Cyclodehydrations leading to indene products having n-heterocyclic substituents

Article abstract of DOI:10.1021/jo5007416

In this Note, we describe superacid-promoted cyclodehydrations leading to functionalized indenes. The product indenes are synthesized having N-heterocyclic substituents, including pyridyl, imidazolyl, pyrimdyl, and other groups. A mechanism is proposed in

Full text of DOI:10.1021/jo5007416

Note
pubs.acs.org/joc
Cyclodehydrations Leading to Indene Products Having
N‑Heterocyclic Substituents
Kenneth N. Boblak and Douglas A. Klumpp*
Department of Chemistry and Biochemistry, Northern Illinois University, DeKalb, Illinois 60115, United States
S
* Supporting Information
ABSTRACT: In this Note, we describe superacid-promoted cyclo-
dehydrations leading to functionalized indenes. The product indenes
are synthesized having N-heterocyclic substituents, including pyridyl,
imidazolyl, pyrimdyl, and other groups. A mechanism is proposed
involving dicationic, superelectrophilic intermediates. The protonated
N-heterocyclic rings are shown to dramatically lower the LUMO
energy level of the carboxonium electrophile (compared to that of a
similar uncharged system).
To begin our studies, we sought to prepare dihydrocinna-
moyl-substituted heterocycles. Two approaches were found to
be useful, one involving the reaction of a heterocyclic nitrile
with phenethylmagnesium bromide (eq 1) and another
unctionalized indenes are useful scaffolds in synthetic and
1
Fmedicinal chemistry.
For example, indenes with N-
heterocyclic substituents have been utilized as pharmaceutical
agents and metal ligands. 2-(1H-Inden-3-yl)pyridine com-
pounds (1) were examined by Merck researchers for use as
growth hormone release promoters,2 whereas compound 2
(fenistil) is a well-known antihistamine drug.3 Pyridyl-
substituted indenes have also been used to prepare zirconium
(3),4 manganese (4),5 and ruthenium complexes.6
Cyclodehydration is a well-known route to carbocyclic
products.7 For example, many polycyclic aromatic hydro-
carbons have been prepared using this chemistry.8 Product ring
systems include dihydronaphthalenes and indenes. The
conversions involve the acid-promoted reactions of aldehydes,
ketones, or analogous substrates, and they often occur through
carboxonium ion intermediates. Over the years, we have
described several types of superelectrophilic condensation
reactions involving dicationic carboxonium ions.9,10 These
types of reactive intermediates have shown high reactivities in
Friedel−Crafts-type reactions. In this Note, we describe a
cyclodehydration to give indenes with heterocyclic substituents,
and a mechanism is proposed involving dicationic carboxonium
ions as the key intermediates.
involving formation of the heterocyclic organolithium reagent
(eq 2).A series of dihydrocinnamoyl-substituted heterocycles
was prepared and combined with superacidic, CF3SO3H, to
give the cyclodehydration products (Table 1). In general, the
expected indene products were formed in good yields. The
indenes were found to be somewhat unstable unless they were
stored at a low temperature under an inert atmosphere. The
product indenes include pyridyl, pyrimidyl, imidazolyl, oxazolyl,
thiazolyl, and benzothiazolyl derivatives (14−20). Cyclization
of ketone 13 leads to the analogue of fenistil, a functionalized
indene (21), rather than a product having an exocyclic double
bond. Good conversion of 7 to 14 was also accomplished using
perfluoro(2-ethoxyethane)sulfonic acid, another Brønsted
superacid. Other acids, such as concentrated sulfuric acid,
trifluoroacetic acid, BF3·OEt2, and TiCl4, did not promote the
conversion to 14 in reactions at 25 °C. As few as 4 equivalents
of CF3SO3H promotes the cyclization of 7 to 14, but the
Received: March 31, 2014
Published: May 19, 2014
© 2014 American Chemical Society
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Note
Table 1. Products and Yields from the Cyclodehydration
Reactions of Ketones 5 and 7−13 with CF3SO3H
Scheme 1
Cyclization of carboxonium ion 25 provides dicationic oxonium
ion 26, and dehydration gives carbocation 27. Deprotonation
steps then give the observed indene product, 14. In the case of
spirocyclic product 22, the indenyl intermediate (28) is likely in
equilibrium with the superelectrophilic carbocation (29), as
small amounts of the corresponding indene product may be
isolated if the reaction is done at low temperature (eq 5). Thus,
superelectrophile 29 undergoes cyclization with the benzyl
group to give product 22. A similar process is envisaged for
spirocyclic product 24.
