.5
50.5:49.5
51.1:48.9
52.8:47.2
50.7:49.3
49.6:50.4
49.1:50.9
51.6:48.4
49.5:50.5
51.4:48.6
50.8:49.2
aThe reactions were performed with 0.1 mmol of 43, 0.1 mmol of 44 (or 45), 30 mol% of catalyst in 1 mL of toluene.
bIsolated yield after thin-layer chromatography on silica gel.
cDetermined by HPLC on chiral OD-H column.
NR: no reaction.
L-proline, benzoic acid, and TFA. Acid co-catalysts did not also produce any positive
effects on the yield or especially enantioselectivity of the transformation.
Next, the Morita–Baylis–Hillman reactions of 2-cyclohexen-1-one (43) and 4-(trifluoro-
methyl)benzaldehyde (44) and 4-nitrobenzaldehyde (45) in the presence of 30mol% of 10,
12, 30, and 31 as organocatalysts and 4-dimethylaminopyridine (DMAP) as a nucleophile
were examined without using the solvent (Table 2, Entries 2–9, 11–18). The expected allylic
alcohols 46 and 47 were obtained in 83–96% yields although in racemic in all runs (Table
2).[26,27] Catalysts 31a/b afforded the best reaction yields. Also, the use of L-proline as co-
catalyst could not promote the desired enantioselectivity for the corresponding reactions.
As a result of these studies, most of the novel indoline-(thio)urea hybrids were able to
catalyze both Michael additions and Morita–Baylis–Hillman reactions selected as model
reactions in high yields. However, catalysis did not proceed with high enantioselectivity.
We believe that the driving force for the similar transformations is the interactions via
single and dual hydrogen-bond between the electrophiles and the catalysts (Fig. 5).
Based on extensive experimental studies, we hypothesized that the observed non-
enantioselectivity for these reactions could be explained by the high conformational
flexibility of the transition states, steric and electronic effects or the distance between
the chiral unit and the reaction center, which lead to stereocontrol of the reaction prod-
ucts (Fig. 6).
Since the catalysts 10 and 11 are not capable of double hydrogen bonding, transition
state geometries have probably more flexibility (Fig. 6, transition state TSI). We espe-
cially hoped that the other structural motifs 30–31 could promote as bifunctional
hydrogen-bond donor/Lewis base catalysts to afford enantioselective products.
Unfortunately, they could not provide the expected enantioselectivity. Presumably, the
steric hindrance and electronic effect produced by the benzene moiety in indoline

10
F. LAFZI ET AL.
Figure 5. Proposed activation modes between electrophiles and catalysts.
Figure 6. Possible transition states for Michael addition reaction and MBH reaction.
structure plays a crucial role in stereo directing. While basicity of nitrogen in ring
decreases due to delocalization into the benzene ring, the presence of benzene fragment
can also result in unfavorable steric congestion or the large distance between the reac-
tion center and the asymmetric center during the formation of transition states.

R
SYNTHETIC COMMUNICATIONSV
11
Figure 7. Free energy profile for 12a and 30a catalyzed and uncatalyzed Michael addition reaction of
indole (38) to b-nitrostyrene (39). M06-2X/6-31 þ G(d,p) with IEF-PCM in toluene; free energies in
kcal/mol at 298 K and 1 atm. Results for TS-S, TS-12a-S and TS-30a-S are shown in parenthesis.
A Density Functional Theory (DFT) study was performed to assess the non-enantio-
selectivity of catalysts 12a and 30a towards the Michael addition of indole (38) to
b-nitrostyrene (39) and to understand the catalyst’s effect on the reaction (Table 1).
The meta-hybrid GGA M06-2X[28] was used for the optimizations due to the widely
used functionally in organic systems including non-covalent interactions.[29–32] All DFT
calculations were performed at the M06-2X/6-31 þ G(d,p) level of theory considering IEF-
PCM[33] (in toluene (e ¼ 2.3741)) as implemented in Gaussian 09.[34] Since proton trans-
fer is a fast process and carbon-carbon (C–C) bond formation is the rate-determining
step (RDS), only C–C bond formation transition states (TSs) were used to compare the
selectivity of the catalysts. Conformational spaces of catalysts 12a and 30a were thor-
oughly investigated, and only the TSs with the lowest activation barriers leading to R and
S enantiomers were reported in Figs. 7–9. In this context, the uncatalyzed Michael add-
ition reaction of indole (38) and b-nitrostyrene (39) were also modeled to elucidate ener-
getic cost of the reaction, and the results were compared with the urea catalyzed Michael
reaction (Fig. 7). Computed data indicates that the free energy of activation of the uncata-
lyzed Michael addition of 38 with 39 is significantly high (DG‡ ¼ 31.5 kcal/mol) com-
pared to the urea catalyzed Michael reaction (DG‡ ꢁ 20kcal/mol) confirming the
experimentally high yields and the stabilizing effects of the novel catalysts (Fig. 7).
