3-(Hetero)aryl-4-indolylamino-α-tetralones by diastereoselective internal redox cyclization: An "azaenamine" conjugate addition

Article abstract of DOI:10.1021/jo200896y

(E)-3-(Hetero)aryl-1-(2-((E)-(indolin-1-ylimino)methyl)phenyl) prop-2-en-1-ones 1 undergo 6-exo-trig cyclization reactions upon treatment with BF₃?Me₂S in dichloromethane at low temperature to give the tetralones 10 in good yield. Th

Full text of DOI:10.1021/jo200896y

FEATURED ARTICLE
pubs.acs.org/joc
3-(Hetero)aryl-4-indolylamino-r-tetralones by Diastereoselective
Internal Redox Cyclization: An “Azaenamine” Conjugate Addition
Nugzar Ghavtadze,* Rishikesh Narayan, Birgit Wibbeling, and Ernst-Ulrich W€urthwein*
Organisch-Chemisches Institut, Westf€alische Wilhelms-Universit€at, Corrensstrasse 40, 48149 M€unster, Germany
S Supporting Information
b
ABSTRACT: (E)-3-(Hetero)aryl-1-(2-((E)-(indolin-1-ylimi-
no)methyl)phenyl)prop-2-en-1-ones 1 undergo 6-exo-trig cy-
clization reactions upon treatment with BF3 Me2S in dichlo-
3
romethane at low temperature to give the tetralones 10 in good
yield. This cyclization process can be considered to be an
intramolecular Michael-type addition which is accompanied
by an internal redox reaction as the indoline fragment is
oxidized to indole with simultaneous hydrogen shift to nitrogen
atom N1 and the R-carbon atom of the Michael system. The
reactions at the iminic centers take place via umpolung of the classical carbonyl reactivity. The reaction is diastereoselective and
affords exclusivly 3,4-disubstituted R-tetralones 10 as trans-diastereomers. According to quantum chemical calculations the
reactions take place under kinetic control with the trans-diastereomer being the kinetically favored product as it has the lower
activation barrier compared to the cis-diastereomer.
Scheme 1. Aza-Nazarov synthesis of 2H-pyrroles
’ INTRODUCTION
Polyunsaturated N-aminoindoline-derived hydrazones exhibit
chemical properties different from other hydrazone derivatives,
as we have learned from our previous studies.1 Although these
investigations were mainly focused on electrophilic cyclization
reactions2 we could demonstrate that in the case of aza-Nazarov
cyclization reactions3 the indoline fragment as part of N-
aminoindoline-derived hydrazones might be used as precursor of
the indole leaving group, which is formed in the NꢀN-bond
fission step (Scheme 1).1 The formation of 2H-pyrroles from
azadienones and silver nitrate mediated cyclizations of alkyne
hydrazones to give annulated pyridine derivatives are the first
examples of the application of aminoindoline-derived hydra-
zones in the synthesis of nitrogen-containing heterocycles.1
The strong tendency toward aromatization of the indoline fragment
upon oxidation giving the indole is a key factor which explains the
unique behavior of N-aminoindoline-derived hydrazones.
Scheme 2
We designed the system 1, which could be considered as a
precursor for the vinylogous aza-Nazarov ring-closure process.4
Here, a phenylene unit is introduced between the iminic and the
carbonyl carbon atoms in comparison to our previous system 2.
We were interested to learn about the chemical reactivity of this
system under electrophilic conditions, e.g., in the presence of
Brønsted or Lewis acids (Scheme 2).
transformed into hydrazone 5 by reacting it with N-aminoindo-
line in methanol. N-Aminoindoline was prepared from commer-
cially available indoline via a nitrosationꢀreduction sequence.6
In the next step, the ester group of 5 was converted into the
corresponding phosphonate by reacting it with deprotonated
methyl dimethylphosphonate in THF at ꢀ78 °C.7 The resulting
phosphonate 6 was used in HornerꢀWadsworthꢀEmmons
reactions8 (HWE reaction) employing various aldehydes to afford
’ RESULTS AND DISCUSSION
The cyclization precursor 1 was synthesized by a straightfor-
ward route starting with the esterification of 2-formylbenzoic
acid 3 to give 4, which was conducted in DMF using MeI in
the presence of K2CO3 under reflux.5 The ester 4 was then
Received: May 3, 2011
Published: June 10, 2011
r
2011 American Chemical Society
5185
dx.doi.org/10.1021/jo200896y J. Org. Chem. 2011, 76, 5185–5197
|

The Journal of Organic Chemistry
FEATURED ARTICLE
Scheme 3. Synthesis of (E)-3-(Hetero)aryl-1-(2-((E)-(indolin-1-ylimino)methyl)phenyl)prop-2-en-1-ones 1aꢀk
Scheme 4. Expected Reactivity of Compounds 1 upon Treatment with Lewis Acids (LA)
the E-olefination products 1aꢀk in moderate to excellent yield. The
HWE reactions were carried out at rt in THF applying t-BuOK as
base (Scheme 3).
Constitution, configuration, and conformation in the solid
state of the olefination product 1e were elucidated by X-ray
diffraction (Figure 1).9 The structures of the precursors 1aꢀk
with isolated yields of the olefination step are given in Table 1.
In order to induce a cyclization process,10 our aim was the
selective electrophilic activation of compounds 1 at the carbonyl
oxygen in the presence of the hydrazone unit by using oxophilic
Lewis acids.11 We were expecting 3-substituted benzazepinones
9 as cyclic products (Scheme 4).12
In the course of these studies, we noticed that the BF3 Et2O
3
and BF3 Me2S complexes were the best choice for promoting
3
the cyclization. Other tested Lewis acids like TiCl4 gave no
reaction at low temperature (ꢀ78 °C) but gave complex
mixtures at ꢀ15 to þ10 °C. Thus, in the following experiments
the hydrazones were treated with BF3 Me2S in dry DCM in the
3
temperature range of ꢀ10 to 0 °C. In contrast to our expecta-
Figure 1. Molecular structure of compound 1e in the solid state (X-ray
diffraction).9
tions, the products obtained were six-membered R-tetralone
derivatives 10 containing a hydrazine fragment in the side chain
and no seven membered heterocycles as analyzed by NMR
spectroscopy and X-ray diffraction (Scheme 5).
This new reaction is quite versatile with respect to the sub-
stitution pattern. Thus, the R1 substituents might be aryl moieties
5186
dx.doi.org/10.1021/jo200896y |J. Org. Chem. 2011, 76, 5185–5197

The Journal of Organic Chemistry
Table 1. Structures and Yields of (E)-3-(Hetero)aryl-1-(2-((E)-(indolin-1-ylimino)methyl)phenyl)prop-2-en-1-ones 1
FEATURED ARTICLE
bearing electron-donating or -withdrawing groups at different
positions of the aryl ring. Even aryl groups containing additional
olefinic and alkyne substituents could be introduced. Among the
tested heterocyclic groups we were successful with thiophene
and benzothiophene groups as R1 substituent. The structures
and the isolated yields of the products 10 obtained are given in
Scheme 5. Synthesis of 3-(Hetero)aryl-4-indolylamino-r-
tetralones 10 from (E)-3-(Hetero)aryl-1-(2-((E)-(indolin-1-
ylimino)methyl)phenyl)prop-2-en-1-ones 1
Table 2.
1
The H NMR spectra of the compounds 10 gave clear
evidence that exclusively the diastereomers in which substitu-
ents at position 3 and 4 are trans located to each other were
generated in the ring-forming step. The selective formation of
the trans-product was further confirmed by X-ray diffraction
(Figure 2).
5187
dx.doi.org/10.1021/jo200896y |J. Org. Chem. 2011, 76, 5185–5197

The Journal of Organic Chemistry
FEATURED ARTICLE
Table 2. Structures and Yields of 3-(Hetero)aryl-4-indolylamino-r-tetralones 10
In most cases, 1.2 equiv of the Lewis acid was sufficient to
complete the reaction, but for 10d, 10j, and 10k we used 2 equiv
of BF3 Me2S.
3
We propose the following mechanism for the observed
transformation (Scheme 6).
The key step of the reaction is the Lewis acid induced
intramolecular conjugate addition of the imine carbon atom of
the hydrazone unit to the β-carbon atom of the R,β-unsaturated
carbonyl subunit of the activated substrate 11. As a result a 6-exo-
trig cyclization affords cyclic species 12 containing the diazenium
cation fragment. Tautomerization of the diazenium cation 12
into an iminium cation 132d,13 followed by deprotonation from
the 3-position of the indoline, further protonꢀBF3 exchange and
Figure 2. Molecular structure of compound 10d in the solid state
(X-ray diffraction).9
5188
dx.doi.org/10.1021/jo200896y |J. Org. Chem. 2011, 76, 5185–5197

The Journal of Organic Chemistry
FEATURED ARTICLE
Scheme 6. Proposed Mechanism of the BF3 Me2S-Assisted Cyclization Reaction of (E)-3-(Hetero)aryl-1-(2-((E)-(indolin-1-
3
ylimino)methyl)phenyl)prop-2-en-1-ones 1 To Give Compounds 10
Scheme 7. Calculated Relative Energies for the Complete Cyclization Pathway of Compound 11 To Give 10-trans Product
(CPCM(UAKS)-HF/def2-QZVPP//HF/6-311G(d,p) and HF/def2-QZVPP//HF/6-311G(d,p) (in Parentheses) Including
Zero-Point Correction (ZPE)) (kcal/mol)
ketoꢀenol tautomerism leads to the formation of the observed
products 10 without cleavage of the NꢀN bond. Quite
interesting in this reaction sequence is the function of the
hydrazone carbon atom as a nucleophile,14 illustrating once more
5189
dx.doi.org/10.1021/jo200896y |J. Org. Chem. 2011, 76, 5185–5197

The Journal of Organic Chemistry
FEATURED ARTICLE
the reactivity of hydrazones in the sense of an “azaenamine”
featuring “Umpolung reactivity” of the CdNꢀNR2 subunit.
Furthermore, this transformation illustrates the value of indoline
substituents as internal reduction partners, which are able to
transfer hydrogen to other parts of the molecule, while being
oxidized to the much more stable aromatic indole moieties. Thus,
this reaction may be considered as an internal redox cyclization
process.15 Recently, Pan et al. and Seidel et al. have reported on
redox isomerizations of indolines to give indoles via azomethine
ylide intermediates.16
Interestingly, the computational gas-phase modeling17 by
HF/6-311G(d,p) geometry optimizations of the complete cycli-
zation pathway starting with one of the conformer of the BF3
complex 11-II (R1 = Ph)18 to give the product complex 10-
trans BF3 (Scheme 7) gave quite positive reaction energies. To
3
our surprise, B3LYP/6-311G(d,p) gas-phase calculations of the
products 12 completely failed to give the expected cyclic
structures and transition states but led back to the open-chain
BF3 complexes 11 of the starting materials. However, reason-
able reaction energies could be obtained from CPCM(UAKS)-
HF/def2-QZVPP//HF/6-311G(d,p)-(single point) calculations
with a dichloromethane solvent sphere19 on the HF structures.20
The failure of the gas phase calculations without solvent sphere
might be traced back to the change of a well delocalized
zwitterionic system (like 11) into a system with distinct charge
separation (like 12). According to the solvent sphere single-point
calculations, the ring-closing step includes an activation barrier
of approximately 20 kcal/mol, which is in agreement with
the experimental conditions (1 h of stirring at ꢀ10 to 0 °C).
The importance of the formation of the aromatic indole moiety
as driving force for this ring-closure process is nicely seen form
the relative energies of the last two tautomerisation steps.
Figure 4. Calculated relative energies for the 1,7-cyclization pathway
starting from different conformations 11-III, 11-IV (as obtained from
IRC calculations) to give 8-cis (upper line) and 8-trans (lower line) via
the corresponding transition states TS-11-III-8-cis and TS-11-IV-8-
trans (CPCM(UAKS)-HF/def2-QZVPP//HF/6-311G(d,p) and HF/
def2-QZVPP//HF/6-311G(d,p) (in parentheses) including zero-point
correction (ZPE)) (kcal/mol).
These single-point calculations also explain the exclusive
formation of the trans diastereomer by kinetic reaction control.
Thus, the transition structure TS-11-II-12-trans for the for-
mation of the trans-6-membered ring product 12-trans is
5.1 kcal/mol lower in energy compared to the transition struc-
ture TS-11-I-12-cis which leads to the cis-6-membered
ring product 12-cis. Both cis- and trans-pathways have similar
thermochemistry (Figure 3). The calculated (gas phase) transi-
tion structure TS-11-II-12-trans is nonplanar and is character-
ized by a relatively short CꢀC distance (1.92 Å) of the forming
bond. This is in accord with a Michael-type addition with small
charge separation (NBO ꢀ0.076 for the “azaenamine” carbon
and 0.026 for the β-carbon atom).21
As discussed above, experimentally, the formation of a
7-membered ring structure is not observed. The calculations
show that the cyclization reaction path starting from conformer
11-III leading to the cis-7-membered ring structure 8-cis is
endothermic by 12.7 kcal/mol and the one from 11-IV to the
trans-7-membered ring 8-trans requires a high energy conforma-
tion for the cyclization of the open-chain species (11-IV), while
the activation barrier is also very high (32.5 kcal/mol) (Figure 4).
IRC calculations prove the mutual relationship of these struc-
tures on the energy hypersurface.
’ CONCLUSIONS
In conclusion, we have shown that upon treatment with
BF3 Me2S, aminoindoline-derived unsaturated hydrazones 1
3
undergo 6-exo-trig cyclization reactions to form the tetralone
derivatives 10. This intramolecular Michael type cyclization
reactions are accompanied by an internal redox process as the
indoline fragment is oxidized into an indole with simultaneous
hydrogen shift to the H2C-CHRR0 and RHC-NH subunits,
respectively. The reaction at the iminic center takes place via
umpolung of the classical carbonyl reactivity, underlining the
Figure 3. Calculated relative energies for the 1,6-cyclization pathway
starting from different conformations of 11 (as obtained from IRC
calculations) to give 12-cis (upper line) and 12-trans (lower line) via the
corresponding transition states TS-11-I-12-cis and TS-11-II-12-trans
(CPCM(UAKS)-HF/def2-QZVPP//HF/6-311G(d,p) and HF/def2-
QZVPP//HF/6-311G(d,p) (in parentheses) including zero-point cor-
rection (ZPE)) (kcal/mol).
5190
dx.doi.org/10.1021/jo200896y |J. Org. Chem. 2011, 76, 5185–5197