In order to evaluate the effects of the pyridinium ring on the
cyclodehydration, the cyclization of compound 7 was compared
with the same reaction involving 1,3-diphenylpropan-1-one
(30).11 Previous work by Shudo and Ohwada estimated the
+
pKBH value for compound 30 to be −5.9 in CF3SO3H−
CF3CH2OH solution.11 Cyclodehydration of 30 may be
accomplished in good yield with CF3SO3H (Ho −14), but it
requires elevated temperature (eq 6). NMR experiments
a
Isolated yield of purified product.
synthesis proceeds to 100% conversion within 4 h when 12 or
more equivalents of acid are used. The CF3SO3H may be
quantitatively recycled using a published procedure (see
Experimental).
When the ketone substrates have pendant aryl groups, they
have the capability of undergoing a second cyclization, leading
to spirocyclic indanes (eqs 3 and 4).Thus, the imidazole and
quinolone derivatives (6 and 23) provide the respective
spirocyclic products (22 and 24) in excellent yields.
indicated that compound 30 is completely protonated in
solutions more acidic than Ho −9, and evidence from kinetic
experiments have suggested the involvement of superelectro-
phile 33 as the key reactive intermediate in the cyclo-
dehydration (eq 7). If the monocationic species (32)
undergoes cyclization to the indene, it does so at an exceedingly
slow rate.11
In these dehydrative cyclizations, a mechanism is proposed
involving a series of dicationic intermediates (Scheme 1).
Protonation of the pyridyl nitrogen and the carbonyl group
leads to superelectrophilic carboxonium ion intermediate 25.
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Note
dicationic species exhibit significantly lowered LUMO orbitals
compared to the monocationic species, and, not surprisingly,
the LUMO coefficients are high at the carboxonium carbon
(see LUMO 25). Moreover, the heterocyclic dications (25 and
35−37) all exhibit LUMO energy levels (−11.51 to −12.08
eV) comparable to that of superelectrophilic carboxonium
dication 33 (−11.81 eV). Olah and Koltunov have previously
correlated the relative reactivities of superelectrophiles with
LUMO characteristics.14 These observations are consistent with
the electrophilic activating effects of protonated N-heterocyclic
rings. It also is notable that the heterocyclic dications (25 and
35−37) are formed by protonation of a strong base site, the
heterocyclic ring, and a relatively weak base site, the carbonyl
group. With superelectrophilic carboxonium dication 33,
superelectrophile formation requires protonation of two weak
base sites, the carbonyl group and carboxonium oxygen.
In summary, we have described a convenient route to N-
heterocyclic substituted indenes. The chemistry involves a
cyclodehydration of 3-phenyl-1-propanones in superacidic
solution. The results suggest a significant role of the protonated
N-heterocycle in activation of the electrophilic carboxonium
ion. Previously, aryl-substituted indenes have been synthesized
from the dehydration of functionalized indanols (which were
prepared from the corresponding 1-indanones and an organo-
metallic reagent).15 The present work involving super-
electrophilic cyclizations is general in scope, and it improves
synthetic access to functionalized indenes, a structure with
general utility.
Figure 1. Cyclodehydrations (7 → 14 and 30 → 31) in excess
CF3SO3H (22 equiv) at 25 °C.
Both compounds 7 and 30 were mixed with excess
CF3SO3H, and the relative rates of cyclization were compared
(Figure 1). The conversions were done by combining a
solution of the ketone in CH2Cl2 with CF3SO3H, and the
mixture was quenched after the reaction period. The product
mixtures were then subjected to GC-FID analysis. Heterocyclic
ketone 7 was completely converted to the indene condensation
product (14) within 30 min. Conversely, no detectable
condensation product 31 was observed during the same
reaction period from 1,3-diphenylpropan-1-one (30). This is
consistent with Shudo and Ohwada’s observation that forcing
conditions are required for cyclodehydration of compound 30
in CF3SO3H.
At 25 °C, the reaction of 30 with CF3SO3H presumably
involves formation of the monocation carboxonium ion
intermediate (32) with little or no superelectrophile (33)
formation. Thus, indene 31 is not produced.
