Convenient preparation of 1-amidoindenes

Article abstract of DOI:10.1021/jo0005565

Lewis acid-catalyzed α-amidoalkylation of enolizable aldehydes with N-(α-benzotriazolyl-α-arylalkyl)amides followed by intramolecular Friedel - Crafts cyclization provides a convenient route to 2-substituted 1-amidoindenes.

Full text of DOI:10.1021/jo0005565

8066
J . Org. Chem. 2000, 65, 8066-8068
Con ven ien t P r ep a r a tion of 1-Am id oin d en es
Alan R. Katritzky,* Olga V. Denisko, and Sophie Busont
Center for Heterocyclic Compounds, Department of Chemistry, University of Florida,
Gainesville, Florida 32611-7200
katritzky@chem.ufl.edu
Received April 12, 2000
Lewis acid-catalyzed R-amidoalkylation of enolizable aldehydes with N-(R-benzotriazolyl-R-aryl-
alkyl)amides followed by intramolecular Friedel-Crafts cyclization provides a convenient route to
2-substituted 1-amidoindenes.
In tr od u ction
afford the corresponding 1-hydroxyindenes, and (viii) ring
contraction of arynes under flash-vacuum pyrolysis to
form unstable 1-vinylideneindenes.15
Although indene chemistry has a very long history,
functionalized indenes and indanes have only recently
begun to receive detailed attention from both medicinal
and industrial chemists. 1-Aminoindanes are effective
dopamine re-uptake blockers,1 active against neurological
disorders and neurotrauma2 and, as their sulfonylated
derivatives, are potential potassium channel blockers.3
Cyano- and chloro-polysubstituted indenes can form self-
organized supramolecular assemblies and thus be used
as constituents for discotic liquid crystals.4 3-(ω-Phthal-
imidoalkyl)indenes undergo intramolecular cyclization
upon irradiation and are useful intermediates in the
synthesis of biologically active polycyclic compounds.5
Classically, indenes are prepared by intramolecular
Friedel-Crafts alkylation of an appropriately located
aromatic ring with vinylic or allylic carbocations gener-
ated in situ by (i) acid-catalyzed treatment of aryl-
substituted allyl alcohols,6 (ii) pyrolysis of the correspond-
ing magnesium alkoxides,7 (iii) cyclization of chalcones8
or â-aralkyl carbonyl compounds,9 (iv) ring-opening of
5-arylfuranones,10 or (v) from 3,5,5-triaryloxazolidines.11
Further approaches include (vi) Lewis acid-catalyzed
reactions of substituted benzyl chlorides with alkynes,12
(vii) condensation of alkynes with aryl ketones intramo-
lecularly under irradiation13 or intermolecularly in the
presence of a (tetracarbonyl)manganese catalyst14 to
3-Aminoindenes, as enamines, are readily available
from 2,3-dihydro-1H-inden-1-one and secondary amines,16
and base-catalyzed cyclizations of aromatic R-ketonitriles
give 3-aminoinden-1-ones.17 Routes to 1- and 2-amino-
or -amidoindenes are less obvious, although they are
potential precursors for rhoeadine, isopavine, and ceph-
alotaxime alkaloids.18 Acid-catalyzed condensation of
R-alkylcinnamaldehydes with carbamates gives hemi-
aminals, which cyclize to 2-alkyl-1-(alkoxycarbonyl-
amino)indenes.19 Regioselective ring opening-ring clo-
sure of 1-amino-2,3-diarylpropenes in a basic medium
forms 1-amino- or 2-aminoindenes depending on the
conditions.20 1-Aminoindene(tricarbonyl)chromium com-
plexes are formed in thermal21 or photochemical22 reac-
tions of alkynes with pentacarbonyl[amino(aryl)carbene]-
chromiums. Previous acylation of the amino moiety in
the organometallic reagent leads to 1-(alkoxycarbonyl-
amino)indenes.21
Convenient access to 1-amino- and 1-amidoindenes
could help to elucidate their properties (including biologi-
cal activity) and potential utility. As enolizable â-aralkyl
carbonyl compounds in the presence of a Lewis acid
undergo intramolecular cyclization to indenes,9 intramo-
lecular Friedel-Crafts reaction of â-amido-â-aryl-alde-
hydes or -ketones 3 (R3 ) Ar) (Scheme 1) could result in
1-amidoindenes.
(1) Froimowitz, M.; Wu, K.-M. PCT Int. Appl. WO 98 06,689; Chem.
Abstr. 1998, 128, 180231u.