Along with the stabilization of TSs resulting from hydrogen-bonding interactions,
there is also stabilizing T-shaped p-interactions (edge-to-face) as shown in Fig. 8.
In the case of TS-12a-R, intramolecular N–Hꢂꢂꢂp interactions are coming from both
H’s of amine and aromatic phenyl ring on 12a (NHꢂꢂꢂp distance ¼3.27 Å and 3.31 Å);
and for TS-12a-S, CHꢂꢂꢂp stacking is shown between aromatic phenyl ring on 12a and
indole (38) (CHꢂꢂꢂp distance ¼2.28 Å). However, the stabilization through H-bonding
and T-shaped interactions are not selective, and similar interactions are preserved in

12
F. LAFZI ET AL.
Figure 8. Optimized transition states and activation barriers (DG‡) for asymmetric Michael addition of
38 to 39 using catalyst 12a. M06-2X/6-31 þ G(d,p) with IEF-PCM in toluene at 298K and 1 atm, critical
distances in Å.
Figure 9. Optimized transition states and activation barriers (DG‡) for the Michael addition of 38 to
39 catalyzed by 30a. M06-2X/6-31 þ G(d,p) with IEF-PCM in toluene at 298 K and 1 atm, critical distan-
ces in Å.

R
SYNTHETIC COMMUNICATIONSV
13
Figure 10. Proposed phenyl functionalized catalysts 48. M06-2X/6-31 þ G(d,p) with IEF-PCM in tolu-
ene at 298 K and 1 atm.
TS-12a-R and TS-12a-S. Activation barriers for Si face (TS-12a-R, DG‡ ¼ 20.1 kcal/
mol) and Re face (TS-12a-S, DG‡ ¼ 20.7 kcal/mol) attacks are nearly the same, validat-
ing the lack of enantioselectivity of 12a.
Similarly, Fig. 9 illustrates how the urea NH’s activate the b-nitrostyrene (39) through
bidentate hydrogen-bond interactions (N–HꢂꢂꢂO), as a result, indole (38) attacks 39
leading to product 40. Additionally, T-shaped p-interactions between the aromatic ring
of 30a and 38 were identified. Electron clouds on aromatic rings of 30a stabilize 38
through CH-p stacking interactions (CHꢂꢂꢂp distance¼ 2.70 Å (TS-30a-R) and 2.31 Å
and 3.00 Å (TS-30a-S)). Additionally, an N–Hꢂꢂꢂp interaction between 30a and 38 also
contributes to stabilization of indole 38 (TS-30a-S, NHꢂꢂꢂp distance ¼ 2.99 Å).
The stacked TS structures (TS-30a-R and TS-30a-S) were favored in case of bidentate
catalyst 30a. Moreover, Fig. 9 shows that the activation barriers of Re and Si face attacks
for 30a-catalyzed Michael reaction are approximately isoenergetic (DG‡ ¼ 20.9 kcal/mol
and DG‡ ¼ 20.7 kcal/mol, respectively) confirming the lack of enantioselectivity of the
catalysts, affording both R and S Michael products (40). Accordingly, intermolecular
H-bonding interactions and T-shaped stacking interactions unselectively lower the acti-
vation barriers. In line with the experimental results, 12a and 30a catalysts display non-
enantioselectivity towards the Michael addition of indole (38) to b-nitrostyrene (39).
Due to the high conformational flexibility of the catalysts, enantioselectivity was not
achieved in the current study. To enhance enantioselectivity, more rigid and sterically
crowded organocatalysts can be used by modifying the indoline moiety of the catalysts
under study. To gain insight on the effect of the R1 group on the catalyst’s ability to
select for the desired enantiomer, a phenyl substituted 48 is proposed as a selective cata-
lyst for the Michael addition reaction (Fig. 10).