The facile cyclodehydration of compound 7 may be
understood with the involvement of dicationic intermediate
25. Previous work has shown the activating effects of
protonated N-heterocyclic rings on adjacent electrophilic
sites.12 In this case, the pyridinium ring of 25 enhances the
reactivity of the neighboring carboxonium ion group. Several
protonated heterocyclic ketones were studied computationally
and compared with monocationic intermediates 32 and 34
(Figure 2). Calculations were done at the B3LYP 6-311G(d,p)
level, using the Gaussian09 program suite.13 In all cases, the
EXPERIMENTAL SECTION
■
General. All reactions were performed using oven-dried glassware
under an argon atmosphere. Trifluoromethanesulfonic acid was freshly
distilled prior to use. All commercially available compounds and
1
solvents were used as received. H and 13C NMR were done using a
either a 500 or 300 MHz spectrometer; chemical shifts were made in
reference to NMR solvent signals. Low-resolution mass spectra were
obtained from a gas chromatography instrument equipped with a
mass-selective detector, whereas high-resolution mass spectra were
obtained from a commercial analytical laboratory (electron impact
ionization; sector instrument analyzer type). Triflic acid may also be
recovered and recycled quantitatively.16
Preparation of 1,3-Diarylpropan-1-one Derivatives, General
Method A. The heterocyclic nitrile (2 mmol) is dissolved in
anhydrous ether (20 mL) and cooled to 0 °C. To this solution is
slowly added phenethylmagnesium chloride (2.4 mL, 1.0 M in THF),
and the mixture is stirred for 2 h at 0 °C, warmed to 25 °C, and
quenched with ca. 3 mL of 1.0 M HCl. This solution is stirred
overnight. Following neutralization with 2 M NaOH, the product
mixture is partitioned between ether and water. The aqueous phase is
subjected to two further extractions with ether, and the combined
ether extracts are washed with water and then brine. After drying the
solution with anhydrous Na2SO4, the solvent is evaporated. The
product, 1,3-diarylpropan-1-one, may be purified by column
chromatography (silica gel, ether/hexane or ethyl acetate/hexane).
Preparation of 1,3-Diarylpropan-1-one Derivatives, General
Method B. The heterocyclic substrate (2 mmol) is dissolved in
anhydrous THF (15 mL), the solution is cooled to −78 °C, and an n-
BuLi solution (5.25 mL, 2.5 M in THF, 2.1 mmol) is added slowly
with stirring. Following a 2 h period, hydrocinnamaldehyde (2 mmol
in 5 mL of THF) is added, and the solution is allowed to warm to
room temperature. Stirring for 2 h is followed by a workup procedure:
water (20 mL) is added to the mixture, the organic phase is partitioned
off, and the aqueous phase is extracted twice ether. The combined
organic extracts are washed twice with brine and then dried with
anhydrous sodium sulfate. The crude alcohol is then isolated by
removal of solvent with reduced pressure. The crude alcohol is
Figure 2. Calculated LUMO energies and the graphical representation
of LUMO (25).
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Note
oxidized to the corresponding ketone using an adapted procedure
from the literature.17
6H), 8.13−8.19 (m, 2H), 8.29−8.33 (m, 2H). 13C NMR (CDCl3, 75
MHz) δ 30.0, 42.7, 126.0, 126.7, 127.3, 128.1, 128.5, 128.5, 128.6,
128.9, 130.6, 131.0, 135.1, 141.5, 153.2, 158.7, 195.9. LR-MS (EI): 353
(M+), 325, 251, 221, 105. HR-MS (EI) calcd for C24H19NO2,
353.1415; found, 353.1414.
3-Phenyl-1-(thiazol-2-yl)propan-1-one (11). Using general
method B, thiazole (0.170 g, 2.0 mmol) gives compound 11 (0.207
g, 0.95 mmol, 48%), isolated as clear, colorless oil, Rf = 0.44 (5:1
hexane/ethyl acetate). 1H NMR (CDCl3, 300 MHz) δ 3.13 (t, J = 7.6
Hz, 2H), 3.54 (t, J = 7.9 Hz, 2H), 7.21−7.24 (m, 1H), 7.29−7.34 (m,
4H), 7.66 (d, J = 3.1 Hz, 1H), 8.01 (d, J = 3.1 Hz, 1H). 13C NMR
(CDCl3, 75 MHz) δ 30.0, 40.1, 126.2, 126.3, 128.49, 128.52, 140.8,
144.8, 167.0, 193.0. LR-MS (EI): 217 (M+), 189, 188, 112, 85. HR-
MS (EI) calcd for C12H11NOS, 217.0561; found, 217.0562.