The good leaving ability of the benzotriazolyl moiety23
enables its displacement in N-(R-benzotriazolylalkyl)-
(2) (a) Gilad, G.; Gilad, V.; Sterling, J .; Herzig, Y.; Lerner, D.;
Veinberg, A.; Milman, I.; Finkelstein, N. PCT Int. Appl. WO 97 02,-
027; Chem. Abstr. 1997, 126, 185897j. (b) Levy, R.; Youdim, M. B. H.;
Finberg, J . P. M.; Cohen, S.; Sterling, J . PCT Int. Appl. WO 98 02,-
152; Chem. Abstr. 1998, 128, 149588s. (c) Youdim, M. B. H.; Finberg,
J . P. M.; Levy, R.; Sterling, J .; Lerner, D.; Yellin, H.; Veinberg, A. U.S.
US 5,744,500; Chem. Abstr. 1998, 128, 312931j.
(13) Kravitz, J . I.; Margaretha, P.; Agosta, W. C. Tetrahedron Lett.
1991, 32, 31.
(14) Liebeskind, L. S.; Gasdaska, J . R.; McCallum, J . S.; Tremont,
S. J . J . Org. Chem. 1989, 54, 669.
(3) Castle, N. A.; Hollinshead, S. P.; Hughes, P. F.; Mendoza, J . S.;
Wilson, J . W.; Amato, G.; Beaudoin, S. PCT Int. Appl. WO 98 04,521;
Chem. Abstr. 1998, 128, 153932s.
(4) Barbera, J .; Rakitin, O. A.; Ros, M. B.; Torroba, T. Angew. Chem.,
Int. Ed. Engl. 1998, 37, 296.
(5) Machida, M.; Oda, K.; Kanaoka, Y. Tetrahedron 1985, 41, 4995.
(6) (a) Pittman, C. U., J r.; Miller, W. G. J . Am. Chem. Soc. 1973,
95, 2947. (b) Singh, G.; Ila, H.; J unjappa, H. Synthesis 1986, 744.
(7) Tolbert, L. M. J . Org. Chem. 1979, 44, 4584.
(15) Kirmse, W. Angew. Chem., Int. Ed. Engl. 1997, 36, 1164.
(16) Noland, W. E.; Kameswaran, V. J . Org. Chem. 1981, 46, 1940.
(17) Kayaleh, N. E.; Gupta, R. C.; Morrissey, J . F.; J ohnson, F.
Tetrahedron Lett. 1997, 38, 8121.
(18) Kametani, T.; Premila, M. S.; Hirata, S.; Seto, H.; Nemoto, H.;
Fukumoto, K. Can. J . Chem. 1975, 53, 3824.
(19) Kraft, W. M. J . Am. Chem. Soc. 1948, 70, 3569.
(20) Yoshida, H.; Sano, H.; Ogata, T.; Matsumoto, K. Bull. Chem.
Soc. J pn. 1988, 61, 4341.
(8) Venugopal, M.; Perumal, P. T. Synth. Commun. 1991, 21, 515.
(9) Olah, G. A. Friedel-Crafts Chemistry; Wiley: New York, 1973;
p 62.
(10) Canevet, J . C.; Graff, Y. Tetrahedron 1978, 34, 1935.
(11) Casuscelli, F.; Chiacchio, U.; Liguori, A.; Romeo, G.; Sindona,
G.; Uccella, N. Tetrahedron 1993, 49, 5147.
(21) Do¨tz, K. H.; Grotjahn, D.; Harms, K. Angew. Chem., Int. Ed.
Engl. 1989, 28, 1384.
(22) (a) Aumann, R.; Heinen, H.; Kru¨ger, C.; Betz, P. Chem. Ber.
1990, 123, 605. (b) Do¨tz, K. H.; Rau, A.; Harms, K. J . Organomet.
Chem. 1992, 439, 263.
(23) Katritzky, A. R.; Lan, X.; Yang, J . Z.; Denisko, O. V. Chem Rev.
1998, 98, 409.
(12) Maroni, R.; Melloni, G. Tetrahedron Lett. 1972, 2869.