Computed data in Fig. 11 show that TS-48-S considerably lowers the activation bar-
rier (by 2.7 kcal/mol) when compared to TS-48-R and could lead to higher experimental
enantioselectivities.
TS-48-S is closely packed compared to TS-48-R, which causes the stabilization of the
TS leading to the S enantiomer. The b-nitrostyrene prefers monodentate stabilization of

14
F. LAFZI ET AL.
Figure 11. Optimized TSs and relative free energies for asymmetric Michael addition of 38 to 39
using catalyst 48. M06-2X/6-31 þ G(d,p) with IEF-PCM in toluene at 298 K and 1 atm, critical distances
in Å.
the urea N–H in TS-48-S, and the amine moiety on the indoline only stabilizes the NH
of indole (N–HꢂꢂꢂN) through H-bonding interactions. Additionally, indole (38) is stabi-
lized by both phenyl groups on the catalyst 48 via T-shaped p-interactions (CHꢂꢂꢂp dis-
tance¼ 2.54 Å and 2.27 Å). In case of TS-48-R, both amine moieties on the indoline
and the urea N–H activate b-nitrostyrene (39) via H-bonding interactions. Similar to
unmodified TS-12a-R, an intramolecular N–Hꢂꢂꢂp interaction was identified (NHꢂꢂꢂp
distance ¼ 3.35 Å) in TS-48-R. However, indole (38) only interacts with the phenyl
group (R1) through T-shaped p-interaction (CHꢂꢂꢂp distance¼ 2.50 Å) in comparison to
TS-48-S. Si face approach of 38 leading to the R enantiomer (40-R) is hindered by the
phenyl group on 48 compared to Re face, affording the S enantiomer (40-S).
Consequently, computational data showed that Michael addition of 38 over the Re face
of 39 selectively leads to the S enantiomer (40-S) via phenyl functionalization of the
catalyst. In this context, it is proposed that the modification of R1 could induce higher
experimental enantioselectivities.
Conclusion
In summary, we have developed the efficient synthesis of chiral (thio)urea organocata-
lysts derived from indolines and demonstrated that the new (thio)urea derivatives can
catalyze the asymmetric Michael addition of indole with trans-b-nitrostyrene and

R
SYNTHETIC COMMUNICATIONSV
15
Morita–Baylis–Hillman reaction of 2-cyclohexen-1-one (43) with benzaldehydes (44 and
45), giving high yields (up to 93% and 96%) but low enantioselectivities. Our results,
however, indicate that PIFA and DDQ may use for an unusual conversion to urea from
thiourea without loss of the optical activity. In the future, we aim the further investiga-
tion of these catalysts in other enantioselective transformations and hope to find more
applications of these exciting molecules in asymmetric organocatalysis. DFT study pro-
vided remarkable insights into the lack of enantioselectivity for the novel catalysts con-
firming the experimental observations. Further efforts to improve the catalysts and the
development of related modified catalysts are currently underway.
Experimental section
General experimental methods
All reagents and solvents were purchased from commercial suppliers and used without
further purification. Column chromatography and thin-layer chromatography (TLC)
were performed using silica gel 60 (70–230 Fluka) and silica gel 60 HF254 (Fluka),
respectively. Melting points were carried out on a Buchi 539 capillary melting apparatus
and uncorrected. Infrared spectra were recorded on a Mattson 1000 FT-IR spectropho-
1
tometer. H NMR and 13C NMR spectra were recorded on 400 (100)-MHz Varian and
Bruker spectrometer and are reported in d units with SiMe4 as the internal standard.
Elemental analyses were carried out on a Leco CHNS-932 instrument. Enantiomeric
purity for enantioselective syntheses was determined by chiral HPLC (Hewlett Packard
1200) analysis using an enantiopure stationary phase (Daicel Chiralcel OD, OJ), eluting
with i-PrOH/hexane, and using UV detection at 254 nm. High-resolution mass
spectrometry measurements were recorded on a Q-TOF mass spectrometer.