1-(Benzo[d]thiazol-2-yl)-3-phenylpropan-1-one (12). Using
general method B, benzothiazole (0.270 g, 2.0 mmol) gives compound
12 (0.313 g, 1.12 mmol, 59%), isolated as a light yellow solid (mp 69−
70 °C) in 59% yield, Rf = 0.47 (5:1 hexane/ether). 1H NMR (CDCl3,
500 MHz) δ 3.17, (t, J = 7.5 Hz, 2H), 3.67 (t, J = 8.0 Hz, 2H), 7.23−
7.26 (m, 1H), 7.33−7.35 (m, 4H), 7.54−7.62 (m, 2 H), 8.00−8.01 (m,
1H), 8.19−8.21 (m, 1H). 13C NMR (CDCl3, 125 MHz) δ 29.7, 40.4,
122.5, 125.4, 126.3, 127.0, 127.8, 128.6, 137.2, 140.7, 153.5, 166.2,
194.5. LR-MS (EI): 267 (M+), 238, 162, 135, 91. HR-MS (EI) calcd
for C16H13NOS, 267.0718; found, 267.0717.
Cyclodehydration to the Heterocyclic Indenes, General
Method C. The heterocyclic ketone (1 mmol) is dissolved in
CH2Cl2 (2 mL), and CF3SO3H (1 mL, 11 mmol) is added to the
stirred solution. After 4 h, the mixture is poured over ca. 10 g of ice
and 50 mL CHCl3. The aqueous layer is then made basic (ca. pH 8)
by addition of 10 M NaOH, and the mixture is partitioned in a
separatory funnel. The aqueous layer is extract twice with CHCl3, the
combined organic extracts are washed with water and then brine, and
the solution is dried over anhydrous sodium sulfate. Although the
indene products are often obtained in greater than 95% purity, the
products may be further purified with silica gel chromatography.
1-(3-Methylpyridin-2-yl)-3-phenylpropan-2-one (5). Using
general method A, 3 methyl-2-pyridinecarbonitrile (0.236 g, 2.0
mmol) gives compound 5 (0.391g, 1.74 mmol, 87%), isolated as a
1
clear, yellow oil, Rf = 0.30 (4:1 hexane:ether). H NMR (CDCl3, 300
MHz) δ 2.57 (s, 3H), 3.07 (t, J = 7.4 Hz, 2H), 3.58 (t, J = 8.0 Hz, 2H),
7.17−7.35 (m, 6H), 7.55 (dq, J = 0.7, 1.6, 7.7 Hz, 1H), 8.50 (dd, J =
1.2, 4.6 Hz, 1H). 13C NMR (CDCl3, 75 MHz) δ 20.2, 30.1, 41.4,
125.9, 126.0, 128.4, 128.5, 134.4, 140.1, 141.5, 146.1, 151.8, 203.2. LR-
MS (EI): 225 (M+), 197, 182, 93, 65. HR-MS (EI) calcd for
C15H15NO, 225.1154; found, 225.1157.
1-(1-Benzyl-1H-imidazol-2-yl)-3-phenylpropane-1-one (6).
Using general method B, 1-benzylimidazole (0.63 g, 4.0 mmol) gives
compound 6 (0.79 g, 2.7 mmol, 68%), isolated as clear, yellow oil, Rf =
1-Phenyl-4-(pyridin-2-yl)pentan-3-one (13). 2-Ethylpyridine
(0.286 mL, 2.5 mmol) is dissolved in 15 mL of THF, and the
solution is cooled to −5 °C. n-BuLi (1.0 mL, 2.5 M solution in
hexanes, 2.5 mmol) was added, and this solution is stirred for 45 min.
To this solution is added 0.328 mL of hydrocinnamonitrile (0.328 g,
2.5 mmol), and the mixture is allowed to stir for 30 min. Following
this period, 2 M HCl (30 mL) is added, and the solution is stirred for
10 min. The solution is made basic with a 10% NaOH solution and
extracted three times with CHCl3. The organic extracts are combined,
washed with H2O and then brine, and dried over sodium sulfate, and
the solvent is evaporated. Compound 13 is isolated as a clear, yellow
oil (0.1089 g, 0.46 mmol, 18%), Rf = 0.20 (4:1 hexane/ethyl acetate).