10.1021/jo0005565 CCC: $19.00 © 2000 American Chemical Society
Published on Web 10/21/2000

Convenient Preparation of 1-Amidoindenes
J . Org. Chem., Vol. 65, No. 23, 2000 8067
Sch em e 1
Sch em e 2
Ta ble 1. P r ep a r a tion of
N-(r-Ben zotr ia zolyla lk yl)-Su bstitu ted Am id es 6
compd
R
X
Y
yield, %
mp, °C (lit. mp, °C)
6a
6b
6ca
6d
6e
6f
Me
Me
Me
Me
Me
Me
Me
Ph
H
Cl
H
H
H
Cl
H
H
H
H
H
55
65
35
73
62
69
64
85
153-154 (154-15628b
146-147
)
210 dec
Me
182-183 (186-18928a
186-187 (183-18524b
179-181
)
)
MeO
NO2
Me2N
H
6g
6h
170 dec
181-182 (188-19028a
)
a
This compound is poorly soluble in common solvents and was
used in the next step without additional purification and full
characterization.
substituted amides (1, A ) Bt) in reactions with C-
nucleophiles including (i) active methylene and methine
compounds,24 (ii) propen-2-yl acetate (one example),25 and
(iii) alkyl vinyl ethers, silyl enol ethers, and enamines
under mild conditions (ZnBr2/CH2Cl2, 40 °C) (2, B ) OEt,
OSiMe3, NR2).26 Reactions of class (iii) provide convenient
syntheses of â-amido aldehydes and â-amido ketones of
type 3 which expand and complement previous amido-
alkylation of derivatives 2 (A ) OH, OMe, Cl) (for a
review see27).
Thus, based on the literature data discussed above, we
reasoned that the condensation of benzotriazole-contain-
ing amides with enolizable aldehydes in the presence of
a Lewis acid should allow the development of a new
synthetic route to â-amido aldehydes in accordance with
Scheme 1 (A ) Bt, B ) OH). Subsequent cyclization
under Friedel-Crafts conditions could provide a conve-
nient approach to the preparation of various 1-
amidoindenes.
Ta ble 2. P r ep a r a tion of 1-Am id oin d en es 7
run
compd
R
X
Y
R′
yield, %
mp, °C
1
2
3
4
5
6
7
8
9
7a
7b
7c
7d
7e
7f
7g
7h
7i
Me
Me
Me
Me Cl
Me Cl
Me Cl
H
H
H
H
H
H
H
H
H
Et
n-Bu
Ph
Et
Ph
50
40
44
51
44
39
38
27
14
33
21
24
134-135
134-135
202-203
176 dec
158-159
158-159
220-221
163-164
165 dec
PhCH2
Me
H
Cl Ph
Me Me
Me Me
Me Me
Ph
Ph
H
H
H
H
H
Et
Ph
PhCH2
Ph
PhCH2
10
11
12
7j
7k
7l
143-145
159 dec
121-122
H
H
5 h formed only trace amounts of product, the hexanal
underwent aldol condensation and the amide was decomposed.
However, providing a constant large excess of the N-(R-
benzotriazolylalkyl)amide with respect to the aldehyde during
the first stage of the reaction (by adding slowly a solution of
hexanal in toluenes3 mmolsof the aldehyde in 20 mL of
toluene during 1 hsto a refluxing mixture of the amide 6a
and zinc bromides1 equivsin toluene) led to the formation of
product 7b in 40% yield (Scheme 2). It seems that a â-amido
aldehyde, formed as an intermediate under the reaction
conditions, undergoes intramolecular Friedel-Crafts cycliza-
tion to give an indene derivative.
The effect of the nature of a Lewis acid on the yield of the
product was studied on the analogous reaction of 6a with
phenylacetaldehyde: zinc bromide in refluxing toluene pro-
vides the corresponding 1-amidoindene 7c in 44% yield. Use
of the less reactive Lewis acid, boron trifluoride etherate,
decreased the yield to less than 10%. However, Lewis acids
stronger than zinc bromide were also unsuccessful: thus,
SnCl2 or TiCl4 led to fast decomposition of the starting amide
6a under the reaction conditions and no product of type 7 was
detected.
Amides 6b,c, with mild electron-accepting substituents X
or Y, afford indenes 7 in the same or higher yields as the
analogous amides with X ) Y ) H (compare runs 1 and 4, or
3 and 5; Table 2). However, the introduction of electron-
donating groups into the para position of the aromatic ring (X
in 6d ,e) leads to a significant decrease in the product yield
(compare runs 1 and 8, or 3 and 9; Table 2). The reaction with
the anilino derivative (X ) Me2N) does not occur at all. As it
is well-known that Friedel-Crafts alkylation is facilitated by
electron-donating substituents, especially in the ortho and para
positions of the aromatic ring, this led us to the conclusion
that the rate-determining step in this reaction is the substitu-
Resu lts a n d Discu ssion
Benzotriazolyl-substituted amides 6a -h were prepared
using the well-known Mannich three-component condensations
of benzotriazole, amides 4a ,b and the appropriate aromatic
aldehyde 5a -g in the presence of catalytic p-toluenesulfonic
acid (Table 1).23 As found previously,24b,28 the yields of amides
6a -h are moderate to good (55-85%), except for the o-chloro
derivative 6c.