(S)-N-(1-Phenylethyl)indoline-1-carboxamide (10a)
To a stirred solution of (S)-(1-isocyanatoethyl)benzene (123.5 mg, 0.84 mmol) in CH2Cl2
(10 mL) was added indoline (100 mg, 0.84 mmol) and stirred at room temperature for
30 min. The solvent was removed under reduced pressure and the residue was recrystal-
lized from CH2Cl2/hexane to give compound 10a as a white solid (219 mg, 98%) (Mp:
1
121–122 ꢀC). H-NMR (400 MHz, CDCl3): d 7.87 (d, J ¼ 7.9 Hz, 1 H), 7.40–7.32 (m,
4 H), 7.29–7.23 (m, 1 H), 7.16–7.12 (m, 2 H), 6.91–6.88 (m, 1 H), 5.10 (p, J ¼ 7.0 Hz,
1 H), 4.78 (bd, J ¼ 7.0 Hz, 1 H), 3.96-3.89 (m, 2 H), 3.16 (t, J ¼ 8.6 Hz, 2 H), 1.56 (d,
J ¼ 7.0 Hz, 3 H); 13C-NMR (100 MHz, CDCl3): d 154.7, 144.2, 143.9, 130.5, 128.9, 127.8,
127.5, 126.4, 124.8, 122.0, 114.9, 50.0, 47.3, 28.0, 22.8. IR (CH2Cl2, cmꢃ1): 3293, 3032,
2968, 2854, 1634, 1599, 1523, 1480, 1460, 1386, 1342, 1319, 1289, 1209, 1099, 919, 698.
HPLC (OD column; hexane/2-propanol ¼ 80/20; flow rate 0.8 mL/min; T ¼ 25 ꢀC;
25
254 nm): tR-(-) ¼ 19.3 min. Enantiomeric rate: (þ) ¼ 0.0 and (ꢃ) ¼ 100.0. ½aꢄD
¼
–40.0 (c ¼ 0.25, CH2Cl2). Anal. Calcd for C17H18N2O: C, 76.66; H, 6.81; N, 10.52.
Found: C, 76.60; H, 6.76; N, 10.60.

16
F. LAFZI ET AL.
(S)-indolin-2-ylmethanol (S-19)19
To a stirred suspension of LiAlH4 (698 mg, 18.4 mmol) in THF (15 mL) under N2 at
0 ꢀC, (S)-indoline-2-carboxylic acid (1 g, 6.1 mmol) solution in THF (20 mL) was added.
The reaction mixture was stirred at 0 ꢀC for 5 h. The reaction mixture was quenched
with saturated ammonium chloride and then extracted with dichloromethane. The com-
bined organic layers were washed with brine then dried over Na2SO4 and concentrated
on rotary evaporator. The residue was purified using column chromatography (EtOAc/
hexane ¼ 6:4, 600 mL) to give desired alcohol as light brown solid (780 mg, 85%)
1
(Mp: 65–66 ꢀC). H-NMR (400 MHz, CDCl3): d 7.05 (d, J ¼ 7.5 Hz, ¼CH, 1 H), 6.99 (t,
J ¼ 7.5 Hz, ¼CH, 1 H), 6.70 (t, J ¼ 7.5 Hz, ¼CH, 1 H), 6.59 (d, J ¼ 7.5 Hz, ¼CH, 1 H),
3.97–3.90 (m, CH, 1 H), 3.70 (br, OH, 1 H), 3.62 (dd, J ¼ 10.9, 3.8 Hz, A part of AB sys-
tems, CH2, 1 H), 3.49 (dd, J ¼ 10.9, 7.1 Hz, B part of AB systems, CH2, 1H), 3.04 (dd,
J ¼ 15.8, 9.2 Hz, A part of AB systems, CH2, 1 H), 2.72 (dd, J ¼ 15.8, 7.6 Hz, B part of
AB systems, CH2, 1H); 13C-NMR (100 MHz, CDCl3): d 150.5, 128.8, 127.5, 124.9, 119.2,
110.10, 65.4, 60.5, 32.1. IR (CH2Cl2, cmꢃ1): 3328, 3047, 2918, 2845, 1608, 1485, 1398,
1337, 1317, 1246, 1155, 1039, 748. HPLC (OJ column; hexane/2-propanol ¼ 80/20; flow
rate 1.0 mL/min; T ¼ 25 ꢀC; 254 nm): tR-(þ) ¼ 9.4 min. Enantiomeric rate: (þ) ¼ 100.0
and (-) ¼ 0.0. Anal. Calcd for C9H11NO: C, 72.46; H, 7.43; N, 9.39. Found: C, 72.44; H,
7.40; N, 9.35.
