Bismuth nitrate-catalyzed versatile Michael reactions

Article abstract of DOI:10.1021/jo026550s

Bismuth nitrate-catalyzed versatile Michael reaction was developed to reduce the complications that characterize the current standard Michael reaction and used for facile preparation of organic compounds of widely different structures. For example, several substituted amines, imidazoles, thio compounds, indoles, and carbamates were prepared at room temperature by following this method. In contrast with the existing methods using many acidic catalysts, this method is very general, simple, high-yielding, environmentally friendly, and oxygen and moisture tolerant. However, the promoting role of bismuth nitrate in this reaction is not understood at this time.

Full text of DOI:10.1021/jo026550s

Bism u th Nitr a te-Ca ta lyzed Ver sa tile Mich a el Rea ction s†
Neeta Srivastava and Bimal K. Banik*
The University of Texas M. D. Anderson Cancer Center, Department of Molecular Pathology, Box 89,
1
515 Holcombe Boulevard, Houston, Texas 77030
bbanik@mail.mdanderson.org
Received October 10, 2002
Bismuth nitrate-catalyzed versatile Michael reaction was developed to reduce the complications
that characterize the current standard Michael reaction and used for facile preparation of organic
compounds of widely different structures. For example, several substituted amines, imidazoles,
thio compounds, indoles, and carbamates were prepared at room temperature by following this
method. In contrast with the existing methods using many acidic catalysts, this method is very
general, simple, high-yielding, environmentally friendly, and oxygen and moisture tolerant.
However, the promoting role of bismuth nitrate in this reaction is not understood at this time.
In tr od u ction
in catalyzing a similar reaction with carbamates; because
carbamates7 are weakly nucleophilic, the yield of the
reaction is very low. However, recent results show that
platinum salts are very effective for addition reactions
The Michael reaction, which was discovered many
years ago, is one of the most important reactions in
organic chemistry. In general, this type of conjugate
addition reaction of nucleophiles to unsaturated carbonyl
7
with carbamates. Therefore, development of an alterna-
tive method, which can be applied to a number of
substrates of different natures in a catalytic process, is
highly desirable.
1
2
compounds requires basic conditions or acidic catalysts.
Some of the methods classified as Michael reactions
require stoichiometric amounts of the reagents, and many
side reactions can occur if the reactive partners are
We have been studying reactions mediated by metals
or their salts with the aim of developing several biologi-
3
sensitive. Recently, a number of reagents that overcome
8
cally active compounds, including anticancer agents and
these drawbacks have been developed. The main im-
provement of these reagents is the ability to limit the
catalysts used to catalytic amounts. These methods are
9
â-lactams. We have also reported the use of bismuth-
10
derived reagents in several organic transformations. For
4
example, nitration of aromatic hydrocarbons, phenolic
really very fascinating from a synthetic chemist’s point
of view. In addition, these processes are less expensive
and environmentally friendly. Despite their tremendous
success, however, the literature reveals that these cata-
lysts are very substrate selective. For example, indium
salts are very effective for Michael reactions between
compounds, and â-lactams by bismuth nitrate was per-
10c,d
formed in excellent yields.
Facile deprotection of
hydrazones and oximes also worked well using bismuth
(6) Yadav, J . S.; Abraham, S.; Reddy, B. V. S.; Sabitha, G. Tetra-
hedron Lett. 2001, 42, 8063.
5
6
indoles and pyrroles, but they are practically ineffective
(7) Kobayashi, S.; Kakumoto, K.; Sugiura. M. Org. Lett. 2002, 4,
1
319.
8) (a) Becker, F. F.; Banik, B. K. Bioorg. Med. Chem. Lett. 1998, 8,
(
†
Dedicated to Professor Swapnadeep Thakur of Burdwan Univer-
2877. (b) Becker, F. F.; Mukhopadhyay, C., Hackfeld, L., Banik, I.;
Banik, B. K. Bioorg. Med. Chem. 2000, 8, 2693. (c) Banik, B. K.; Becker,
F. F. Bioorg. Med. Chem. 2001, 9, 593. (d) Banik, B. K.; Becker, F. F.
Cur. Med. Chem. 2001, 8, 1513. Also see: (a) Becker, F. F.; Banik, B.