The Journal of Organic Chemistry
FEATURED ARTICLE
“azaenamine” character of such species. The reaction products,
trans-3,4-disubstituted R-tetralones 10, were obtained as single
diastereomers. Quantum chemical calculations suggest that the
cyclization reaction takes place under kinetic control, thus
explaining the observed diastereoselectivity.
R-Tetralones are reported to have significant medicinal
importance.22 As both tetralone and indole moieties are biologically
active entities these novel products might be interesting for
pharmaceutical and medicinal purposes.
(neat) ~ν: 3509 (w), 3030 (w), 2957 (w), 2928 (w), 2853 (w), 1688 (w),
1666 (m), 1606 (w), 1562 (w), 1531 (m), 1487(m), 1476 (s), 1462 (m),
1402 (s), 1302 (m), 1254 (s), 1194 (s), 1167 (m), 1130 (w), 1117 (w),
1045 (s), 1022 (s), 986 (s), 891 (m), 876 (m), 835 (m), 804 (m), 760
(s), 750 (s), 725 (m), 667 (w) cmꢀ1. HRMS (ESI): calcd for C19H21N2-
O4PNa 395.1131, found 395.1130. Anal. Calcd for C19H21N2O4P
(372.35): C, 61.29; H, 5.68; N, 7.52. Found: C, 60.62; H, 5.73; N, 7.24.
General Procedure for the Preparation of (E)-3-(Hetero)-
aryl-1-(2-((E)-(indolin-1-ylimino)methyl)phenyl)prop-2-en-
1-ones (1). t-BuOK (1.2 equiv) was dissolved in abs THF (1 mmol of
the base in 10 mL of solvent), and the ketophosphonate 3 (1 equiv) in
THF (1 mmol of the compound in 2 mL of the solvent) was added. The
reaction mixture was stirred for 1 h at rt, and the aromatic aldehyde
(1 equiv) in THF was added. The reaction mixture was stirred for the
time indicated in Table 1 at rt, and then the solvent was evaporated.
The residue was dissolved in dichloromethane, washed with brine, dried
with MgSO4, concentrated, and purified by column chromatography.
In all cases, the E-product is observed in crude NMR.
’ EXPERIMENTAL SECTION
Melting points are uncorrected. 1H, 13C, 19F, 31P, GCOSY, GHSQC,
GHMBC and 1D-NOE NMR spectroscopy: TMS (1H) (0.00 ppm) and
CDCl3 (13C) (77.0 ppm) were used as internal references, and CFCl3
(19F) (0.0 ppm) and 85% H3PO4 (31P) (0.0 ppm) were used as external
references. When necessary, the experiments were carried out with
complete exclusion of moisture.
(E)-1-(2-((E)-(Indolin-1-ylimino)methyl)phenyl)-3-phenyl-
prop-2-en-1-one (1a). This compound was obtained from (E)-
dimethyl 2-(2-((indolin-1-ylimino)methyl)phenyl)-2-oxoethylphospho-
nate 6 (0.225 g, 0.6 mmol) and benzaldehyde (0.064 g, 0.6 mmol)
according to the general procedure. The subsequent chromatographic
purification (Et2O/pentane, 1:4) gave 0.180 g (0.51 mmol, 85%) of 1a
(E)-Methyl 2-((Indolin-1-ylimino)methyl)benzoate (5).
This compound was prepared from the 2-methoxycarbonylbenzaldezyde
4 and N-aminoindoline. 2-Methoxycarbonylbenzaldehyde 4 0.164 g
(1 mmol) was dissolved in methanol (4 mL), and N-aminoindoline
(1.1 mmol) in ethanol (1 mL) was added slowly at 0 °C. The reaction
mixture was stirred at rt for 30 min. The resulting product was separated
by filtration and washed with water and cold methanol. 5. Yellow solid,
1
as a yellow solid. Mp: 113ꢀ114 °C. H NMR (400 MHz, CDCl3): δ
1
3.04 (t, J = 8.2 Hz, 2H, CH2), 3.67 (t, J = 8.2 Hz, 2H, CH2N), 6.70 (td, J =
7.2, 1.1 Hz, 1H, H-arom), 6.98 (d, J = 7.3 Hz, 1H, H-arom), 7.04ꢀ7.13
(m, 3H), 7.21 (td, J = 7.5, 0.9 Hz, 1H, H-arom), 7.25ꢀ7.27 (m, 3H),
7.36ꢀ7.43 (m, 5H), 7.54 (s, 1H, CHN), 7.97 (d, J = 7.9 Hz, 1H, H-
arom). 13C NMR (100 MHz, CDCl3): δ 26.9 (CH2), 47.9 (CH2N),
109.0 (CH), 120.4 (CH), 124.7 (CH), 126.2 (CH), 126.8 (CH), 126.9
(CH), 127.4, 127.8 (CH), 128.3 (CH), 128.4 (CH), 128.9 (CH), 130.4
(CH), 130.5 (CH), 130.6 (CH), 134.5, 135.2, 137.2, 145.1 (CH), 147.6,
196.0 (CO). IR (neat) ν~: 3051 (w), 3030 (w), 2953 (w), 2926 (w), 2897
(w), 2872 (w), 2853 (w), 1659 (m), 1607 (m), 1570 (m), 1547 (m),
1485 (m), 1435 (m), 1396 (m), 1329 (m), 1298 (m), 1265 (m), 1252
(m), 1204 (m), 1192 (m), 1161 (m), 1113 (m), 999 (m), 988 (m),
978 (m), 955 (m), 918 (w), 891 (w), 843 (w), 797 (w), 775 (w), 754
(s), 739 (s), 689 (m), 679 (m), 650 (m), 619 (w) cmꢀ1. HRMS (ESI):
calcd for C24H20N2OH 353.1648, found 353.1655. Anal. Calcd for
C24H20N2O (352.43): C, 81.79; H, 5.72; N, 7.95. Found: C, 81.22; H,
5.68; N, 7.69.
0.194 g (0.69 mmol, 69%). Mp: 105ꢀ106 °C. H NMR (300 MHz,
CDCl3): δ 3.25 (t, J = 8.2 Hz, 2H, CH2), 3.91 (s, 1H, CH3O), 3.94 (t, J =
8.2 Hz, 2H, CH2N), 6.83 (td, J = 7.2, 1.3 Hz, 1H, H-arom), 7.13ꢀ7.31
(m, 4H, H-arom), 7.51 (t, J = 7.6 Hz, 1H, H-arom), 7.91 (dd, J = 7.9, 1.1
Hz, 1H, H-arom), 8.23 (d, J = 8.0 Hz, 1H, H-arom), 8.30 (s, 1H, CHN).
13C NMR (75 MHz, CDCl3): δ 27.0 (CH2), 48.2 (CH2N), 52.1
(CH3O), 109.0 (CH), 120.5 (CH), 124.9 (CH), 126.0 (CH), 126.9
(CH), 127.0, 127.7, 127.8 (CH), 130.6 (CH), 131.8 (CH), 132.0 (CH),
137.6, 147.8, 167.9 (COO). IR (neat) ν~ 3057 (w), 3024 (w), 2988 (w),
2945 (w), 1709 (m), 1609 (w), 1572 (m), 1543 (m), 1477 (m), 1431
(m), 1398 (m), 1352 (w), 1300 (m), 1240 (s), 1188 (m), 1161 (m),
1074 (m), 1047 (w), 1036 (w), 970 (w), 897 (m), 841 (w), 764 (w), 754
(m), 743 (s), 702 (m), 660 (w) cmꢀ1. HRMS (ESI): calcd for
C17H16N2O2Na 303.1109, found 303.1127. Anal. Calcd for C17H16-
N2O2 (280.32): C, 72.84; H, 5.75; N, 9.99. Found: C, 72.89; H, 5.67;
N, 10.05.
(E)-Dimethyl 2-(2-((Indolin-1-ylimino)methyl)phenyl)-2-
oxoethylphosphonate (6). Dimethyl methylphosphonate 0.14 mL
(1.3 mmol, d = 1.161) was dissolved in abs THF (1 mmol of the
compound in 1.5 mL of solvent) and cooled to ꢀ78 °C, and 0.81 mL
of n-BuLi (1.6 M in hexane, 1.3 mmol) was added slowly. The reaction
mixture was stirred for 1 h at ꢀ78 °C. Then the hydrazone 5 0.280 g
(1 mmol) in abs THF (1 mmol of the compound in 0.5 mL) was added.
The reaction mixture was stirred for 4 h at ꢀ78 °C and then quenched
with AcOH (1 equiv) and water (ca. 10 equiv). After evaporation of most
of the liquid phase, the residue was dissolved in dichloromethane and
washed with water and then with saturated aqueous NaHCO3 solution
and again with water. The residue was dried with MgSO4 and purified by
(E)-1-(2-((E)-(Indolin-1-ylimino)methyl)phenyl)-3-p-tolyl-
prop-2-en-1-one (1b). This compound was obtained from (E)-dimethyl
2-(2-((indolin-1-ylimino)methyl)phenyl)-2-oxoethylphosphonate 6 (0.225
g, 0.6 mmol) and 4-methylbenzaldehyde (0.072 g, 0.6 mmol) according
to the general procedure. The subsequent chromatographic purification
(Et2O/pentane, 1:5) gave 0.160 g (0.44 mmol, 73%) of 1b as an orange
solid. Mp: 134ꢀ135 °C. 1HNMR(400MHz, CDCl3):δ2.26 (s, 3H, CH3),
3.06 (t, J = 8.3 Hz, 2H, CH2), 3.69 (t, J = 8.3 Hz, 2H, CH2N), 6.71 (td, J =
7.2, 1.3 Hz, 1H, H-arom), 6.99 (d, J = 7.4 Hz, 1H, H-arom), 7.03 (d, J =
16.0 Hz, 1H, H-olef), 7.07ꢀ7.14 (m, 4H), 7.22 (td, J = 7.5, 1.1 Hz, 1H,
H-arom), 7.32ꢀ7.43 (m, 5H), 7.56 (s, 1H, CHN), 8.00 (d, J = 7.9 Hz, 1H,
H-arom). 13C NMR (100 MHz, CDCl3): δ 21.5 (CH3), 26.9 (CH2), 47.9
(CH2N), 109.0 (CH), 120.4 (CH), 124.7 (CH), 126.0 (CH), 126.1 (CH),
126.8 (CH), 127.4, 127.8 (CH), 128.38 (CH), 128.43 (CH), 129.7 (CH),
130.5 (CH), 131.8, 135.2, 137.4, 141.1, 145.5 (CH), 147.6, 196.1 (CO). IR
(neat) ~ν: 3049 (w), 3026 (w), 2914 (w), 2855 (w), 1659 (m), 1597 (m),
1568 (m), 1545 (m), 1487 (m), 1476 (m), 1439 (m), 1400 (m), 1325 (m),
1300 (m), 1256 (s), 1217 (w), 1198 (s), 1163 (m), 1115 (w), 1059 (w),
1015 (m), 991 (m), 970 (w), 878 (w), 812 (s), 773 (m), 743 (s), 716 (w),
650 (w), 633 (w) cmꢀ1. HRMS (ESI): calcd for C25H22N2OH 367.1805,
found 367.1817. Anal. Calcd for C25H22N2O (366.45): C, 81.94; H, 6.05; N,
7.64. Found: C, 81.81; H, 6.00; N, 7.42.
1
column chromatography. 6. Yellow oil, 0.310 g (0.83 mmol, 83%). H
NMR (400 MHz, CDCl3): δ 3.24 (t, J = 8.3 Hz, 2H, CH2), 3.58 (d, J =
22.1 Hz, 2H, CH2P), 3.72 (d, J = 11.2 Hz, 6H, CH3O), 3.88 (t, J = 8.2 Hz,
2H, CH2N), 6.83 (td, J = 7.2, 1.6 Hz, 1H, H-arom), 7.13ꢀ7.20 (m, 3H, H-
arom), 7.32 (td, J = 7.6, 1.1 Hz, 1H, H-arom), 7.47 (td, J = 7.9, 1.1 Hz, 1H,
H-arom), 7.60 (dd, J = 7.7, 0.9 Hz, 1H, H-arom), 7.73 (s, 1H, CHN), 7.88
(d, J = 7.8 Hz, 1H, H-arom). 13C NMR (100 MHz, CDCl3): δ 27.0
(CH2), 40.8 (d, J = 128.4 Hz, CH2P), 48.0 (CH2N), 52.9 (d, J = 6.4 Hz,
CH3O), 108.8 (CH), 120.8 (CH), 124.9 (CH), 126.9 (CH), 127.0 (CH),
127.5, 128.0 (CH), 129.1 (CH),130.6 (CH), 131.4 (CH), 135.3, 136.2 (d,
J = 2.0 Hz), 147.3, 196.3 (CO). 31P NMR (162 MHz, CDCl3): δ 23.2. IR
5191
dx.doi.org/10.1021/jo200896y |J. Org. Chem. 2011, 76, 5185–5197