tert-Butyl (S)-2-((3-((S)-1-phenylethyl)ureido)methyl)indoline-1-carboxylate (33a)
To a solution of tert-butyl (S)-2-(aminomethyl)indoline-1-carboxylate (32) (400 mg,
1.6 mmol) in CH2Cl2 (15 mL) was added (S)-(1-isocyanatoethyl)benzene (237 mg,
1.6 mmol) and was stirred at room temperature for 4 h. The solvent was removed and
crude product was purified using column chromatography respectively (EtOAc/hexane
¼ 8:2, 300 mL) and (MeOH, 50 mL) to give 33a as a dark yellow oil (520 mg, 78%).1H-
NMR (400 MHz, CDCl3): d 7.41–7.18 (m, ¼CH, 6 H), 7.18–7.07 (m, ¼CH, 2 H), 6.94 (t,
J ¼ 7.4 Hz, ¼CH, 1 H), 5.07 (s, NH, 1 H), 4.78–4.73 (m, CH, 1 H), 4.48–4.47 (m, CH,
1 H), 3.49–3.36 (m, CH2, 1 H), 3.39–3.3.20 (m, CH2, 2 H), 2.75–2.70 (m, CH2, 1 H), 1.56
(s, CH3, 9 H), 1.41 (d, J ¼ 6.1 Hz, CH3, 3 H). IR (CH2Cl2, cmꢃ1): 3288, 3026, 2959, 2929,
2631, 2525, 1713, 1296, 1205, 1156, 1125, 1063, 1032, 965, 943, 922, 741, 697. Anal.
Calcd for C23H29N3O3: C, 69.85; H, 7.39; N, 10.62. Found: C, 69.80; H, 7.34; N, 10.58.
1
Full experimental detail, H and 13C NMR spectra, HPLC traces, and optical rotation
data. This material can be found via the “Supplementary Content” section of this
article’s webpage.’
Funding
We would like to thank The Scientific and Technological Research Council of Turkey
€ _
(TUBITAK) [Project No: 111T998]for its financial support. DFT calculations reported in this
paper were partially performed at the TUBITAK ULAKBIM High Performance and Grid
Computing Center (TRUBA resources) as well as at the computational resources at CCBG
(www.ccbg.chem.boun.edu.tr) funded by the Bogazici University Research Fund (BAP-SUP pro-
ject no. 8245).

R
SYNTHETIC COMMUNICATIONSV
17
ORCID
Ferruh Lafzi
Haydar Kilic
http://orcid.org/0000-0002-3371-0899
http://orcid.org/0000-0002-7009-9953
http://orcid.org/0000-0001-8710-2170
http://orcid.org/0000-0001-7903-6038
http://orcid.org/0000-0002-4396-8375
Gamze Tanriver
€
Oyku€m Naz Avcı
Saron Catak
Nurullah Saracoglu
http://orcid.org/0000-0002-1504-7480
References
[1] (a) List, B. Chem. Rev. 2007, 107, 5413–5413. DOI: 10.1021/cr078412e. (b) Dalko, P. I.;
Moisan, L. Angew. Chem. Int. Ed 2004, 43, 5138. DOI: 10.1002/anie.200400650. (c) Ma, J.
A.; Cahard, D. Angew. Chem. Int. Ed. 2004, 43, 4566. DOI: 10.1002/anie.200300635.
[2] (a) Shibasaki, M.; Yoshikawa, N. Chem. Rev. 2002, 102, 2187. DOI: 10.1021/cr010297z. (b)
Seayad, J.; List, B. Org. Biomol. Chem. 2005, 3, 719. DOI: 10.1039/b415217b.
[3] Takemoto, Y. Org. Biomol. Chem. 2005, 3, 4299. DOI: 10.1039/b511216h.
[4] (a) List, B.; Yang, J. W. Science 2006, 313, 1584. DOI: 10.1126/science.1131945. (b)
Enders, D.; Grondal, C.; Hu€ttl, M. R. M. Angew. Chem. Int. Ed. 2007, 46, 1570. DOI: 10.
1002/anie.200603129. (c) Pellissier, H. Tetrahedron 2007, 63, 9267. DOI: 10.1016/j.tet.