K. U.S. Patent 6,015,811, 2000. (b) Becker, F. F.; Banik, B. K. U.S.
Patent 6,184,224, 2001. (c) Becker, F. F.; Banik, B. K. U.S. Patent 0,-
103,191, 2002, A1. (d) Becker, F. F.; Banik, B. K. U.S. Patent 6,362,-
200, 2002.
(9) (a) Ghatak, A.; Becker, F. F.; Banik, B. K. Heterocycles 2000,
53, 2769. (b) Banik, B. K.; Ghatak, A.; Becker, F. F. J . Chem. Soc.,
Perkin Trans 1 2000, 2179. (c) Banik, B. K.; Becker, F. F. Tetrahedron
Lett. 2000, 41, 6551. (d) Ng, S.; Banik, I.; Okawa, A.; Becker, F. F.;
Banik, B. K. J . Chem. Res. 2001, 118. (e) Dasgupta, S. K.; Banik, B.
K. Tetrahedron Lett. 2002, 43, 9445. (f) Banik, I.; Becker, F. F.; Banik,
B. K. J . Med. Chem. 2003, in press. (g) Banik, I.; Hackfeld, L.; Banik,
B. K. Heterocycles 2003, in press.
(10) (a) Banik, B. K.; Mukhopadhyay, C.; Venkatraman, M. S.;
Becker, F. F. Tetrahedron Lett. 1998, 39, 7243. (b) Banik, B. K.;
Ghatak, A.; Mukhopadhyay, C.; Becker, F. F. Synth. Commun. 2000,
30, 108. (c) Samajdar, S.; Becker, F. F.; Banik, B. K. Tetrahedron Lett.
2000, 41, 8017. (d) Samajdar, S.; Becker, F. F.; Banik, B. K. Arkivoc
2001, TG-223. (e) Banik, B. K.; Ghatak, A.; Venkatraman, M. S.;
Becker, F. F. Synth. Commun. 2000, 30, 2701. (f) Samajdar, S.; Becker,
F. F.; Banik, B. K. Synth. Commun. 2002, 32, 1917.
sity, India, for his remarkable lifetime contributions in teaching
university students.
(1) (a) Bull, S. D.; Davies, S. G.; Delgado-Ballester, S.; Fenton, G.;
Kelly, P. M.; Smith, A. D. Synlett 2000, 1257. (b) Davies, S. G.;
McCarthy, T. D. Synlett 1995, 700.
(
2) Rosenthal, D.; Braundrup, G.; Davis, K. H.; Wall, M. E. J . Org.
Chem. 1965, 30, 3689.
3) (a) Clariana, J .; Galvez, N.; Marchi, C.; Moreno-Manas, M.;
(
Vallribera, A.; Mollins, E. Tetrahedron 1999, 55, 7331. (b) Christoffers,
J . Eur. J . Org. Chem. 1998, 1259. (c) Giuseppone, N.; Vander Weghe,
P.; Mellah, M.; Collin, J . Tetrahedron 1998, 54, 13129.
(4) (a) Cabral, J .; Laszlo, P.; Mahe, L.; Montaufier, M.-T.; Ran-
driamahefa, S. L. Tetrahedron Lett. 1989, 30, 3969. (b) Perez, M.;
Pleixats, R. Tetrahedron 1995, 51, 8355. (c) Falborg, L.; J orgensen, K.
A. J . Chem. Soc., Perkin Trans. 1996, 1, 2823. (d) Sibi, M. P.; Shay, J .
J .; Liu, M.; J asperse, C. P. J . Am. Chem. Soc. 1998, 120, 6615. (e) Sibi.
M. P.; Liu, M. Org. Lett. 2000, 2, 3393. (f) Zhuang, W.; Hazell, R. G.;
J orgensen, K. A. Chem. Commun. 2001, 1240; For
enantioselective conjugate addition, see: Sibi, M. P.; Manyem, S.
a review for
Tetrahedron 2000, 56, 8033.