1H NMR (CDCl3, 300 MHz) δ 1.46 (d, J = 7.0 Hz, 3H), 2.72−2.80
(m, 2H), 2.84−2.92 (m, 2H), 4.00 (q, J = 7.0, 1H), 7.08−7.25 (m,
1
0.12 (5:1 hexane/ethyl acetate). H NMR (CDCl3, 500 MHz) δ 3.07
(t, J = 7.7 Hz, 2H), 3.54 (t, J = 8.0 Hz, 2H), 5.65 (s, 2H), 7.10 (d, J =
0.8 Hz, 1H), 7.19−7.23 (m, 4 H), 7.28−7.39 (m, 7H). 13C NMR
(CDCl3, 125 MHz) δ 30.0, 40.7, 51.8, 126.1, 127.6, 128.1, 128.4,
128.5, 128.9, 129.5, 136.4, 141.0, 142.4, 192.1. LR-MS (EI): 290 (M
+), 262, 185, 157, 91. HR-MS (EI) calcd for C19H18N2O, 290.1419;
found, 290.1419.
3-Phenyl-1-(pyridin-2-yl)propan-1-one (7).17 Using general
method A, 2-cyanopyridine (0.507 g, 4.9 mmol) gives compound 7
(0.90 g, 4.3 mmol, 88%), isolated as a clear, light yellow oil, Rf = 0.27
1
(4:1 hexane/ether). H NMR (CDCl3, 300 MHz) δ 3.09 (t, J = 7.9
Hz, 2H), 3.60 (t, J = 7.95 Hz, 2H), 7.17−7.24 (m, 1H), 7.27−7.34 (m,
4H), 7.48 (dq, J = 7.6, 4.8, 1.2 Hz, 1H), 7.84 (dt, J = 7.7, 1.7 Hz, 1H),
8.1 (dt, J = 7.9, 1.1 Hz, 1H), 8.68 (dq, J = 4.7, 1.7. 0.9 Hz, 1H). 13C
NMR (CDCl3, 75 MHz) δ 29.9, 39.4, 121.8, 126.0, 127.1, 128.4, 128.5,
136.9, 141.4, 148.9, 153.3, 201.0. LR-MS (EI): 211 (M+), 183, 182,
107, 91, 79. HR-MS (EI) calcd for C14H13NO, 211.0997; found,
211.0996.
7H), 7.60−7.65 (td, J = 7.7 Hz, 1.9 Hz, 1H), 8.54−8.56 (m, 1H). 13
C
NMR (CDCl3, 75 MHz) δ 16.2, 29.8, 42.9, 55.3, 122.1, 122.3, 126.0
128.3, 128.4, 137.0, 141.0, 139.5 160.0. LR-MS (EI): 239 (M+), 224,
107, 106, 91. HR-MS (EI) calcd for C16H17NO, 239.1310; found,
239.1311.
2-(1H-Inden-3-yl)pyridine (14).18 Using general method C,
ketone 7 (0.216 g, 1.02 mmol) gives compound 14 (0.149 g, 0.774
mmol, 76%) as a yellow resin, Rf = 0.26 (9:1 hexane/ethyl acetate). 1H
NMR (CDCl3, 300 MHz) δ 3.58 (d, J = 2.2 Hz, 2H), 7.01 (t, J = 2.2
Hz, 1H), 7.24−7.33 (m, 2H), 7.40 (t, J = 7.9, 1H), 7.56 (d, J = 7.4 Hz,
1H), 7.69−7.79 (m, 2H), 8.15 (d, J = 7.6 Hz, 1H), 8.75−8.77 (m,
1H). 13C NMR (CDCl3, 75 MHz) δ 38.3, 122.0, 122.03, 122.2, 123.9,
125.1, 126.3, 133.9, 136.4, 142.9, 144.1, 144.6, 149.4, 154.9. LR-MS
(EI): 211 (M+), 183, 182, 107, 91, 79. HR-MS (EI) calcd for
C14H13NO, 211.0997; found, 211.0996.
3-Phenyl-1-(pyrimidin-2-yl)propan-1-one (8). Using general
method A, 2-cyanopyrimidine (0.5035 g, 4.8 mmol) gives compound 8
(0.808 g, 3.8 mmol, 80%), isolated as clear, yellow oil, Rf = 0.6 (100%
1
ether). H NMR (CDCl3, 300 MHz) δ 3.13 (t, J = 7.2 Hz, 2H), 3.60
(t, J = 8.1 Hz, 2H), 7.13−7.31 (m, 6H), 7.46 (t, J = 4.8 Hz, 1H), 8.93
(d, J = 4.9, 1H). 13C NMR (CDCl3, 75 MHz) δ 29.8, 40.8, 124.0,
136.1, 128.5, 128.5, 141.1, 157.6, 160.0, 198.9. LR-MS (EI): 212 (M
+), 183, 169, 105, 80. HR-MS (EI) calcd for C13H12N2O, 212.0950;
found, 212.0952.