2007.06.024. (d) MacMillan, D. W. Nature 2008, 455, 304. DOI: 10.1038/nature07367. (e)
Dondoni, A.; Massi, A. Angew. Chem. Int. Ed. 2008, 47, 4638. DOI: 10.1002/anie.
200704684.
[5] List, B.; Lerner, R. A.; Barbas, C. F. J. Am. Chem. Soc. 2000, 122, 2395. DOI: 10.1021/
ja994280y.
ꢀ
[6] Aleman, J.; Cabrera, S. Chem. Soc. Rev. 2013, 42, 774. DOI: 10.1039/c2cs35380f.
[7] Connon, S. J. Angew. Chem. Int. Ed. Engl. 2006, 45, 3909. DOI: 10.1002/anie.200600529.
[8] (a) List, B. Tetrahedron 2002, 58, 5573. DOI: 10.1016/S0040-4020(02)00516-1. (b) Panday,
S. K. Tetrahedron: Asymmetry 2011, 22, 1817. DOI: 10.1016/j.tetasy.2011.09.013. (c)
Nguyen, T.-H.; Toffano, M.; Bournaud, C.; Vo-Thanh, G. Tetrahedron Lett. 2014, 55,
6377. DOI: 10.1016/j.tetlet.2014.10.004.
[9] (a) O’donnell, M. J. Acc. Chem. Res. 2004, 37, 506. DOI: 10.1021/ar0300625. (b) Lygo, B.;
Andrews, B. I. Acc. Chem. Res. 2004, 37, 518. DOI: 10.1021/ar030058t. (c) Jew, S.-S.;
Jeong, B.-S.; Yoo, M.-S.; Huh, H.; Park, H.-G. Chem. Commun. 2001, 1244. DOI: 10.1021/
ar030058t.
ꢀ
[10] Alba, A.-N. R.; Companyo, X.; Rios, R. Chem. Soc. Rev. 2010, 39, 2018. DOI: 10.1039/
b911852g.
[11] (a) Vachal, P.; Jacobsen, E. N. J. Am. Chem. Soc. 2002, 124, 10012. DOI: 10.1021/
ja027246j. (b) Connon, S. J. Chem. Commun. 2008, 2499. DOI: 10.1039/b719249e. (c)
Koutoulogenis, G.; Kaplaneris, N.; Kokotos, C. G. Beilstein J. Org. Chem. 2016, 12, 462.
DOI: 10.3762/bjoc.12.48.
[12] Liu, X.; Lin, L.; Feng, X. Acc. Chem. Res. 2011, 44, 574. DOI: 10.1021/ar200015s.
[13] Chai, Z.; Zhao, G. Catal. Sci. Technol. 2012, 2, 29. DOI: 10.1039/C1CY00347J.
[14] (a) Pietruszka, J.; Simon, R. C. Chem. Eur. J. 2010, 16, 14534. DOI: 10.1002/chem.
201002130. (b) Pietruszka, J.; Simon, R. C. ChemCatChem 2010, 2, 505. DOI: 10.1002/
cctc.201000041. (c) Kunz, R. K.; MacMillan, D. W. J. Am. Chem. Soc. 2005, 127, 3240.
DOI: 10.1021/ja042774b.
[15] Wei, S.; Yalalov, D. A.; Tsogoeva, S. B.; Schmatz, S. Catal. Today 2007, 121, 151. DOI: 10.
1016/j.cattod.2006.11.018.
[16] (a) T.; Sharma, N.; Sahni, A.; Lal, . BCSJ 1978, 51, 1245. DOI: 10.1246/bcsj.51.1245. (b)
B. R.; Rani, M.; Rahman, U.; Bhalerao, Tetrahedron 1992, 48, 1953. DOI: 10.1016/S0040-
4020(01)88517-3. (c) Corsaro, A.; Pistara, V. Tetrahedron 1998, 54, 15027. DOI: 10.1016/
S0040-4020(98)00880-1.

18
F. LAFZI ET AL.
ꢀ
ꢀ
[17] Alatorre-Santamarıa, S.; Gotor-Fernandez, V.; Gotor, V. Tetrahedron: Asymmetry 2010,
21, 2307. DOI: 10.1016/j.tetasy.2010.08.002.