(5) (a) Bandini, M.; Cozzi, P. G.; Giacomoni, M.; Melchiorre, P.;
Selva, S.; Ronchi, A. U. J . Org. Chem. 2002, 67, 3700. (b) Yadav, J . S.;
Abraham, S.; Reddy, B. V. S.; Sabitha, G. Synthesis 2001, 2165.
1
0.1021/jo026550s CCC: $25.00 © 2003 American Chemical Society
Published on Web 02/19/2003
J . Org. Chem. 2003, 68, 2109-2114
2109

Srivastava and Banik
nitrate.10f These reactions, in principle, require the
presence of acids. We hypothesized that the drawbacks
of the catalysts employed in the Michael reaction may
be avoided if we used bismuth nitrate as a mild reagent,
as long as the acidity is controlled by using it in catalytic
proportions. Our hypothesis was further strengthened by
the recent discovery by Mohan and his group, who
demonstrated that bismuth triflate is an efficient catalyst
for the deprotection of acyclic O,O-acetals derived from
ketones and conjugated aldehydes.11 However, reactions
of cyclic acetals and TBDMS ethers are not affected by
this reagent. Since Michael reactions are among the most
important acid-mediated reactions, development of a
reaction that uses catalytic quantities of minimally toxic,
readily available, economic reagent should greatly con-
tribute to the creation of environmentally benign pro-
cesses. Our results and the facts described above prompted
us to investigate a bismuth nitrate-mediated Michael
reaction (conjugate reaction) with a wide variety of
substrates in a general reaction. This paper describes the
development of a new bismuth nitrate-mediated Michael
reaction of amines, carbamates, indoles, imidazoles, and
thiols with unsaturated ketones for the first time. No
other reports in the literature demonstrated methods
that are as versatile and general.
TABLE 1. Bi(NO)3-Ca ta lyzed Mich a el Rea ction of
En on es w ith Am in es a n d Im id a zolesa
Resu lts a n d Discu ssion
Bism u th Nitr a te-Ca ta lyzed Ad d ition of Am in es,
Im id a zoles, a n d Th iols to En on es. â-Amino ketones
are versatile intermediates for a large number of organic
compounds, as exemplified in the preparation of antibiot-
ics, natural products, γ-amino alcohols, and chiral aux-
iliaries.12 In addition, they are present as a structural
a
Reaction was completed at room temperature within 12-15
h. b For the preparation of 1, see: Greenhill, J . V. J . Org. Chem.
1971, 14, 971. For the preparation of 2 and 3, see ref 17.
c
1
3
unit in a variety of compounds of biological interest.
Other applications of this type of compound are in the
fine chemical and pharmaceutical fields.14 As a result of
this vast range of applications, synthesis of â-amino
ketones has remained an important objective for a
number of years. Acid- or base-induced conjugate addition
reaction of unsaturated carbonyl groups to amines has
been the method used for this purpose for many years.
But because of the many side reactions that result from
the presence of strong acids (polymerization of vinyl
ketones) or bases in the medium, this method has not
been applied in industry or resulted in any practical
applications. The most common reaction for the prepara-
tion of these types of compounds is by the Mannich
reaction, which has also several disadvantages.15 There-
fore, many other attractive methods have been reported.
One such elegant method involves the addition of vinyl
16
Grignard reagents. To avoid many of the disadvantages
of stoichiometric addition of a Lewis acid-mediated (AlCl
3
,
SnCl , or TiCl ) conjugate addition reaction, two new
4
4
methods have appeared in the literature. The first is
Michael reaction of amines to enones in the presence of
the CeCl
3
‚7H O-NaI system supported in silica gel under
2
17
refluxing conditions. It can produce â-amino ketones
and is the most useful known reaction for this purpose.