1-(1-Butyl-1H-imidazol-2-yl)-3-phenylpropan-1-one (9).
Using general method B, 1-butylimidazole (0.5 mL, 3.83 mmol)
gives compound 9 (0.673 g, 2.63 mmol, 69%), isolated as a clear, light
brown oil, Rf = 0.11 (5:1 hexane/ether). 1H NMR (CDCl3, 500 MHz)
δ 0.92 (t, J = 7.4 Hz, 3H), 1.26−1.34 (m, 2H), 1.67−1.73 (m, 2H),
3.04 (t, J = 7.5 Hz, 2H), 3.48 (t, J = 8.0 Hz, 2H), 4.34 (t, J = 7.4 Hz,
2H), 7.01 (d, J = 0.8 Hz, 1H), 7.10 (d, J = 0.9 Hz, 1H), 7.12−7.17 (m,
1H), 7.24 (s, 2H), 7.25 (s, 2H). 13C NMR (CDCl3, 125 MHz) δ 13.6,
19.7, 30.0, 33.1, 40.7, 48.4, 125.9, 125.9, 128.3, 128.4, 129.0, 141.1,
142.3, 191.7. LR-MS (EI): 256 (M+), 228, 199, 123, 82. HR-MS (EI)
calcd for C16H20N2O, 256.1576; found, 256.1569.
1-(2,5-Diphenyloxazol-4-yl)-3-phenylpropan-1-one (10).
Using general method B, 2,4-diphenyloxazole (0.442 g, 2.0 mmol)
gives compound 10 (0.218 g, 0.62 mmol, 31%), isolated as colorless
solid resin (mp 107−109 °C), Rf = 0.18 (5:1 hexane/ether). 1H NMR
(CDCl3, 300 MHz) δ 3.13 (t, J = 7.4 Hz, 2 H), 3.55 (t, J = 8.2 Hz,
2H), 7.22−7.29 (m, 1H), 7.34 (s, 2H), 7.36 (s, 2H), 7.50−7.57 (m,
2-(1H-Inden-3-yl)-3-methylpyridine (15). Using general meth-
od C, ketone 5 (0.2251 g, 1.0 mmol) provides compound 15 (0.1749
g, 0.85 mmol, 87%) as a clear, orange oil, Rf = 0.21 (7:1 hexane/ethyl
acetate). 1H NMR (CDCl3, 500 MHz) δ 2.37 (s, 3H), 3.61 (d, J = 1.8
Hz, 2H) 6.68 (t, J = 1.8 Hz, 1H), 7.20−7.39 (m, 4H), 7.54−7.57 (m,
1H), 7.61−7.66 (m, 1H), 8.59 (d, J = 3.9 Hz, 1H). 13C NMR (CDCl3,
125 MHz) δ 19.6, 38.6, 121.1, 122.2, 123.8, 124.9, 126.2, 132.0, 133.4,
138.2, 143.8, 143.8, 144.3, 146.9, 154.4. LR-MS (EI): 207 (M+), 206,
180, 102. HR-MS (EI) calcd for C15H13N, 207.10480; found,
207.10441.
2-(1H-Indene-3-yl)pyrimidine (16). Using general method C,
ketone 8 (0.1051 g, 0.496 mmol) provides compound 16 (0.0662 g,
0.341 mmol, 69%) as a clear, dark red resin, Rf = 0.21 (9:1 hexane/
1
ethyl acetate). H NMR (CDCl3, 300 MHz) δ 3.63 (d, J = 2.1 Hz,
2H), 7.19−7.22 (m,1H), 7.28−7.34 (m, 2H), 7.40−7.57 (m, 2H), 7.68
(t, J = 2.1 Hz, 1H) 8.57 (d, J = 7.7 Hz, 1H), 8.85 (d, J = 4.8 Hz, 1H).
13C NMR (CDCl3, 75 MHz) δ 38.3, 119.0, 123.3, 123.8, 125.1, 123.4,
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128.5, 139.4, 142.9, 144.9, 156.9, 163.1. LR-MS (EI): 194 (M+), 193,
168, 140, 115. HR-MS (EI) calcd for C13H10N2, 194.08440; found,
194.08441.
solutionis added phenethylmagnesium chloride (0.6 mL, 1.0 M in
THF, 0.6 mmol), and the mixture is stirred at room temperature for 4
h. The reaction mixture is then quenched with slightly acidic water (20
mL of H2O with several drops of 1.0 M HCl), and 40 mL of ether is
added. The products are extracted into the ether. The resulting organic
solution is washed with brine and dried with anhydrous sodium sulfate.