The Journal of Organic Chemistry
FEATURED ARTICLE
(E)-1-(2-((E)-(Indolin-1-ylimino)methyl)phenyl)-3-(3-metho-
xyphenyl)prop-2-en-1-one (1c). This compound was obtained
from (E)-dimethyl 2-(2-((indolin-1-ylimino)methyl)phenyl)-2-oxoethyl-
phosphonate 6 (0.225 g, 0.6 mmol) and 3-methoxybenzaldehyde (0.082 g,
0.6 mmol) according to the general procedure. The subsequent chro-
matographic purification (Et2O/pentane, 1:4) gave 0.200 g (0.52 mmol,
87%) of 1c as an orange solid. Mp: 100ꢀ101 °C. 1H NMR (300 MHz,
CDCl3): δ 3.05 (t, J = 8.2 Hz, 2H, CH2), 3.69 (m, 5H, CH2N, CH3O),
6.71 (td, J = 7.1, 1.5 Hz, 1H, H-arom), 6.83 (dd, J = 8.2, 2.5 Hz, 1H, H-
arom), 6.94ꢀ7.25 (m, 8H), 7.34ꢀ7.44 (m, 3H), 7.55 (s, 1H, CHN),
7ꢀ97 (d, J = 7.9 Hz, 1H, H-arom). 13C NMR (75 MHz, CDCl3): δ 26.9
(CH2), 47.9 (CH2N), 55.2 (CH3O), 109.0 (CH), 113.1 (CH), 116.4
(CH), 120.5 (CH), 121.0 (CH), 124.7 (CH), 126.2 (CH), 126.8 (CH),
127.2 (CH), 127.4, 127.8 (CH), 128.5 (CH), 129.9 (CH), 130.4 (CH),
130.6 (CH), 135.2, 135.9, 137.2, 145.0 (CH), 147.6, 159.8, 196.0 (CO).
IR (neat) ν(tilde): 3055 (w), 3030 (w), 3005 (w), 2936 (w), 2853 (w),
2835 (w), 1645 (m), 1597 (s), 1578 (s), 1551 (m), 1477 (s), 1464 (s),
1435 (m), 1402 (s), 1321 (m), 1298 (m), 1258 (s), 1231 (s), 1192 (s),
1157 (s), 1117 (w), 1042 (m), 1015 (m), 982 (m), 883 (m), 853 (m),
(m), 970 (w), 874 (w), 820 (s), 800 (w), 760 (m), 746 (s), 716 (w), 662
(w), 637 (w) cmꢀ1. HRMS (ESI): calcd for C24H19ClN2ONa 409.1078,
found 409.1070.
X-ray crystal structure analysis of 1e:9 formula C24H19ClN2O, M =
386.86, orange crystal 0.25 ꢁ 0.10 ꢁ 0.05 mm, a = 6.0519(2) Å, b =
10.2844(8) Å, c = 16.9410(8) Å, R = 74.927(5)°, β = 88.001(4)°, γ =
77.262(5)°, V = 992.79(10) Å3, Fcalc = 1.294 g cmꢀ3, μ = 1.825 mmꢀ1
,
empirical absorption correction (0.658 e T e 0.914), Z = 2, triclinic,
space group P1 bar (No. 2), λ= 1.54178 Å, T = 223(2) K, ω and j scans,
11836 reflections collected ((h, ( k, ( l), [(sin θ)/λ] = 0.60 Åꢀ1, 3302
independent (Rint = 0.039) and 2883 observed reflections [I g 2σ(I)],
253 refined parameters, R = 0.071, wR2 = 0.195, max (min) residual
electron density 1.27 (ꢀ0.39) e Åꢀ3, hydrogen atoms calculated and
refined as riding atoms.
(E)-3-(2-Bromophenyl)-1-(2-((E)-(indolin-1-ylimino)methyl)-
phenyl)prop-2-en-1-one (1f). This compound was obtained from
(E)-dimethyl 2-(2-((indolin-1-ylimino)methyl)phenyl)-2-oxoethylpho-
sphonate 6 (0.225 g, 0.6 mmol) and 2-bromobenzaldehyde (0.111 g,
0.6 mmol) according to the general procedure. The subsequent chro-
matographic purification (Et2O/pentane, 1:4) gave 0.240 g (0.56 mmol,
789 (m), 743 (s), 708 (m), 677 (m), 654 (w), 636 (w), 606 (w) cmꢀ1
.
1
HRMS (ESI): calcd for C25H22N2O2H 383.1754, found 383.1753. Anal.
Calcd for C25H22N2O2 (382.45): C, 78.51; H, 5.80; N, 7.32. Found: C,
78.36; H, 5.97; N, 6.87.
93%) of 1f as a red oil. H NMR (400 MHz, CDCl3): δ 3.12 (t, J =
8.3 Hz, 2H, CH2), 3.76 (t, J = 8.3 Hz, 2H, CH2N), 6.73 (td, J = 7.0,
1.8 Hz, 1H, H-arom), 6.98 (d, J = 16 Hz, 1H, H-olef), 7.02 (d, J = 7.3 Hz,
1H, H-arom), 7.07ꢀ7.28 (m, 5H, H-arom), 7.40ꢀ7.54 (m, 4H, H-
arom), 7.59 (s, 1H, CHN), 7.78 (d, J = 16 Hz, 1H, H-olef), 7.94 (d, J =
7.8 Hz, 1H, H-arom). 13C NMR (100 MHz, CDCl3): δ 27.0 (CH2), 48.0
(CH2N), 109.1 (CH), 120.5 (CH), 124.8 (CH), 125.7, 126.5 (CH),
126.9 (CH), 127.4, 127.7 (CH), 127.8 (CH), 127.9 (CH), 128.7 (CH),
129.7 (CH), 130.5 (CH), 130.8 (CH), 131.2 (CH), 133.4 (CH), 134.9,
135.4, 136.9, 143.1 (CH), 147.6, 195.8 (CO). IR (neat) ν~: 3040 (w),
3030 (w), 2924 (w), 2853 (w), 1657 (m), 1607 (m), 1595 (m), 1545
(m), 1477 (s), 1464 (s), 1439 (m), 1400 (s), 1352 (w), 1319 (m), 1300
(m), 1260 (s), 1202 (s), 1194 (s), 1161 (m), 1113 (m), 1047 (m), 1024
(m), 1012 (m), 976 (m), 926 (w), 883 (w), 860 (w), 804 (w), 743 (s),
667 (m), 646 (m), 604 (w) cmꢀ1. HRMS (ESI): calcd for C24H19BrN2-
OH 431.0754/433.0734, found 431.0753/433.0734.
(E)-3-(Benzo[d][1,3]dioxol-5-yl)-1-(2-((E)-(indolin-1-ylimi-
no)methyl)phenyl)prop-2-en-1-one (1d). This compound was
obtained from (E)-dimethyl 2-(2-((indolin-1-ylimino)methyl)phenyl)-
2-oxoethylphosphonate 6 (0.225 g, 0.6 mmol) and piperonal (0.090 g,
0.6 mmol) according to the general procedure. The subsequent chro-
matographic purification (Et2O/pentane, 1:4) gave 0.130 g (0.33 mmol,
1
55%) of 1d as a red solid. Mp: 169ꢀ170 °C. H NMR (300 MHz,
CDCl3): δ 3.09 (t, J = 8.2 Hz, 2H, CH2), 3.72 (t, J = 8.3 Hz, 2H, CH2N),
5.92 (s, 2H, OCH2O), 6.70ꢀ6.75 (m, 2H), 6.88ꢀ7.13 (m, 6H), 7.23
(td, J = 7.5, 1.1 Hz, 1H, H-arom), 7.31ꢀ7.43 (m, 3H), 7.57 (s, 1H,
CHN), 8.01 (d, J = 7.9 Hz, 1H, H-arom). 13C NMR (75 MHz, CDCl3):
δ 27.0 (CH2), 47.9 (CH2N), 101.6 (OCH2O), 106.6 (CH), 108.6 (CH),
109.0 (CH), 120.4 (CH), 124.7 (CH), 125.0 (CH), 125.1 (CH), 126.1
(CH), 126.8 (CH), 127.4, 127.8 (CH), 128.4 (CH), 129.0, 130.50 (CH),
130.54 (CH), 135.1, 137.5, 145.2 (CH), 147.7, 148.4, 149.9, 195.9
(CO). IR (neat) ν~: 3055 (w), 3024 (w), 2928 (w), 2911 (w), 2853 (w),
1655 (m), 1607 (m), 1587 (m), 1564 (m), 1539 (m), 1487 (s), 1446 (s),
1402 (s), 1368 (m), 1269 (s), 1261 (s), 1248 (s), 1196 (s), 1159 (s),
1111 (w), 1103 (m), 1028 (s), 982 (s), 918 (m), 864 (m), 847 (m), 818
(m), 768 (s), 750 (s), 735 (s), 702 (w), 656 (m) cmꢀ1. HRMS (ESI):
calcd for C25H20N2O3H 397.1547, found 397.1552. Anal. Calcd for
C25H20N2O3 (396.44): C, 75.74; H, 5.08; N, 7.07. Found: C, 75.13; H,
5.11; N, 6.92.
(E)-1-(2-((E)-(Indolin-1-ylimino)methyl)phenyl)-3-(4-(tri-
fluoromethyl)phenyl)prop-2-en-1-one (1g). This compound was
obtained from (E)-dimethyl 2-(2-((indolin-1-ylimino)methyl)phenyl)-
2-oxoethylphosphonate 6 (0.225 g, 0.6 mmol) and 4-trifluoromethyl-
benzaldehyde (0.105 g, 0.6 mmol) according to the general procedure.
The subsequent chromatographic purification (Et2O/pentane, 1:4)
gave 0.170 g (0.40 mmol, 67%) of 1g as a red solid. Mp: 142ꢀ
1
143 °C. H NMR (400 MHz, CDCl3): δ 3.06 (t, J = 8.3 Hz, 2H,
CH2), 3.69 (t, J = 8.3 Hz, 2H, CH2N), 6.71 (td, J = 7.1, 1.7 Hz, 1H, H-
arom), 6.98 (d, J = 7.3 Hz, 1H, H-arom), 7.03ꢀ7.14 (m, 3H), 7.23 (td,
J = 7.5, 1.1 Hz, 1H, H-arom), 7.37ꢀ7.44 (m, 3H), 7.47ꢀ7.52 (m, 4H, H-
arom), 7.54 (s, 1H, CHN), 7.90 (d, J = 7.6 Hz, 1H, H-arom). 13C NMR
(100 MHz, CDCl3): δ 26.9 (CH2), 47.9 (CH2N), 109.0 (CH), 120.6
(CH), 123.8 (q, J = 272.3 Hz, CF3), 124.8 (CH), 125.8 (q, J = 3.8 Hz,
CHCCF3), 126.6 (CH), 126.9 (CH), 127.4, 127.8 (CH), 128.3 (CH),
128.5 (CH), 129.1 (CH), 130.3 (CH), 130.9 (CH), 131.2, 131.7 (q, J =
(E)-3-(4-Chlorophenyl)-1-(2-((E)-(indolin-1-ylimino)methyl)-
phenyl)prop-2-en-1-one (1e). This compound was obtained from
(E)-dimethyl 2-(2-((indolin-1-ylimino)methyl)phenyl)-2-oxoethylphos-
phonate 6 (0.225 g, 0.6 mmol) and 4-chlorobenzaldehyde (0.085 g,
0.6 mmol) according to the general procedure. The subsequent chro-
matographic purification (Et2O/pentane, 1:4) gave 0.135 g (0.35 mmol,
58%) of 1e as an orange solid. Mp: 165ꢀ166 °C. 1H NMR (400 MHz,
CDCl3): δ 3.09 (t, J = 8.3 Hz, 2H, CH2), 3.72 (t, J = 8.3 Hz, 2H, CH2N),
6.73 (td, J = 7.1, 1.6 Hz, 1H, H-arom), 7.00ꢀ7.12 (m, 4H), 7.22ꢀ7.27
(m, 3H), 7.34ꢀ7.44 (m, 5H, H-arom), 7.56 (s, 1H, CHN), 7.96 (dd, J =
7.9, 0.5 Hz, 1H, H-arom). 13C NMR (100 MHz, CDCl3): δ 27.0 (CH2),
47.9 (CH2N), 109.0 (CH), 120.6 (CH), 124.8 (CH), 126.4 (CH), 126.9
(CH), 127.38 (CH), 127.43, 127.8 (CH), 128.5 (CH), 129.2 (CH),
129.5 (CH), 130.4 (CH), 130.7 (CH), 133.1, 135.3, 136.4, 137.1, 143.4
(CH), 147.6, 195.7 (CO). IR (neat) ν~: 3049 (w), 3028 (w), 2914 (w),
2853 (w), 1665 (m), 1605(m), 1566 (m), 1543 (m), 1487 (s), 1477 (s),
1467 (m), 1436 (m), 1400 (s), 1350 (w), 1298 (m), 1263 (s), 1254 (s),
1202 (s), 1194 (s), 1163 (m), 1115 (w), 1088 (m), 1011 (m), 986
32.6 Hz, CCF3), 135.4, 136.8, 138.1, 142.3 (CH), 147.5, 195.5 (CO). 19
F
NMR (282.5 MHz, CDCl3): δ ꢀ62.8. IR (neat) ~ν: 3057 (w), 3028 (w),
2920 (w), 2876 (w), 2859 (w), 1668 (m), 1631 (m), 1607 (m), 1566
(w), 1543 (m), 1485 (m), 1477 (s), 1439 (m), 1400 (m), 1321 (s), 1300
(m), 1263 (m), 1206 (m), 1163 (s), 1126 (s), 1109 (s), 1067 (s), 1040
(w), 1011 (m), 989 (m), 968 (w), 959 (w), 895 (w), 829 (s), 760 (m),
745 (s), 685 (w), 656 (m), 617 (w) cmꢀ1. HRMS (ESI): calcd for
C25H19F3N2OH 421.1522, found 421.1523. Anal. Calcd for C25H19-
F3N2O (420.43): C, 71.42; H, 4.56; N, 6.66. Found: C, 71.28; H, 4.58;
N, 6.51.
(E)-1-(2-((E)-(Indolin-1-ylimino)methyl)phenyl)-3-(2-vinyl-
phenyl)prop-2-en-1-one (1h). This compound was obtained from
5192
dx.doi.org/10.1021/jo200896y |J. Org. Chem. 2011, 76, 5185–5197