The second method is addition reaction of zinc ester
enolates to sulfones.18
(11) Carrigan, M. D.; Sarapa, D.; Smith, R. C.; Wieland, L. C.;
Our method of bismuth nitrate-catalyzed Michael
reaction of enones with amino compounds is very simple
and efficient (Table 1, entries 1-5). The starting materi-
als (amines and ketones) are mixed with bismuth nitrate
(10 mol %) in dichloromethane, and the solvent is
evaporated under reduced pressure while the residual
mass is maintained at room temperature for a specified
time. Unlike the processes described in previous reports,
Mohan, R. S. J . Org. Chem. 2002, 67, 1027. Also see: Eash, K. J .;
Paulia, M. S.; Wieland, L. C.; Mohan, R. S. J . Org. Chem. 2000, 65,
8
399.
12) (a) Wang, Y.-F.; Izawa, T.; Kobayashi, S.; Ohno, M. J . Am.
(
Chem. Soc. 1982, 104, 6465. (b) Hashiguchi, S.; Kawada, A.; Natsugari,
H. J . Chem. Soc., Perkin Trans. 1 1991, 2435. (c) Senanayake, C. H.;
Fang, K.; Grover, P.; Bakale, R. P.; Vandenbassche, C. P.; Wald, S. A.
Tetrahedron Lett. 1999, 40, 819. (d) Genov, M.; Dimitrov, V.; Ivanova,
V. Tetrahedron: Asymmetry 1997, 8, 3703. (e) Hayashi, Y.; Rode, J . J .;
Corey, E. J . J . Am. Chem. Soc. 1996, 118, 5502. (f) Eliel, E. L.; He,
X.-C. J . Org. Chem. 1990, 55, 2114.
(
13) Traxler, P.; Trinks, U.; Buchdunger, E.; Mett, H.; Meyer, T.;
Muller, M.; Regenass, U.; Rosel, J .; Lydon, N. J . Med. Chem. 1995,
8, 2441.
14) (a) Bartoli, G.; Cimarelli, C.; Marcantoni E.; Palmieri, G.;
(15) Arend, M.; Westermann, B.; Risch, N. Angew Chem., Int. Ed.
Engl. 1998, 37, 1044.
(16) (a) Gomtsyan, A.; Koening, R. J .; Lee, C. H. J . Org. Chem. 2001,
66, 3613. (b) Gomtsyan, A. Org. Lett. 2000, 2, 11.
(17) Bartoli, G.; Bosco M.; Marcantoni, E.; Petrinim, M.; Sambri,
L.; Torregiani, E. J . Org. Chem. 2001, 66, 9052.
(18) Petrini, M.; Profeta, R.; Righi, P. J . Org. Chem. 2002, 67, 4530.
3
(
Petrinim, M. J . Org. Chem. 1994, 59, 5328. (b) Devine, P. N.; Heid, R.
M.; Tschaen, D. M. Tetrahedron 1997, 53, 6739. (c) Graul, A.; Castaner,
J .; Castaner, J . Drugs Future 1997, 22, 956. (d) Angiolini, L.; Bizzarri,
P. C.; Scapini, G.; Tramontini, M. Tetrahedron 1981, 37, 2137.
2
110 J . Org. Chem., Vol. 68, No. 6, 2003

Bismuth Nitrate-Catalyzed Versatile Michael Reactions
TABLE 2. Bi(NO)3-Ca ta lyzed Mich a el Rea ction of
TABLE 3. Bi(NO)3-Ca ta lyzed Mich a el Rea ction of
En on es w ith In d olesa
a
En on es w ith Th iols
a
Reaction was completed within 2-4 h at room temperature.
b
For the preparation of 8, see ref 5a.
7
this method is totally independent of solvent choice or
external proton source.5 We have used dichloromethane,
tetrahydrofuran, diethyl ether, ethyl acetate, methanol,
and acetonitrile without any loss of yield. If one of the
reactants is a liquid, the reaction can proceed without
using solvent. However, if the reaction mixture is a very
thick slurry, the addition of a small amount of any of the
above listed solvents is helpful for the success of the
reaction. An external proton source is not necessary to
promote the reaction. Even ordinary-grade solvents and
reagents that are undistilled or unpurified can be used
with equal success. Additionally, it has been found that
the dibenzylamine (Table 1, entries 2-4) reacts very
easily with cyclic and acyclic enones and gives products
in high yield. Heterocyclic bases (Table 1, entries 1 and
a
5
) also react with enones, affording products in good yield.