Amidoalkylations of enolizable aldehydes were studied using
amide 6a as a model. No reaction of 6a occurred with hexanal
under the conditions described for the reactions with methyl-
ene active compounds24b or silyl enol ethers,26 in presence of
zinc bromide at reflux in benzene or at reflux in 1,1,1-
trichloroethane. In all these experiments, hexanal underwent
aldol condensation while the amide 6a was recovered intact.
Refluxing a mixture of 6a and hexanal in toluene in the
presence of zinc bromide or boron trifluoride etherate for
(24) (a) Katritzky, A. R.; Saczewski, F. Gazz. Chim. Ital. 1990, 120,
375. (b) Katritzky, A. R.; Pernak, J .; Fan, W.-Q.; Saczewski, F. J . Org.
Chem. 1991, 56, 4439.
(25) Katritzky, A. R.; Ignatchenko, A. V.; Lang, H. J . Org. Chem.
1995, 60, 4002.
(26) Katritzky, A. R.; Fang, Y.; Silina, A. J . Org. Chem. 1999, 64,
7622.
(27) Zaugg, H. E. Synthesis 1984, 185.
(28) (a) Katritzky, A. R.; Drewniak, M. J . Chem. Soc., Perkin Trans.
1 1988, 2339. (b) Katritzky, A. R.; Harris, P. A. Tetrahedron: Asym-
metry 1992, 3, 437.

8068 J . Org. Chem., Vol. 65, No. 23, 2000
Katritzky et al.
75 MHz, respectively) in CDCl3 as a solvent and with TMS as
an internal standard. Column chromatography was carried out
on silica gel (activated, neutral, 50-200 micron). Toluene was
purified by distillation from Na under nitrogen. Benzotriazolyl-
substituted amides 6 were prepared using the procedures
already described.28b
Sch em e 3
Gen er a l P r oced u r e for th e Syn th esis of Su bstitu ted
1-Am id oin d en es (7). A mixture of a benzotriazolyl-substi-
tuted amide 6 (2 mmol) and anhydrous zinc bromide (1 mmol)
was heated in dry toluene (50 mL) until reflux. A solution of
an aldehyde (3 mmol) in dry toluene (20 mL) was added
dropwise to the refluxing reaction mixture during 1 h. The
obtained reaction mixture was refluxed for another 4 h, then
it was allowed to cool and washed successively with saturated
aqueous NH4Cl, water, saturated aqueous Na2CO3, and water.
The organic extract was dried over MgSO4. The solvent was
removed under reduced pressure and the residue obtained was
purified by column chromatography (silica, ethyl acetate/
hexane ) 1:1) and then recrystallized from ethanol to give the
corresponding 1-amidoindene 7 as long white needles.
tion of the benzotriazole moiety. It should also be noted that
the increased reaction rate is crucial to obtain higher yields
of the products because of the competing reactions of aldol
condensation and starting amide decomposition.
However, contrary to our expectations, the reactions of 6
bearing a strong electron-accepting substituent (X ) NO2)
failed to produce the corresponding 1-amidoindene, leading
instead to the partial recovery of 4-nitrobenzaldehyde (in the
reaction with volatile butyraldehyde) or its aldol condensation
product (in the reaction with phenylacetaldehyde). These
results could be explained by retro-Mannich reaction of the
starting benzotriazolyl-substituted amide 6f under the reaction
conditions, and this conclusion was confirmed by a blank
experiment of degradation of 6f on heating in toluene in the
presence of zinc bromide.
N-(2-Eth yl-in d en -1-yl)a ceta m id e (7a ): white needles; mp
134 °C (from EtOH); 1H NMR δ 7.27 (d, J ) 7.0 Hz, 1H), 7.20-
7.02 (m, 3H), 6.35 (d, J ) 1.3 Hz, 1H), 6.07 (d, J ) 9.1 Hz,
1H), 5.49 (d, J ) 9.2 Hz, 1H), 2.33-2.18 (m, 2H), 1.97 (s, 3H),
1.16 (t, J ) 7.4 Hz, 3H); 13C NMR δ 170.8, 152.9, 144.1, 143.5,
127.8, 125.6, 124.5, 123.1, 120.1, 57.5, 23.0, 21.3, 12.3. Anal.