The Journal of Organic Chemistry
FEATURED ARTICLE
(E)-dimethyl 2-(2-((indolin-1-ylimino)methyl)phenyl)-2-oxoethylpho-
sphonate 6 (0.225 g, 0.6 mmol) and 2-vinylbenzaldehyde (0.080 g,
0.6 mmol) according to the general procedure. The subsequent chro-
matographic purification (Et2O/pentane, 1:5) gave 0.130 g (0.34 mmol,
147.6, 195.3 (CO). IR (neat) ~ν: 3100 (w), 3084 (w), 3049 (w), 3028
(w), 2936 (w), 2920 (w), 2899 (w), 2859 (w), 1654 (m), 1607 (m), 1582
(s), 1545 (s), 1485 (s), 1477 (s), 1462 (m), 1443 (w), 1404 (s), 1364
(m), 1300 (m), 1267 (m), 1256 (s), 1231 (m), 1206 (s), 1194 (s), 1163
(m), 1115 (w), 1086 (w), 1044 (w), 1013 (s), 964 (s), 880 (w), 870 (m),
847 (m), 827 (m), 768 (m), 745 (s), 729 (s), 700 (m), 690 (m), 656 (m),
626 (w) cmꢀ1. HRMS (ESI): calcd for C22H18N2OSH 359.1213, found
359.1213.
1
57%) of 1h as a red oil. H NMR (400 MHz, CDCl3): δ 3.10 (t,
J = 8.3 Hz, 2H, CH2), 3.74 (t, J = 8.3 Hz, 2H, CH2N), 5.26 (dd, J = 11.0,
1.1 Hz, 1H, CH2-olef), 5.50 (dd, J = 17.3, 1.1 Hz, 1H, CH2-olef), 6.73
(td, J = 7.2, 1.3 Hz, 1H, H-arom), 6.88 (dd, J = 17.3, 11.0 Hz, 1H,
CH-olef), 6.98 (d, J = 15.9 Hz, 1H, H-olef), 7.02 (d, J = 7.3 Hz, 1H, H-
arom), 7.07ꢀ7.29 (m, 5H), 7.38ꢀ7.48 (m, 4H), 7.59 (s, 1H, CHN),
7.79 (d, J = 15.9 Hz, 1H, H-olef), 7.96 (d, J = 7.7 Hz, 1H, H-arom). 13C
NMR (100 MHz, CDCl3): δ 27.0 (CH2), 48.0 (CH2N), 109.1 (CH),
118.1 (CH2), 120.5 (CH), 124.8 (CH), 126.4 (CH), 126.9 (CH), 127.0
(CH), 127.1 (CH), 127.4, 127.88 (CH), 127.91 (CH), 128.6 (CH),
129.0 (CH), 130.1 (CH), 130.5 (CH), 130.7 (CH), 132.8, 134.1 (CH),
135.3, 137.3, 138.4, 142.6 (CH), 147.6, 195.9 (CO). IR (neat) ν~: 3084
(w), 3057 (w), 3028 (w), 2928 (w), 2855 (w), 1657 (m), 1589 (m),
1545 (m), 1477 (s), 1464 (s), 1441 (m), 1400 (m), 1321 (m), 1300 (m),
1260 (s), 1194 (s), 1161 (m), 1113 (w), 1061 (w), 1013 (m), 978 (m),
920 (m), 883 (w), 858 (w), 820 (w), 743 (s), 708 (w), 691 (w), 652
(w) cmꢀ1. HRMS (ESI): calcd for C26H22N2OH 379.1805, found
379.1798. Anal. Calcd for C26H22N2O (378.47): C, 82.51; H, 5.86; N,
7.40. Found: C, 82.24; H, 5.91; N, 7.35.
(E)-1-(2-((E)-(Indolin-1-ylimino)methyl)phenyl)-3-(2-(phe-
nylethynyl)benzo[b]thiophene-3-yl)prop-2-en-1-one (1k).
This compound was obtained from (E)-dimethyl 2-(2-((indolin-1-
ylimino)methyl)phenyl)-2-oxoethylphosphonate 6 (0.225 g, 0.6 mmol)
and 2-(phenylethynyl)benzo[b]thiophene-3-carbaldehyde (0.157 g,
0.6 mmol) according to the general procedure. The subsequent chro-
matographic purification (Et2O/pentane, 1:5) gave 0.150 g (0.30 mmol,
1
49%) of 1k as a red solid. Mp: 173ꢀ174 °C. H NMR (400 MHz,
CDCl3): δ 3.03 (t, J = 8.2 Hz, 2H, CH2), 3.70 (t, J = 8.2 Hz, 2H, CH2N),
6.69 (td, J = 7.3, 1.1 Hz, 1H, H-arom), 6.96ꢀ7.10 (m, 3H), 7.15ꢀ7.35
(m, 8H), 7.41 (td, J = 7.9, 1.0 Hz, 1H, H-arom), 7.53 (dd, J = 7.7, 0.9 Hz,
1H, H-arom), 7.62 (s, 1H, CHN), 7.65ꢀ7.67 (m, 1H, H-arom), 7.75 (d,
J = 16.2 Hz, 1H, H-olef), 7.86ꢀ7.88 (m, 1H, H-arom), 7.91 (d, J =
16.2 Hz, 1H, H-olef), 7.98 (d, J = 7.8 Hz, 1H, H-arom). 13C NMR (100
MHz, CDCl3): δ 26.9 (CH2), 47.9 (CH2N), 82.9 (C-alkyne), 102.4 (C-
alkyne), 109.1 (CH), 120.5 (CH), 121.9, 122.3 (CH), 122.4 (CH), 124.7
(CH), 125.38, 125.43 (CH), 126.1 (CH), 126.3 (CH), 126.9 (CH),
127.4, 127.8 (CH), 128.4 (CH), 128.6 (CH), 128.7 (CH), 129.3 (CH),
130.4 (CH), 130.6 (CH), 131.6 (CH), 133.8, 135.2 (CH), 135.4, 137.1,
137.4, 139.1, 147.6, 196.2 (CO). IR (neat) ν~: 3051 (w), 3030 (w), 2949
(w), 2926 (w), 2853 (w), 2191 (w), 1657 (m), 1589 (s), 1570 (m), 1547
(m), 1481 (s), 1433 (m), 1404 (m), 1360 (m), 1323 (m), 1269 (s), 1254
(m), 1200 (s), 1188 (m), 1163 (m), 1113 (w), 1028 (m), 1018 (m), 966
(m), 881 (m), 851 (w), 748 (s), 735 (s), 725 (s), 699 (w), 661 (w), 650
(w) cmꢀ1. HRMS (ESI): calcd for C34H24N2OSH 509.1682, found
509.1677.
(E)-1-(2-((E)-(Indolin-1-ylimino)methyl)phenyl)-3-(naphth-
alen-1-yl)prop-2-en-1-one (1i). This compound was obtained
from (E)-dimethyl 2-(2-((indolin-1-ylimino)methyl)phenyl)-2-oxo-
ethylphosphonate 6 (0.225 g, 0.6 mmol) and 1-naphthaldehyde
(0.094 g, 0.6 mmol) according to the general procedure. The subsequent
chromatographic purification (Et2O/pentane, 1:4) gave 0.155 g
1
(0.39 mmol, 64%) of 1i as an orange solid. Mp: 107ꢀ108 °C. H
NMR (300 MHz, CDCl3): δ 3.05 (t, J = 8.2 Hz, 2H, CH2), 3.72 (t, J =
8.2 Hz, 2H, CH2N), 6.72 (t, J = 7.3 Hz, 1H, H-arom), 7.00 (d, J = 7.3 Hz,
1H, H-arom), 7.06ꢀ7.17 (m, 3H), 7.27 (td, J = 7.5, 1.0 Hz, 1H,
H-arom), 7.35ꢀ7.45 (m, 4H), 7.52 (d, J = 7.6 Hz, 1H, H-arom), 7.62
(s, 1H, CHN), 7.68 (d, J = 7.2 Hz, 1H, H-arom), 7.74ꢀ7.80 (m, 2H),
7.95ꢀ8.00 (m, 2H, H-arom), 8.28 (d, J = 15.8 Hz, 1H, H-olef). 13C
NMR (75 MHz, CDCl3): δ 27.0 (CH2), 48.0 (CH2N), 109.1 (CH),
120.5 (CH), 123.3 (CH), 124.8 (CH), 125.1 (CH), 125.4 (CH), 126.2
(CH), 126.4 (CH), 126.9 (CH), 127.0 (CH), 127.4, 127.9 (CH), 128.6
(CH), 128.7 (CH), 129.6 (CH), 130.5 (CH), 130.70 (CH), 130.72
(CH), 131.5, 132.1, 133.6, 135.4, 137.4, 141.8 (CH), 147.6, 195.9 (CO).
IR (neat) ν~: 3053 (w), 2924 (w), 2851 (w), 1657 (m), 1638 (m), 1595
(m), 1570 (m), 1543 (m), 1477 (s), 1464 (m), 1441 (m), 1400 (s), 1346
(m), 1300 (m), 1252 (s), 1198 (s), 1161 (m), 1115 (w), 1020 (w), 1007
(m), 976 (m), 885 (w), 853 (w), 799 (m), 777 (s), 746 (s), 698 (m), 683
(w) cmꢀ1. HRMS (ESI): calcd for C28H22N2OH 403.1805, found
403.1813.
General Procedure for the Cyclization of (E)-3-(Hetero)-
aryl-1-(2-((E)-(indolin-1-ylimino)methyl)phenyl)prop-2-en-
1-ones Using BF3 Me2S. A solution of BF3 Me2S (1.2 equiv unless
3
3
otherwise indicated below) in dry dichloromethane (0.1 mL of BF3
3
Me2S in 10 mL of solvent) was cooled to ꢀ10 °C. A solution of the (E)-
3-(hetero)aryl-1-(2-((E)-(indolin-1-ylimino)methyl)phenyl)-prop-2-
en-1-one 1 (1 equiv) in dry dichloromethane (1 mmol of the compound
in 5 mL of solvent) was added dropwise with stirring. After complete
addition, stirring was continued for 1 h, while the temperature increased
to 0 °C. A saturated solution of sodium hydrogen carbonate was
added to neutralize the mixture. The organic layer was washed with a
saturated sodium hydrogen carbonate solution. Then the organic layer
was washed with water and dried with MgSO4, and the solvent was
evaporated. The substances were purified by column chromatography.
(3R(S),4R(S))-4-(1H-Indol-1-ylamino)-3-phenyl-3,4-dihy-
dronaphthalen-1(2H)-one (10a). This compound was obtained
from (E)-1-(2-((E)-(indolin-1-ylimino)methyl)phenyl)-3-phenylprop-
2-en-1-one 1a 0.135 g (0.38 mmol) according to the general procedure.
The subsequent chromatographic purification (Et2O/pentane, 1:4)
gave 0.077 g (0.22 mmol, 57%) of 10a as a yellow solid. Mp: 171ꢀ
172 °C. 1H NMR (400 MHz, CDCl3): δ 2.97 (dd, J = 17.6, 1.5 Hz, 1H,
CH2, axial), 3.46 (m, 1H, CH, equatorial), 3.76 (dd, J = 17.6, 6.1 Hz, 1H,
CH2, equatorial), 4.89 (d, J = 2.4 Hz, 1H, CH, equatorial), 5.02 (s, 1H,
NH), 6.49 (dd, J = 3.3, 0.7 Hz, 1H, 3-H-indole), 6.87 (m, 2H, H-arom),
7.07ꢀ7.29 (m, 6H, H-arom), 7.43ꢀ7.52(m, 3H, H-arom), 7.64 (d, J =
7.9 Hz, 1H, H-arom), 7.89 (m, 1H, H-arom), 8.15 (dd, J = 7.4, 1.7 Hz,
1H, H-arom). 13C NMR (100 MHz, CDCl3): δ 38.6 (CH2), 41.4 (CH),
63.8 (CHN), 100.5 (CH), 109.1 (CH), 120.1 (CH), 121.4 (CH), 122.4
(CH), 126.6, 126.8 (CH), 127.2 (CH), 127.4 (CH), 127.6 (CH), 128.5
(CH), 129.3 (CH), 129.7 (CH), 132.9, 134.3 (CH), 135.9, 138.7, 140.7,
(E)-1-(2-((E)-(Indolin-1-ylimino)methyl)phenyl)-3-(thiophene-
2-yl)prop-2-en-1-one (1j). This compound was obtained from (E)-
dimethyl 2-(2-((indolin-1-ylimino)methyl)phenyl)-2-oxoethylphos-
phonate 6 (0.225 g, 0.6 mmol) and thiophene-2-carbaldehyde (0.068 g,
0.6 mmol) according to the general procedure. The subsequent chroma-
tographic purification (Et2O/pentane, 1:5) gave 0.186 g (0.52 mmol,
87%) of1jasa redsolid. Mp: 132ꢀ133 °C. 1H NMR(400 MHz, CDCl3):
δ 3.08 (t, J = 8.3 Hz, 2H, CH2), 3.72 (t, J = 8.3 Hz, 2H, CH2N), 6.72 (td,
J = 7.2, 1.4 Hz, 1H, H-arom), 6.88 (d, J = 15.7 Hz, 1H, H-olef), 6.96 (dd,
J = 5.1, 3.7 Hz, 1H, H-arom), 7.01 (d, J = 7.3 Hz, 1H, H-arom), 7.07ꢀ7.13
(m, 2H, H-arom), 7.16 (m, 1H, H-arom), 7.23 (td, J = 7.5, 1.2 Hz, 1H,
H-arom), 7.30 (d, J = 5.1 Hz, 1H, H-arom), 7.37ꢀ7.44 (m, 2H, H-arom),
7.55 (d, J = 15.7 Hz, 1H, H-olef), 7.57 (s, 1H, CHN), 8.00 (dd, J = 7.9,
0.5 Hz, 1H, H-arom). 13C NMR (100 MHz, CDCl3): δ 27.0 (CH2), 47.9
(CH2N), 109.0 (CH), 120.5(CH), 124.7(CH), 125.7(CH), 126.1 (CH),
126.8 (CH), 127.5, 127.8 (CH), 128.3 (CH), 128.4 (CH), 129.1 (CH),
130.4 (CH), 130.6 (CH), 131.9 (CH), 135.2, 137.2, 137.6 (CH), 140.0,
5193
dx.doi.org/10.1021/jo200896y |J. Org. Chem. 2011, 76, 5185–5197