The crude alcohol is oxidation to provide the crude ketone.19 Ketone
23 is isolated (0.114 g, 0.34 mmol, 68%) as a colorless oil, Rf = 0.51
1-Butyl-2-(1H-inden-3-yl)-1H-imidazole (17). Using general
method C, ketone 9 (0.121g, 0.472 mmol) provides compound 17
(0.110 g, 0.462 mmol, 98%) as a brown oil, Rf = 0.22 (1:1 hexane/
ethyl acetate). 1H NMR (CDCl3, 500 MHz) 0.78 (t, J = 7.5 Hz, 3H),
1.13−1.23 (m, 2H) 1.69−1.75 (m, 2H), 3.66 (s, 2H), 4.12 (t, J = 7.5
Hz, 2H), 7.19 (s, 1H). 7.22−7.32 (m, 3H), 7.40 (s, 1H), 7.52−7.53
(m, 2H). 13C NMR (CDCl3, 125 MHz) δ 13.3, 19.3, 32.3, 39.8, 48.4,
120.1, 120.7, 121.9, 124.6, 126.7, 127.0, 127.3, 140.0, 140.3, 143.1,
143.4. LR-MS (EI): 238 (M+), 223, 209, 182, 127. HR-MS (EI) calcd
for C16H18N2, 238.14700; found, 238.14720.
1
(5:1 hexane/ether). H NMR (CDCl3, 500 MHz) δ 2.73 (t, J = 7.3
Hz, 2H), 2.85 (t, J = 7.8 Hz, 2H), 6.96 (d, J = 7.1 Hz, 2H), 7.14−7.29
(m, 3H), 7.53, (d, J = 1.4 Hz, 1H), 7.54 (d, J = 1.8 Hz, 2H), 7.63−7.66
(m, 1H), 7.69−7.71 (m, 2H), 7.85−7.88 (m, 1H), 7.93 (d, J = 7.7 Hz,
1H), 8.30 (s, 1H), 8.34 (d, J = 7.9, 1H). 13C NMR (CDCl3, 125 MHz)
δ 30.7, 44.6, 126.1, 126.2, 127.6, 128.3, 128.4, 128.42, 128.96, 129.0,
129.3, 129.7, 131.7, 134.8, 137.4, 140.3, 147.5, 156.3, 204.8. LR-MS
(EI): 337 (M+), 246, 232, 204, 176. HR-MS (EI) calcd for C24H19NO,
337.1466; found, 337.1467.
4-(1H-Inden-3-yl)-2,5-diphenyloxazole (18). Using general
method C, ketone 10 (0.1195 g, 0.339 mmol) provides compound
18 (0.0798 g, 0.238 mmol, 70%) as a clear, light brown oil, Rf = 0.65
1
(9:1 hexane/ethyl acetate). H NMR (CDCl3, 300 MHz) δ 3.63 (d, J
2,3-Dihydrospiro[indene-1,11′-indeno[1,2-b]quinoline (24).
Using general method C, ketone 23 (0.0233 g, 0.069 mmol) provides
compound 24 (0.0209 g, 0.066 mmol, 95%) as an oil, Rf = 0.38 (4:1,
= 2.1 Hz, 2H), 6.93 (t, J = 1.8 Hz, 1H), 7.25−7.57 (m, 10H), 7.71−
7.74 (m, 2H), 8.20−8.23 (m, 2H). 13C NMR (CDCl3, 75 MHz) δ
38.77, 121.62, 123.76, 125.08, 126.19, 126.50, 127.38, 128.29, 128.58,
128.71, 128.79, 130.40, 131.90, 134.34, 136.52, 143.18, 143.98, 146.81,
160.13. LR-MS (EI): 335 (M+), 306, 231, 2−3, 202, 77. HR-MS (EI)
calcd for C24H17NO, 335.13102; found, 335.13051.