[18] Nagata, R.; Tanno, N.; Kodo, T.; Ae, N.; Yamaguchi, H.; Nishimura, T.; Antoku, F.;
Tatsuno, T.; Kato, T.; Tanaka, Y. J. Med. Chem. 1994, 37, 3956. DOI: 10.1021/
jm00049a015.
[19] Brochu, J.-L.; Prakesch, M.; Enright, G. D.; Leek, D. M.; Arya, P. J. Comb. Chem. 2008,
10, 405. DOI: 10.1021/cc800036w.
[20] Lin, W.; Zhang, X.; He, Z.; Jin, Y.; Gong, L.; Mi, A. Synth. Commun. 2002, 32, 3279–3284.
DOI: 10.1081/SCC-120014032.
[21] (a) Padiya, K. J.; Gavade, S.; Kardile, B.; Tiwari, M.; Bajare, S.; Mane, M.; Gaware, V.;
Varghese, S.; Harel, D.; Kurhade, S. Org. Lett. 2012, 14, 2814. DOI: 10.1021/ol301009d.
(b) Azizi, N.; Khajeh-Amiri, A.; Ghafuri, H.; Bolourtchian, M. Mol. Divers 2011, 15, 157.
DOI: 10.1007/s11030-010-9236-7.
[22] Fan, Y.; Kass, S. R. J. Org. Chem. 2017, 82, 13288. DOI: 10.1021/acs.joc.7b02411.
[23] Mendez, I.; Rodriguez, R.; Polo, V.; Passarelli, V.; Lahoz, F. J.; Garcia-Orduna, P.;
Carmona D. Chemistry 2016, 22, 11064. DOI: 10.1002/chem.201601301.
[24] Shubina, T. E.; Freund, M.; Schenker, S.; Clark, T.; Tsogoeva, S. B. Beilstein J Org Chem.
2012, 8, 1485. DOI: 10.3762/bjoc.8.168.
[25] Hong, L.; Sun, W.; Yang, D.; Li, G.; Wang, R. Chem. Rev. 2016, 116, 4006. DOI: 10.1021/
acs.chemrev.5b00676.
[26] You, J.; Xu, J.; Verkade, J. G. Angew. Chem. 2003, 115, 5208. DOI: 10.1002/ange.
200352233.
[27] Patra, A.; Batra, S.; Joshi, B. S.; Roy, R.; Kundu, B.; Bhaduri, A. P. J. Org. Chem. 2002, 67,
5783DOI: 10.1021/jo020199t.
[28] (a) Zhao, Y.; Truhlar, D. G. Theor Chem Account 2008, 120, 215. DOI: 10.1007/s00214-
007-0310-x. (b) Zhao, Y.; Truhlar, D. G. Acc. Chem. Res. 2008, 41, 157. DOI: 10.1021/
ar700111a.
[29] Dedeoglu, B.; Catak, S.; Yildirim, A.; Bolm, C.; Aviyente, V. ChemCatChem. 2015, 7, 4173.
DOI: 10.1002/cctc.201500852.
[30] Catak, S.; Hemelsoet, K.; Hermosilla, L.; Waroquier, M.; Van Speybroeck, V. Chemistry
2011, 17, 12027. DOI: 10.1002/chem.201100712.
[31] Goossens, H.; Winne, J. M.; Wouters, S.; Hermosilla, L.; De Clercq, P. J.; Waroquier, M.;
Van Speybroeck, V.; Catak, S. J. Org. Chem. 2015, 80, 2609. DOI: 10.1021/jo5027639.
[32] Catak, S.; D’hooghe, M.; De Kimpe, N.; Waroquier, M.; Van Speybroeck, V. J. Org. Chem.
2010, 75, 885. DOI: 10.1021/jo902493w.
[33] (a) Mennucci, B.; Tomasi, J. J. Chem. Phys. 1997, 106, 5151. DOI: 10.1063/1.473558. (b)
Mennucci, B.; Cances, E.; Tomasi, J. J. Phys. Chem. B 1997, 101, 10506. DOI: 10.1021/
jp971959k. (c) Tomasi, J.; Mennucci, B.; Cances, E. J. Mol. Struct. THEOCHEM 1999, 464,
211. DOI: 10.1016/S0166-1280(98)00553-3.
[34] Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman,
J. R.; Scalmani, G.; Barone, V.; Mennucci, B.; Petersson, G. A.; et al. Gaussian 09 Revision
E.01. Gaussian, Inc.: Wallingford, CT, 2013.