The Journal of Organic Chemistry
FEATURED ARTICLE
197.0 (CO). IR (neat) ν~: 3273 (w), 3059 (w), 3026 (w), 1903 (w), 1674
(s), 1601 (m), 1495 (w), 1454 (m), 1408 (w), 1337 (w), 1315 (w), 1293
(m), 1246 (m), 1215 (m), 1159 (w), 1090 (w), 1049 (w), 1028 (w), 955
(w), 934 (m), 841 (w), 799 (w), 775 (w), 760 (m), 741 (s), 723 (s), 696
(s), 623 (w) cmꢀ1. HRMS (ESI): calcd for C24H20N2ONa 375.1468,
found 375.1466.
H-arom), 7.15 (td, J = 7.1, 0.9 Hz, 1H, H-arom), 7.23ꢀ7.30 (m, 3H, H-
arom), 7.44ꢀ7.54 (m, 3H, H-arom), 7.64 (d, J = 7.9 Hz, 1H, H-arom),
8.14 (dd, J = 7.5, 1.7 Hz, 1H, H-arom). 13C NMR (75 MHz, CDCl3): δ
38.9 (CH2), 41.2 (CH), 63.9 (CHN), 100.6 (CH), 100.9 (OCH2O),
108.1 (CH), 108.2 (CH), 109.1 (CH), 120.1 (CH), 120.7 (CH), 121.4
(CH), 122.4 (CH), 126.6, 127.2 (CH), 127.3 (CH), 129.3 (CH), 129.7
(CH), 132.8, 134.4 (CH), 134.5, 135.9, 138.7, 146.2, 147.7, 196.9 (CO).
IR(neat) ~ν: 3269 (w), 3071 (w), 3028 (w), 2963 (w), 2893(w), 1674 (s),
1601 (m), 1503 (m), 1489 (s), 1441 (m), 1335 (w), 1292 (m), 1233 (s),
1173 (w), 1125 (w), 1092 (w), 1036 (s), 932 (m), 903 (m), 864 (w), 810
(m), 760 (s), 735 (s), 704 (s), 667 (w), 644 (w), 610 (w) cmꢀ1. HRMS
(ESI): calcd for C25H20N2O3Na 419.1366, found 419.1358.
(3R(S),4R(S))-4-(1H-Indol-1-ylamino)-3-p-tolyl-3,4-dihy-
dronaphthalen-1(2H)-one (10b). This compound was obtained
from (E)-1-(2-((E)-(indolin-1-ylimino)methyl)phenyl)-3-p-tolylprop-
2-en-1-one 1b 0.145 g (0.40 mmol) according to the general procedure.
The subsequent chromatographic purification (Et2O/pentane, 1:4) gave
0.111 g (0.30 mmol, 77%) of 10b as a yellow oil. 1H NMR (400 MHz,
CDCl3): δ 2.17 (s, 3H, CH3), 2.94 (dd, J = 17.6, 1.8 Hz, 1H, CH2, axial),
3.41 (m, 1H, CH, equatorial), 3.72 (dd, J = 17.6, 6.0 Hz, 1H,
CH2, equatorial), 4.85 (d, J = 2.3 Hz, 1H, CH, equatorial), 5.02 (s, 1H,
NH), 6.47 (d, J = 3.2, Hz, 1H, 3-H-indole), 6.75 (d, J = 8.0 Hz, 2H, H-
arom), 6.90 (d, J = 8.0 Hz, 2H, H-arom), 7.12ꢀ7.29 (m, 4H, H-arom),
7.41ꢀ7.50 (m, 3H, H-arom), 7.63 (d, J = 7.9 Hz, 1H, H-arom), 8.13 (dd,
J = 7.1, 1.9 Hz, 1H, H-arom). 13C NMR (100 MHz, CDCl3): δ 20.8
(CH3), 38.7 (CH2), 41.1 (CH), 63.8 (CHN), 100.4 (CH), 109.1 (CH),
120.1 (CH), 121.3 (CH), 122.3 (CH), 126.6, 127.1 (CH), 127.4 (CH),
127.5 (CH), 129.2 (CH), 129.7 (CH), 132.9, 134.2 (CH), 135.9, 136.3,
137.6, 138.8, 197.1 (CO). IR (neat) ~ν: 3287 (w), 3053 (w), 3026 (w),
2955 (w), 2920 (w), 1680 (s), 1626 (w), 1601 (m), 1514 (m), 1483
(w), 1454 (m), 1414 (w), 1337 (w), 1315 (w), 1290 (m), 1244 (m), 1215
(m), 1190 (w), 1157 (w), 1090 (w), 1049 (w), 1020 (w), 926 (w), 908
(m), 843 (w), 818 (m), 760 (s), 737 (s), 669 (w), 648 (w) cmꢀ1. HRMS
(ESI): calcd for C25H22N2ONa 389.1624, found 389.1631.
(3R(S),4R(S))-4-(1H-Indol-1-ylamino)-3-(3-methoxyphenyl)-
3,4-dihydronaphthalen-1(2H)-one (10c). This compound was
obtained from (E)-1-(2-((E)-(indolin-1-ylimino)methyl)phenyl)-3-(3-
methoxyphenyl)prop-2-en-1-one 1c 0.155 g (0.41 mmol) according to
the general procedure. The subsequent chromatographic purification
(Et2O/pentane, 1:3) gave 0.130 g (0.34 mmol, 84%) of 10c as a yellow
solid. Mp: 126ꢀ127 °C. 1H NMR (300 MHz, CDCl3): δ 2.94 (ddd, J =
17.6, 1.7, 0.7 Hz, 1H, CH2, axial), 3.42 (m, 1H, CH, equatorial), 3.60 (s,
3H, OCH3), 3.74 (dd, J = 17.6, 6.0 Hz, 1H, CH2, equatorial), 4.89 (d, J =
2.5 Hz, 1H, CH, equatorial), 5.03 (s, 1H, NH), 6.38ꢀ6.48 (m, 2H, H-
arom), 6.49 (dd, J = 3.3, 0.7 Hz, 1H, 3-H-indole), 6.61 (dd, J = 8.0,
2.2 Hz, 1H, H-arom), 7.02 (m, 1H, H-arom), 7.12ꢀ7.29 (m, 4H, H-
arom), 7.42ꢀ7.52 (m, 3H, H-arom), 7.64 (d, J = 7.9 Hz, 1H, H-arom),
8.14 (dd, J = 7.4, 1.8 Hz, 1H, H-arom). 13C NMR (75 MHz, CDCl3): δ
38.7 (CH2), 41.4 (CH), 55.0 (CH3), 63.6 (CHN), 100.5 (CH), 109.1
(CH), 111.8 (CH), 113.8 (CH), 119.9 (CH), 120.1 (CH), 121.4 (CH),
122.3 (CH), 126.6, 127.2 (CH), 127.3 (CH), 129.3 (CH), 129.5 (CH),
129.7 (CH), 132.8, 134.3 (CH), 135.9, 138.8, 142.3, 159.5, 196.9 (CO).
IR (neat) ν~: 3271 (w), 3055 (w), 3028 (w), 2959 (w), 2905 (w), 2835
(w), 1676 (s), 1601 (m), 1584 (m), 1510 (w), 1491 (m), 1454 (m),
1435 (m), 1406 (w), 1337 (w), 1317 (w), 1290 (m), 1256 (m), 1242
(m), 1215 (m), 1198 (w), 1180 (m), 1148 (w), 1125 (w), 1047 (m),
1009 (w), 961 (w), 932 (w), 874 (m), 760 (s), 739 (s), 700 (s), 664 (w),
637 (w) cmꢀ1. HRMS (ESI): calcd for C25H22N2O2Na 405.1573, found
405.1576.
X-ray crystal structure analysis of 10d:9 formula C25H20N2O3, M =
396.43, yellow crystal 0.30 ꢁ 0.07 ꢁ 0.03 mm, a = 11.8959(7) Å, b =
7.2879(3) Å, c = 22.7295(18) Å, β = 91.218(4)°, V = 1970.1(2) Å3,
F
calc = 1.337 g cmꢀ3, μ = 0.714 mmꢀ1, empirical absorption correction
(0.814 e T e 0.979), Z = 4, monoclinic, space group P21/n (No. 14),
λ = 1.54178 Å, T = 223(2) K, ω and j scans, 14105 reflections collected
((h, ( k, ( l), [(sin θ)/λ] = 0.60 Åꢀ1, 3387 independent (Rint = 0.042)
and 2619 observed reflections [I g 2 σ(I)], 274 refined parameters, R =
0.045, wR2 = 0.123, max. (min.) residual electron density 0.25 (ꢀ0.16) e
Å
ꢀ3, hydrogen atoms calculated and refined as riding atoms.
(3R(S),4R(S))-4-(1H-Indol-1-ylamino)-3-(4-chlorophenyl)-
3,4-dihydronaphthalen-1(2H)-one (10e). This compound was
obtained from (E)-3-(4-chlorophenyl)-1-(2-((E)-(indolin-1-ylimino)-
methyl)phenyl)prop-2-en-1-one 1e 0.115 g (0.30 mmol) according to
the general procedure. The subsequent chromatographic purification
(Et2O/pentane, 1:3) gave 0.075 g (0.19 mmol, 65%) of 10e as a yellow
solid. Mp: 140ꢀ141 °C. 1H NMR (300 MHz, CDCl3): δ 2.94 (ddd, J =
17.7, 2.1, 0.9 Hz, 1H, CH2, axial), 3.41 (m, 1H, CH, equatorial), 3.79
(dd, J = 17.7, 6.1 Hz, 1H, CH2, equatorial), 4.84 (d, J = 2.2 Hz, 1H, CH,
equatorial), 5.02 (s, 1H, NH), 6.51 (dd, J = 3.3, 0.8 Hz, 1H, 3-H-indole),
6.77 (d, J = 8.4 Hz, 2H, H-arom), 7.16 (ddd, J = 8.0, 7.2, 1.0 Hz, 1H, H-
arom), 7.24ꢀ7.31 (m, 3H, H-arom), 7.48ꢀ7.54 (m, 3H, H-arom), 7.65
(d, J = 7.9 Hz, 1H, H-arom), 8.15 (dd, J = 7.1, 1.9 Hz, 1H, H-arom). 13C
NMR (75 MHz, CDCl3): δ 38.3 (CH2), 40.7 (CH), 63.8 (CHN), 100.7
(CH), 109.0 (CH), 120.2 (CH), 121.5 (CH), 122.5 (CH), 126.6, 127.3
(CH), 128.7 (CH), 128.9 (CH), 129.5 (CH), 129.7 (CH), 132.6, 132.8,
134.5 (CH), 135.9, 136.3, 138.2, 139.1, 196.7 (CO). IR (neat) ν~: 3281
(w), 3055 (w), 3026 (w), 2955 (w), 2891 (w), 1680 (s), 1599 (m), 1512
(w), 1493 (m), 1454 (m), 1412 (w), 1339 (w), 1290 (m), 1244 (m),
1215 (m), 1200 (w), 1159 (w), 1115 (w), 1092 (m), 1049 (w), 1013
(m), 953 (w), 926 (w), 880 (w), 829 (m), 787 (m), 760 (s), 741 (s), 719
(s), 667 (w), 660 (w), 621 (w) cmꢀ1. HRMS (ESI): calcd for C24H19-
ClN2ONa 409.1078, found 409.1079.
(3R(S),4R(S))-4-(1H-Indol-1-ylamino)-3-(2-bromophenyl)-
3,4-dihydronaphthalen-1(2H)-one (10f). This compound was
obtained from (E)-3-(2-bromophenyl)-1-(2-((E)-(indolin-1-ylimino)-
methyl)phenyl)prop-2-en-1-one 1f 0.220 g (0.51 mmol) according to
the general procedure. The subsequent chromatographic purification
(Et2O/pentane, 1:4) gave 0.186 g (0.43 mmol, 85%) of 10f as a yellow
solid. Mp: 116ꢀ117 °C. 1H NMR (400 MHz, CDCl3): δ 2.87 (d, J =
18.2 Hz, 1H, CH2, axial), 3.71 (dd, J = 18.2, 6.6 Hz, 1H, CH2,
equatorial), 3.96 (d, J = 6.6 Hz, 1H, CH, equatorial), 4.80 (dd, J = 1.6,
0.5 Hz, 1H, CH, equatorial), 5.08 (s, 1H, NH), 6.32 (d, J = 3.3 Hz, 1H,
3-H-indole), 6.65 (dd, J = 7.2, 2.2 Hz, 1H, H-arom), 6.85ꢀ6.92 (m, 3H,
H-arom), 7.05 (t, J = 7.1 Hz, 1H, H-arom), 7.16 (td, J = 7.4, 1.5 Hz, 1H,
H-arom), 7.29 (td, J = 7.4, 1.5 Hz, 1H, H-arom), 7.31ꢀ7.38 (m, 2H, H-
arom), 7.41 (d, J = 8.2 Hz, 1H, H-arom), 7.52 (d, J = 7.9 Hz, 1H, H-
arom), 8.09 (dd, J = 7.7, 1.3 Hz, 1H, H-arom). 13C NMR (100 MHz,
CDCl3): δ 37.9 (CH2), 41.6 (CH), 61.4 (CHN), 99.8 (CH), 108.9
(CH), 119.9 (CH), 121.3 (CH), 122.1 (CH), 124.8, 126.8, 127.0 (CH),
127.6 (CH), 128.3 (CH), 128.4 (CH), 128.5 (CH), 129.4 (CH), 130.1
(CH), 132.5, 133.3 (CH), 134.3 (CH), 135.8, 138.4, 139.5, 197.1 (CO).
(3R(S),4R(S))-4-(1H-Indol-1-ylamino)-3-(benzo[d][1,3]dioxol-
5-yl)-3,4-dihydronaphthalen-1(2H)-one (10d). This compound
was obtained from (E)-3-(benzo[d][1,3]dioxol-5-yl)-1-(2-((E)-(indolin-
1-ylimino)methyl)phenyl)prop-2-en-1-one 1d 0.120 g (0.30 mmol)
according to the general procedure. The subsequent chromatographic
purification (Et2O/pentane, 1:3) gave 0.080 g (0.20 mmol, 67%) of 10d
as a yellow solid. Mp: 174ꢀ175 °C. 1H NMR (300 MHz, CDCl3): δ 2.91
(dd, J = 17.6, 1.6Hz, 1H, CH2, axial), 3.36 (m, 1H, CH), 3.74 (dd, J = 17.6,
6.0 Hz, 1H, CH2, equatorial), 4.84 (d, J = 2.4 Hz, 1H, CH, equatorial),
5.02 (s, 1H, NH), 5.81 (s, 2H, OCH2O), 6.30ꢀ6.34 (m, 2H, H-arom),
6.49 (dd, J = 3.3, 0.6 Hz, 1H, 3-H-indole), 6.53 (d, J = 7.9 Hz, 1H,
5194
dx.doi.org/10.1021/jo200896y |J. Org. Chem. 2011, 76, 5185–5197