1
hexane/ether). H NMR (CDCl3, 300 MHz) δ 2.66−2.77 (m, 2H),
3.42−3.51 (m, 2H), 6.53 (d, J = 7.6 Hz, 1H) 7.02−7.06 (m, 1H),
7.25−7.33 (m, 2H), 7.43−7.55 (m, 4H), 7.68−7.74 (m, 2H), 7.89 (s,
1H), 8.27 (dd, J = 8.3, 25.1 Hz, 2H). 13C NMR (CDCl3, 75 MHz) δ
32.0, 40.7, 60.7, 121.8, 123.7, 124.1, 125.0, 125.8, 127.2, 127.5, 127.9,
128.0, 128.1, 129.0, 129.1, 130.1, 131.0, 138.7, 144.2, 144.6 147.5,
148.5, 154.2, 160.5. LR-MS (EI): 319 (M+), 318, 304, 152. HR-MS
(EI) calcd for C24H17N, 319.13610; found, 319.13566.
2-(1H-Inden-3-yl)thiazole (19). Using general method C, ketone
11 (0.1088 g, 0.5 mmol) provides compound 19 (0.0856 g, 0.043
mmol, 86%) as a white solid (mp 96−102 °C), Rf = 0.40 (9:1 hexane/
1
ethyl acetate). H NMR (CDCl3, 300 MHz) δ 3.61 (d, J = 2.3, 2H),
7.17 (t, J = 2.3 Hz, 1H), 7.28−7.36 (m, 2H), 7.44 (t, J = 8.0 Hz, 1H),
7.55 (d, J = 7.4 Hz, 1H), 7.96 (d, J = 3.3 Hz, 1H), 8.33 (d, J = 7.7 Hz,
1H). 13C NMR (CDCl3, 75 MHz) δ 38.5, 118.2, 122.2, 123.9, 125.7,
126.6, 135.1, 138.0, 141.6, 143.2, 144.0, 163.3. LR-MS (EI): 199 (M
+), 154, 140, 115, 58. HR-MS (EI) calcd for C12H9NS, 199.04557;
found, 199.04520.
ASSOCIATED CONTENT
* Supporting Information
■
S
Computational procedures and results, characterization data,
and 1H and 13C NMR spectra of new compounds. This
material is available free of charge via the Internet at http://
pubs.acs.org.
2-(1H-Inden-3-yl)benzo[d]thiazole (20). Using general method
C, ketone 12 (0.1321 g, 0.514 mmol) provides compound 20 (0.0982
g, 0.394 mmol, 77%) as a light gray solid (mp 100−102 °C), Rf = 0.34
1
(9:1, hexane/ether). H NMR (CDCl3, 500 MHz) δ 3.66 (d, J = 2.2
AUTHOR INFORMATION
Corresponding Author
*E-mail: dklumpp@niu.edu.
Hz, 2H), 7.30 (t, J = 2.3 Hz, 1H), 7.37 (td, J = 1.1, 7.5 Hz, 1H), 7.4
(td, J = 1.1, 7.5 Hz, 1H), 7.49 (t, J = 7.3 Hz, 1H), 7.53−7.58 (m, 2H),
7.94 (d, J = 8.0 Hz, 1H), 8.18 (d, J = 8.1 Hz, 1H), 8.57 (d, J = 7.7 Hz,
1H). 13C NMR (CDCl3, 75 MHz) δ 35.8, 121.4, 122.8, 123.6, 123.9,
125.4, 125.9, 126.2, 126.7, 134.4, 137.9, 138.6, 141.5, 143.9, 154.0,
163.0. LR-MS (EI): 249 (M+), 217, 140, 115. HR-MS (EI) calcd for
C16H11NS, 249.06122; found, 249.06088.
2-(1-(1H-Inden-3-yl)ethyl)pyridine (21). Using general method
C, ketone 13 (0.1070 g, 0.45 mmol) provides compound 21 (0.0917 g,
0.415 mmol, 92%) as a yellow oil, Rf = 0.24 (9:1, hexane/ethyl
acetate). 1H NMR (CDCl3, 300 MHz) δ 1.73 (d, J = 7.2 Hz, 3H), 3.44
(s, 2H), 4.33 (dt, J = 7.1 Hz, 1.7 Hz, 1H), 6.46 (d, J = 1.7 Hz, 1H),
7.11 (ddd, J = 7.45 Hz, 4.90 Hz, 1.10 Hz, 1H), 7.16−720 (m, 4H),
7.45−7.49 (m, 1H), 7.55 (td, J = 15.37 Hz, 1H), 8.60−8.63 (m, 1H).
13C NMR (CDCl3, 75 MHz) δ 20.1, 37.8, 41.6, 120.1, 121.4, 121.7,
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This material is based on work supported by the National
Science Foundation under grant no. CHE-1300878.
■
REFERENCES
■
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