Calcd for C13H15NO: C, 77.51; H, 7.45; N, 6.95. Found: C,
77.08; H, 7.63; N, 7.04.
Replacement of the methyl group in the amide moiety by a
phenyl group resulted in a significant decrease in the yield of
the corresponding 1-amidoindenes (see Table 2).
When, instead of an aldehyde, a methyl ketone, such as
acetophenone, was used in the reaction with 6a under the
conditions described above, only decomposition of the starting
benzotriazolyl-substituted amide occurred. However, when,
instead of zinc bromide, boron trifluoride etherate was applied
as a Lewis acid, no benzotriazolyl group substitution was
observed, but the product of the amido group substitution 8
was obtained in low yield (11%) (Scheme 3). Benzotriazole
derivative 8 easily eliminates a molecule of benzotriazole
during column chromatography on silica or alumina and even
on storage at room temperature affording the corresponding
chalcone. This has prevented the full characterization of 8,
which was identified only by means of 1H and 13C NMR
spectroscopy after flash column chromatography. The aliphatic
N-(2-Bu tyl-in d en -1-yl)a ceta m id e (7b): white needles; mp
134-135 °C (from EtOH); 1H NMR δ 7.36 (d, J ) 7.4 Hz, 1H),
7.30-7.10 (m, 3H), 6.43 (s, 1H), 5.64 (d, J ) 9.5 Hz, 1H), 5.35
(d, J ) 9.5 Hz, 1H), 2.32 (t, J ) 7.5 Hz, 2H), 2.10 (s, 3H), 1.52-
1.47 (m, 2H), 1.46-1.32 (m, 2H), 0.93 (t, J ) 7.3 Hz, 3H); 13
C
NMR δ 170.5, 151.5, 144.2, 143.7, 128.1, 126.8, 124.8, 123.3,
120.3, 57.7, 30.4, 28.0, 23.4, 22.5, 13.9. Anal. Calcd for
C15H19NO: C, 78.56; H, 8.37; N, 6.11. Found: C, 78.56; H, 8.91,
N, 6.20.
N-(2-Ben zyl-in d en -1-yl)ben za m id e (7l): white micro-
crystals; mp 121-122 °C (from EtOH); 1H NMR δ 7.58 (m,
2H), 7.45-7.52 (m, 1H), 7.35-7.42 (m, 3H), 7.16-7.30 (m, 7H),
7.12 (dt, J ) 7.3, 1.5 Hz, 1H), 6.44 (s, 1H), 5.89-5.98 (m, 2H),
3.79 (d, J ) 16.0 Hz, 1H), 3.68 (d, J ) 16.0 Hz, 1H); 13C NMR
δ 167.8, 149.8, 144.3, 143.3, 138.9, 133.9, 131.6, 129.1, 128.9,
128.6(2), 128.5(2), 128.2, 126.9, 126.3, 125.3, 123.5, 120.7,
112.1, 58.4, 35.5. Anal. Calcd for C23H19NO: C, 84.89; H, 5.90;
N, 4.31. Found: C, 84.47; H, 5.96; N, 4.39.
1
protons of the Bt-CHCH2 fragment in the H NMR spectrum
display the characteristic ABX pattern with the following
splitting constants: J AB ) 18.0 Hz, J AX ) 8.8 Hz and J BX
4.9 Hz.
)
In conclusion, we now report a tandem substitution-cycliza-
tion reaction of R-benzotriazolyl-substituted amides with eno-
lizable aldehydes which provides a simple and convenient
route to various 1-amidoindenes of type 7a -l. Although the
yields of amidoindenes 7 are moderate, this approach has some
undoubtful advantages over the known methods for the
preparation of analogous compounds (see, for example,19,21),
such as the easy availability and high stability of the starting
materials, the simplicity of the procedure and the mild reaction
conditions.
Ack n ow led gm en t. We thank the National Science
Foundation (CHE-9629854) for partial support.
Su p p or tin g In for m a tion Ava ila ble: Discussion of the
characteristic features of NMR spectra of 1-amidoindenes and
experimental data. This material is available free of charge
via the Internet at http://pubs.acs.org.
Exp er im en ta l Section
Gen er a l Com m en ts. Melting points were measured on a
hot-stage apparatus and are uncorrected. 1H and 13C NMR
data were recorded on 300 MHz NMR spectrometer (300 and
J O0005565