The Journal of Organic Chemistry
FEATURED ARTICLE
IR (neat) ν~: 3279 (w), 3063 (w), 3026 (w), 2957 (w), 2909 (w), 1680
(s), 1599 (m), 1568 (w), 1512 (w), 1470 (m), 1470 (m), 1454 (m),
1439 (w), 1402 (w), 1337 (w), 1294 (m), 1242 (m), 1217 (w), 1200
(w), 1125 (w), 1047 (w), 1022 (s), 943 (w), 928 (w), 880 (w), 835 (w),
792 (w), 739 (s), 719 (s), 664 (m), 621 (w) cmꢀ1. HRMS (ESI): calcd
for C24H19N2OBrNa 453.0578/455.0558, found 453.0567/455.0557.
(3R(S),4R(S))-4-(1H-Indol-1-ylamino)-3-(4-(trifluoromethyl)-
phenyl)-3,4-dihydronaphthalen-1(2H)-one (10g). This compound
was obtained from (E)-1-(2-((E)-(indolin-1-ylimino)methyl)phenyl)-3-(4-
(trifluoromethyl)phenyl)prop-2-en-1-one 1g 0.155 g (0.37 mmol) according
to the general procedure. The subsequent chromatographic purification
(Et2O/pentane, 1:4) gave 0.085 g (0.20 mmol, 55%) of 10g as a yellow
oil. 1H NMR (400 MHz, CDCl3): δ 2.95 (dd, J = 17.7, 1.0 Hz, 1H, CH2,
axial), 3.48 (m, 1H, CH, equatorial), 3.81 (dd, J = 17.7, 6.1 Hz, 1H, CH2,
equatorial), 4.87 (d, J = 2.0 Hz, 1H, CH, equatorial), 5.06 (s, 1H, NH), 6.51
(dd, J = 3.3, 0.7 Hz, 1H, 3-H-indole), 6.94 (d, J = 8.4 Hz, 2H, H-arom), 7.16
(td, J = 7.1, 0.9 Hz, 1H, H-arom), 7.26ꢀ7.30 (m, 3H, H-arom), 7.34 (d, J =
8.2 Hz, 2H, H-arom), 7.47ꢀ7.56 (m, 3H, H-arom), 7.65 (d, J = 7.9 Hz, 1H,
H-arom), 8.16 (dd, J = 7.6, 1.5 Hz, 1H, H-arom). 13C NMR (100 MHz,
CDCl3): δ 38.1 (CH2), 41.3 (CH), 63.6 (CHN), 100.8 (CH), 109.0 (CH),
120.3 (CH), 121.5 (CH), 122.5 (CH), 123.9 (q, J = 271 Hz, CF3), 125.4 (q,
J = 3.7 Hz, CHCCF3), 126.6, 127.2 (CH), 127.3 (CH), 128.0 (CH), 129.1
(q, J = 32.6 Hz, CCF3), 129.6 (CH), 129.7 (CH), 132.8, 134.6 (CH), 135.9,
138.0, 144.7, 196.4 (CO). 19F NMR (282.5 MHz, CDCl3):δꢀ62.7 ppm. IR
(neat)~ν:3279(w),3059(w),3028(w),2959(w),2914(w),1680(s),1620
(w), 1601 (w), 1514 (w), 1472 (w), 1456 (w), 1418 (w), 1323 (s), 1290
(m), 1244 (w), 1215 (w), 1165 (s), 1115 (s), 1069 (s), 1016 (m), 953 (w),
928(w),908(w),880(w),841(m),797(w),760(m),739(s),710(s),650
(w) cmꢀ1. HRMS (ESI): calcd for C25H19F3N2ONa 443.1342, found
443.1341.
(3R(S),4R(S))-4-(1H-Indol-1-ylamino)-3-(2-vinylphenyl)-3,4-
dihydronaphthalen-1(2H)-one (10h). This compound was ob-
tained from (E)-1-(2-((E)-(indolin-1-ylimino)methyl)phenyl)-3-(2-vi-
nylphenyl)prop-2-en-1-one 1h 0.090 g (0.24 mmol) according to the
general procedure. The subsequent chromatographic purification
(Et2O/pentane, 1:4) gave 0.055 g (0.15 mmol, 61%) of 10h as a yellow
solid. Mp: 151ꢀ152 °C. 1H NMR (400 MHz, CDCl3): δ 2.94 (d, 1H, J =
16.9 Hz, CH2, axial), 3.75ꢀ3.84 (m, 2H, CH, CH2), 4.69 (dd, J = 10.9,
1.6 Hz, 1H, CH2-olefin), 4.73 (s, 1H, CH), 5.03 (s, 1H, NH), 5.33 (dd,
J = 17.1, 1.6 Hz, 1H, CH2-olefin), 6.00 (dd, J = 17.1, 10.9 Hz, 1H, CH-
olefin), 6.50 (dd, J = 3.3, 0.8 Hz, 1H, 3-H-indole), 6.71 (dd, J = 7.8, 1.1
Hz, 1H, H-arom), 6.93 (td, J = 7.6, 1.4 Hz, 1H, H-arom), 7.04 (td, J = 7.5,
0.9 Hz, 1H, H-arom), 7.16 (ddd, J = 8.0, 7.1, 1.0 Hz, 1H, H-arom),
7.21ꢀ7.29 (m, 4H, H-arom), 7.43ꢀ7.52 (m, 3H, H-arom), 7.67 (d, J =
7.8 Hz, 1H, H-arom), 8.18 (m, 1H, H-arom). 13C NMR (100 MHz,
CDCl3): δ 37.6 (CH), 37.8 (CH2), 62.5 (CHN), 100.0 (CH), 109.1
(CH), 116.9 (CH2-olefin), 120.1 (CH), 121.4 (CH), 122.3 (CH), 126.6
(CH), 126.8 (CH), 126.9, 127.0 (CH), 127.1 (CH), 127.7 (CH), 128.1
(CH), 129.3 (CH), 130.0 (CH), 132.7, 133.4 (CH), 134.4 (CH), 135.7,
136.9, 137.4, 138.3, 197.4 (CO). IR (neat) ν~: 3275 (w), 3123 (w), 3103
(w), 3086 (w), 3059 (w), 3028 (w), 2914 (w), 1672 (w), 1599 (m),
1512 (w), 1483 (w), 1456 (m), 1443 (w), 1406 (w), 1314 (w), 1290
(m), 1248 (m), 1215 (m), 1125 (w), 1092 (w), 1026 (w), 989 (w), 951
(w), 924 (m), 851 (w), 839 (m), 806 (w), 762 (s), 748 (s), 735 (s), 725
(s), 704 (m), 667 (w), 625 (w) cmꢀ1. HRMS (ESI): calcd for
C26H22N2ONa 401.1624, found 401.1624.
J = 6.3 Hz, 1H, CH, equatorial), 4.98 (s, 1H, CH, equatorial), 5.12 (s,
1H, NH), 6.63 (dd, J = 3.3, 0.8 Hz, 1H, 3-H-indole), 6.84ꢀ6.98 (m, 3H,
H-arom), 7.12 (m, 1H, H-arom), 7.19ꢀ7.34 (m, 4H, H-arom), 7.40 (d,
J = 3.3 Hz, 1H, H-arom), 7.47ꢀ7.51 (m, 2H, H-arom), 7.54ꢀ7.59 (m,
2H, H-arom), 7.70 (d, J = 8.1 Hz, 1H, H-arom), 7.76 (d, J = 7.6 Hz, 1H,
H-arom), 8.23 (m, 1H, H-arom). 13C NMR (75 MHz, CDCl3): δ 37.1
(CH), 38.1 (CH2), 62.8 (CHN), 100.4 (CH), 109.1 (CH), 120.4 (CH),
121.7 (CH), 122.3 (CH), 122.6(CH), 124.9 (CH), 125.1 (CH), 125.5
(CH), 126.2 (CH), 127.0, 127.3 (CH), 127.5 (CH), 128.3 (CH), 128.9
(CH), 129.4 (CH), 130.0 (CH), 130.8, 132.5, 133.7, 134.5 (CH), 135.8,
136.1, 138.6, 197.6 (CO). IR (neat) ν~: 3281 (w), 3119 (w), 3096 (w),
3051 (w), 2965 (w), 2909 (w), 1676 (s), 1597 (m), 1510 (w), 1456 (w),
1406 (w), 1398 (w), 1339 (w), 1292 (m), 1244 (m), 1217 (m), 1184
(w), 1128 (w), 1051 (w), 1028 (w), 934 (w), 908 (m), 858 (w), 785
(m), 770 (s), 756 (s), 743 (s), 727 (s), 694 (m), 644 (w), 621 (w) cmꢀ1
HRMS (ESI): calcd for C28H22N2ONa 425.1624, found 425.1626.
.
(3R(S),4S(R))-4-(1H-Indol-1-ylamino)-3-(thiophene-2-yl)-
3,4-dihydronaphthalen-1(2H)-one (10j). This compound was
obtained from (E)-1-(2-((E)-(indolin-1-ylimino)methyl)phenyl)-3-
(thiophene-2-yl)prop-2-en-1-one 1j 0.120 g (0.34 mmol) according to
the general procedure. The subsequent chromatographic purification
(Et2O/pentane, 1:3) gave 0.090 g (0.25 mmol, 75%) of 10j as a yellow
solid. Mp: 65ꢀ66 °C. 1H NMR (400 MHz, CDCl3): δ 2.97 (ddd, J =
17.3, 2.2, 1.0 Hz, 1H, CH2, axial), 3.72 (m. 1H, CH, equatorial), 3.85
(dd, J = 17.3, 5.6 Hz, 1H, CH2, equatorial), 4.97 (d, J = 2.3 Hz, 1H, CH,
equatorial), 5.05 (s, 1H, NH), 6.48 (dd, J = 3.3, 0.8 Hz, 1H, 3-H-indole),
6.56 (dt, J = 3.5, 1.0 Hz, 1H, H-arom), 6.72 (dd, J = 5.1, 3.6 Hz, 1H, H-
arom), 6.98 (dd, J = 5.1, 1.1 Hz, 1H, H-arom), 7.15 (td, J = 7.1, 1.0 Hz,
1H, H-arom), 7.24ꢀ7.31 (m, 3H, H-arom), 7.45ꢀ7.55 (m, 3H, H-
arom), 7.63 (d, J = 7.9 Hz, 1H, H-arom), 8.12 (dd, J = 7.7, 1.5 Hz, 1H, H-
arom). 13C NMR (100 MHz, CDCl3): δ 37.8 (CH), 40.0 (CH2), 63.6
(CHN), 100.6 (CH), 109.0 (CH), 120.2 (CH), 121.4 (CH), 122.4
(CH), 124.1 (CH), 125.2 (CH), 126.6 (CH), 127.2 (CH), 127.4 (CH),
129.5 (CH), 130.0 (CH), 132.8, 134.4 (CH), 135.9, 138.5, 143.9, 196.0
(CO). IR (neat) ~ν: 3279 (w), 3103 (w), 3071 (w), 3053 (w), 3028 (w),
2957 (w), 2899 (w), 1680 (s), 1614 (m), 1601 (m), 1483 (w), 1466 (w),
1454 (m), 1418 (w), 1335 (m), 1290 (m), 1240 (m), 1213 (m), 1200
(w), 1179 (w), 1159 (w), 1090 (w), 1049 (w), 1028 (w), 1009 (w), 908
(m), 851 (m), 831 (w), 760 (s), 739 (s), 698 (s), 648 (w), 627
(w) cmꢀ1. HRMS (ESI): calcd for C22H18N2OSNa 381.1032, found
381.1035.
(3R(S),4R(S))-4-(1H-Indol-1-ylamino)-3-(2-(phenylethynyl)-
benzo[b]thiophene-3-yl)-3,4-dihydronaphthalen-1(2H)-one
(10k). This compound was obtained from (E)-1-(2-((E)-(indolin-1-
ylimino)methyl)phenyl)-3-(2-(phenylethynyl)benzo[b]thiophene-3-yl)-
prop-2-en-1-one 1k 0.105 g (0.21 mmol) according to the general
procedure. The subsequent chromatographic purification (Et2O/pen-
tane, 1:3) gave 0.060 g (0.12 mmol, 57%) of 10k as a yellow solid. Mp:
1
200ꢀ201 °C. H NMR (400 MHz, CDCl3): δ 3.60ꢀ3.62 (m, 2H,
CH2), 4.04 (m, 1H), 4.98 (s, 1H, NH), 5.06 (d, J = 4.0 Hz, 1H), 6.53 (dd,
J = 3.3, 0.6 Hz, 1H, 3-H-indole), 6.67 (d, J = 8.2 Hz, 1H, H-arom), 6.98
(m, 1H, H-arom), 7.14ꢀ7.30 (m, 5H, H-arom), 7.36ꢀ7.49 (m, 8H, H-
arom), 7.63 (d, J = 8.0 Hz, 1H, H-arom), 7.69 (d, J = 7.3 Hz, 1H, H-
arom), 7.97 (dd, J = 7.6, 1.5 Hz, 1H, H-arom). 13C NMR (75 MHz,
CDCl3): δ 36.4 (CH), 37.3 (CH2), 61.8 (CHN), 82.3 (C-alkyne), 99.4
(C-alkyne), 100.5 (CH), 109.3 (CH), 120.2, 120.3 (CH), 121.4 (CH),
121.5 (CH), 122.0 (CH), 122.2, 122.5 (CH), 124.6 (CH), 125.6 (CH),
126.8, 127.2 (CH), 127.8 (CH), 128.3 (CH), 129.0 (CH), 129.21 (CH),
129.24 (CH), 131.4 (CH), 133.76 (CH), 133.79, 135.7, 136.8, 138.1,
139.1, 139.6, 196.9 (CO). IR (neat) ν~: 3264 (w), 3113 (w), 3061 (w),
3017 (w), 2907 (w), 2859 (w), 2199 (w), 1676 (s), 1597 (m), 1485 (m),
1456 (m), 1441 (m), 1396 (w), 1356 (w), 1312 (w), 1294 (s), 1258 (m),
1242 (m), 1219 (m), 1207 (w), 1196 (w), 1179 (w), 1053 (w), 1024
(m), 1007 (w), 916 (w), 893 (w), 851 (m), 772 (m), 754 (s), 745 (s),
(10R(S),20R(S))-10-(1H-Indol-1-ylamino)-20,30-dihydro-1,20-
binaphthyl-40(10H)-one (10i). This compound was obtained from
(E)-1-(2-((E)-(indolin-1-ylimino)methyl)phenyl)-3-(naphthalen-1-yl)-
prop-2-en-1-one 1i 0.125 g (0.31 mmol) according to the general
procedure. The subsequent chromatographic purification (Et2O/pen-
tane, 1:3) gave 0.075 g (0.19 mmol, 60%) of 10i as a yellow solid. Mp:
195ꢀ196 °C. 1H NMR (300 MHz, CDCl3): δ 3.08 (d, J = 18.0 Hz, 1H,
CH2, axial), 3.99 (dd, J = 18.0, 6.4 Hz, 1H, CH2, equatorial), 4.33 (d,
5195
dx.doi.org/10.1021/jo200896y |J. Org. Chem. 2011, 76, 5185–5197

The Journal of Organic Chemistry
FEATURED ARTICLE
725 (s), 689 (s), 669 (m), 621 (w) cmꢀ1. HRMS (ESI): calcd for
C34H24N2OSNa 531.1502, found 531.1515.
Enzymol. 1997, 276, 307. ), absorption correction Denzo (Otwinowski,
Z.; Borek, D.; Majewski, W.; Minor, W. Acta Crystallogr. 2003, A59,
228. ), structure solution SHELXS-97 (Sheldrick, G. M. Acta Crystallogr.
1990, A46, 467. ), structure refinement SHELXL-97 (Sheldrick, G. M.
Acta Crystallogr. 2008, A64, 112. ), graphics SCHAKAL (Keller, E., Univ.
Freiburg, 1997), R values are given for the observed reflections, wR2
values for all reflections. CCDC 816598 (1e) and 816599 (10d) contain
the supplementary crystallographic data for this paper. These data can be
obtained free of charge at www.ccdc.cam.ac.uk/conts/retrieving.html
[or from the Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: (int.) þ44(1223)336-033, E-mail:
deposit@ccdc.cam.ac.uk].
(10) (a) Zhu, J.; Zhong, C.; Lu, H.-F.; Li, G.-Y.; Sun, X. Synlett 2008,
3, 458. (b) Breit, B.; Winde, R.; Mackewitz, T.; Paciello, R.; Harms, K.
Chem.—Eur. J. 2001, 7, 3106. (c) Marco, J. L. Synth. Commun. 1996, 26
(22), 4225. (d) Satyanarayana, J.; Basaveswara Rao, M. V.; Ila, H.;
Junjappa, H. Tetrahedron Lett. 1996, 37 (20), 3565.
’ ASSOCIATED CONTENT
Supporting Information. 1H and 13C spectra for the
S
b
new compounds; Cartesian coordinates (HF/6-311G(d,p))
and CPCM(UAKS)-HF/def2-QZVPP//HF/6-311G(d,p)þZPE
energies for the calculated structures; graphics of the crystal
structures showing thermal ellipsoids with 50% probability. This
material is available free of charge via the Internet at http://pubs.
acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*Fax: þ49-251-83-39772. E-mail: wurthwe@uni-muenster.de,
(11) (a) Ferraris, D.; Drury, W. J., III; Cox, C.; Lectka, T. J. Org.
Chem. 1998, 63, 4568. (b) Kobayashi, S.; Busujima, T.; Nagayama, S.
Chem.—Eur. J. 2000, 6, 3491.
ghavtadz@uni-muenster.de.
(12) Trybulski, E. J.; Benjamin, L. E.; Earley, J. V.; Ian Fryer, R.;
Gilman, N. W.; Reeder, E.; Walser, A.; Davidson, A. B.; Dale Horst, W.
J. Med. Chem. 1983, 26, 1589.
(13) (a) Snyder, J. P.; Heyman, M. L.; Gundestrup, M. J. Chem.Soc.,
Perkin Trans. 1 1977, 13, 1551. (b) Wirschun, W. G.; Al-Soud, Y. A.;
Nusser, K. A.; Orama, O.; Maier, G.-M.; Jochims, J. C. J. Chem. Soc.,
Perkin Trans. 1 2000, 24, 4356.
’ ACKNOWLEDGMENT
This work was supported by the International Research
Training Group IRTG, M€unster-Amsterdam-Leiden 1444
(Deutsche Forschungsgemeinschaft (DFG), Bad Godesberg),
and the Fonds der Chemischen Industrie (Frankfurt). We thank
Mr. Frank D. Fischer for computational support.
(14) (a) Brehme, R.; Nikolajewski, H. E. Z. Chem. 1968, 226. (b)
Brehme, R.; Enders, D.; Fernandez, R.; Lassaletta, J. M. Eur. J. Org. Chem.
ꢀ
2007, 5629. (c) Monge, D.; Martin-Zamora, E.; Vꢀazquez, J.; Alcarazo,
’ REFERENCES
ꢀ
M.; Alvarez, E.; Fernꢀandez, R.; Lassaletta, J. M. Org. Lett. 2007, 9, 2867.
(15) (a) Barluenga, J.; Fernandez, A.; Rodriguez, F.; Fananas, F. J.
Chem.—Eur. J. 2009, 15, 8121. (b) Yeom, H.-S.; Lee, J.-E.; Shin, S.
Angew. Chem., Int. Ed. 2008, 47, 7040.
(1) (a) Ghavtadze, N.; Fr€ohlich, R.; W€urthwein, E.-U. Eur. J. Org.
Chem. 2008, 3656. (b) Ghavtadze, N.; Fr€ohlich, R.; W€urthwein, E.-U.
Eur. J. Org. Chem. 2010, 1787.
(16) (a) Mao, H.; Wang, S.; Yu, P.; Lv, H.; Xu, R.; Pan, Y. J. Org.
Chem. 2011, 76, 1167. (b) Deb, I.; Das, D.; Siedel, D. Org. Lett. 2011,
13, 812.
(2) (a) Alickmann, D.; Fr€ohlich, R.; Maulitz, A. H.; W€urthwein,
E.-U. Eur. J. Org. Chem. 2002, 1523–1537. (b) Ghavtadze, N.; Fr€ohlich,
R.; Bergander, K.; W€urthwein, E.-U. Synthesis 2008, 3397. (c) Ghav-
tadze, N.; Fr€ohlich, R.; W€urthwein, E.-U. Eur. J. Org. Chem. 2009, 1228.
(d) Ghavtadze, N.; Fr€ohlich, R.; W€urthwein, E.-U. J. Org. Chem. 2009,
74, 4584.
(3) (a) Ciufolini, M. A.; Roschangar, F. Tetrahedron 1997, 53, 11049.
(b) Matoba, K.; Itoh, K.; Yamazaki, T.; Nagata, M. Chem. Pharm. Bull.
1981, 29, 2442. (c) Matoba, K.; Miyata, Y.; Yamazaki, T. Chem. Pharm.
Bull. 1983, 31, 476. (d) Matoba, K.; Terada, T.; Sugiuara, M.; Yamazaki,
T. Heterocycles 1987, 26, 55. (e) Aftfah, A.; Abu-Shuheil, M. Y.; Hill, J.
Tetrahedron 1990, 46, 6483. (f) Kumaraswamy, E.; Rees, C. W. Bull. Soc.
Chim. Belg. 1997, 106, 605. (g) Dieker, J.; Fr€ohlich, R.; W€urthwein, E.-U.
Eur. J. Org. Chem. 2006, 5339. (h) Klumpp, D. A.; Zhang, Y.; O’Connor,
M. J.; Estevens, P. M.; Almeida, L. S. Org. Lett. 2007, 9, 3085. (i)
Nakanishi, W.; West, F. G. Curr. Opin. Drug Discovery Dev. 2009, 12 (6),
732.
(17) Gaussian 09, Revision A.02: 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.; Nakatsuji, H.; Caricato,
M.; Li, X.; Hratchian, H. P.; Izmaylov, A. F.; Bloino, J.; Zheng, G.;
Sonnenberg, J. L.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.;
Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai,
H.; Vreven, T.; Montgomery, J. A., Jr.; Peralta, J. E.; Ogliaro, F.;
Bearpark, M.; Heyd, J. J.; Brothers, E.; Kudin, K. N.; Staroverov,
V. N.; Kobayashi, R.; Normand, J.; Raghavachari, K.; Rendell, A.; Burant,
J. C.; Iyengar, S. S.; Tomasi, J.; Cossi, M.; Rega, N.; Millam, N. J.; Klene,
M.; Knox, J. E.; Cross, J. B.; Bakken, V.; Adamo, C.; Jaramillo, J.;
Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.;
Pomelli, C.; Ochterski, J. W.; Martin, R. L.; Morokuma, K.; Zakrzewski,
V. G.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Dapprich, S.; Daniels,
€
A. D.; Farkas, O.; Foresman, J. B.; Ortiz, J. V.; Cioslowski, J.; Fox, D. J.
(4) Rieder, C. J.; Winberg, K. J.; West, F. G. J. Am. Chem. Soc. 2009,
131, 7504.
Gaussian, Inc., Wallingford CT, 2009.
(18) According to the calculations, BF3 complexation at the oxygen
atom of 1 is favored by approximately 4 kcal/mol over complexation at
either one of the two nitrogen atoms.
(5) Gaenzler, F. C.; Guo, C. (L.); Zhang, Y.-W.; Azab, M. E.; Salem,
M. A. I.; Fan, D. P.; Smith, M. B. Tetrahedron 2009, 65, 8781.
(6) N-Aminoindoline was prepared from commercially available
indoline similar to the procedure described. Smith, A. B., III; K€urti, L.;
Davulcu, A. H. Org. Lett. 2006, 8, 2167.
(7) Neidlein, R.; Feistauer, H. Helv. Chim. Acta 1996, 79, 895.
(8) (a) Horner, L.; Hoffmann, H.; Wippel, H. G. Chem. Ber. 1958,
91, 61. (b) Horner, L.; Hoffmann, H.; Wippel, H. G.; Klahre, G. Chem.
Ber. 1959, 92, 2499. (c) Wadsworth, W. S., Jr.; Emmons, W. D. J. Am.
Chem. Soc. 1961, 83, 1733. (d) Boutagy, J.; Thomas, R. Chem. Rev. 1974,
74, 87. (e) Wadsworth, W. S., Jr. Org. React. 1977, 25, 73. (f) Maryanoff,
B. E.; Reitz, A. B. Chem. Rev. 1989, 89, 863.
(19) (a) Barone, V.; Cossi, M. J. Phys. Chem. A 1998, 102, 1995.
(b) Barone, V.; Cossi, M.; Tomasi, J. J. Comput. Chem. 1998, 19, 404.
(c) Takano, Y.; Houk, K. N. J. Chem. Theory Comput. 2005, 1, 70.
(d) Weigend, F.; Ahlrichs, R. Phys. Chem. Chem. Phys. 2005, 7, 3297.
(e) Weigend, F.; Furche, F.; Ahlrichs, R. J. Chem. Phys. 2003, 119 (24),
12753. (f) Feller, D. J. Comput. Chem. 1996, 17 (13), 1571. (g) Schuchardt,
K. L.; Didier, B. T.; Elsethagen, T.; Sun, L.; Gurumoorthi, V.; Chase, J.; Li, J.;
Windus, T. L. J. Chem. Inf. Model. 2007, 47 (3), 1045.
(20) Geometry optimizations using the CPCM model failed (no
convergence).
(21) NBO Version 3.1: Glendening, E. D.; Reed, A. E.; Carpenter,
J. E.; Weinhold F. (b) Foster, J. P.; Weinhold, F. J. Am. Chem. Soc. 1980,
(9) Data sets were collected with a Nonius KappaCCD diffract-
ometer. Programs used: data collection COLLECT (Nonius B.V.,
1998), data reduction Denzo-SMN (Otwinowski, Z.; Minor, W. Methods
5196
dx.doi.org/10.1021/jo200896y |J. Org. Chem. 2011, 76, 5185–5197

The Journal of Organic Chemistry
FEATURED ARTICLE
102, 7211. (c) Reed, A. E.; Weinhold, F. J. Chem. Phys. 1983, 78, 4066.
(d) Reed, A. E.; Weinstock, R. B.; Weinhold, F. J. Chem. Phys. 1985,
83, 735. (e) Reed, A. E.; Weinhold, F. J. Chem. Phys. 1985, 83, 1736.
(f) Carpenter, J. E.; Weinhold, F. THEOCHEM 1988, 46, 41. (g) Reed,
A. E.; Curtiss, L. A.; Weinhold, F. Chem. Rev. 1988, 88, 899.
(22) Szekeres, H. J.; Atack, J. R.; Chambers, M. S.; Cook, S. M.;
Macaulay, A. J.; Pillai, G. V.; MacLeod, A. M. Bioorg. Med. Chem. Lett.
2004, 14, 2871.
5197
dx.doi.org/10.1021/jo200896y |J. Org. Chem. 2011, 76, 5185–5197