Care should be taken in isolating products that are
heterocyclic bases from the reaction mixtures, as these
products are partially soluble in water or dilute acid used
for the extraction, a trend that was observed when one
of the reactions was repeated using an already published
method.17 The yield of the product continually decreases
with the number of washings with dilute citric acid or
water.
The reaction of imidazoles with enones proceeds very
nicely under these conditions (Table 1, entries 6 and 7).
It is noteworthy that the Michael adducts are formed
with imidazoles. Also, attack does not take place at the
ring of the imidazoles. Extension of this method with
aliphatic and aromatic thiols also gives Michael products
in good yield (Table 2, entries 1-3). In our experience,
by following our bismuth nitrate-catalyzed method, no
electrophilic substitution has been observed when an
aromatic thiol is used (Table 2, entry 1).
Bism u th Nitr a te-Ca ta lyzed Ad d ition of In d oles to
En on es. Our method has been tested with readily
available substituted indoles. Indoles are well suited for
our program, as several of their derivatives are biologi-
cally active. Moreover, indoles can undergo two types of
a
Reaction was completed within 10-15 h at room temperature.
b
For the preparation of 11, see ref 5a.
5
gate addition of enones to indoles. However, with less
electron-rich indoles, the yield of the products was not
satisfactory. In such cases, indium trichloride has proven
to be very effective. Our bismuth nitrate-catalyzed reac-
tion has been tested with several indoles, the results of
which have been very encouraging (Table 3). Specifically,
the reactions are very efficient, and the products are
isolated in high yield without the formation of side
products, such as dimers or trimers that are normally
5
b
formed under the influence of strong acids. Many
structurally diverse indoles reacted efficiently with vari-
ous ketones under bismuth nitrate-catalyzed conditions
3
reaction: at NH (Michael reaction) and at C (Michael
as well as Friedel-Crafts reactions). Several addition
reactions of enones to indoles using Lewis and Bronsted
acids have been published.19 Again, acid-catalyzed reac-
tion of indoles requires careful control of the acidity to
prevent unwanted side reactions, including dimerization
and polymerization.20 Recently, in an elegant study, it
was shown that indium tribromide mediates the conju-
(
19) (a) Harrington, P. E.; Kerr, M. A. Can. J . Chem. 1998, 76, 1256.
(
b) Harrington, P. E.; Kerr, M. A. Synlett 1996, 1047. (c) Iqbal, Z.;
J ackson, A. H.; Rao, K. R. N. Tetrahedron Lett. 1988, 29, 2577. (d)
Szmuszkovicz, J . J . Am. Chem. Soc. 1957, 79, 2819.
(
20) (a) Houlihan, W. J . Indoles; J ohn Wiley & Sons, Inc.: New York,
972; Vol. 1, p 71. (b) Iqbal, Z.; J ackson, A. H.; Rao, K. R. Tetrahedron
Lett. 1988, 29, 21.
1
J . Org. Chem, Vol. 68, No. 6, 2003 2111

Srivastava and Banik
TABLE 4. Bi(NO)3-Ca ta lyzed Mich a el Rea ction of
(10 mol %) of bismuth nitrate are necessary for a
complete reaction, an increase in the proportion to 25%
produced comparable yields. A further increase does not
improve the yield of the product; instead, additional
compounds tend to be formed, as evidenced from TLC.
The reaction did not proceed at all in the absence of
bismuth nitrate, except for the amines (Table 1, entries
a
En on es w ith Ca r ba m a tes
1
-5), in which case a very slow reaction took place,
presumably because of the stronger nucleophilicity of the
substrates. But, the reaction did not proceed at all after
ca. 50% conversion. Since bismuth nitrate can produce
nitric acids, a reaction (Table 3, entry 5) was performed
in the presence of nitric acid in various amounts. The
nature of the reaction mixtures before work-up in the
nitric acid-mediated reaction was clearly different from
that in the bismuth nitrate-catalyzed process. However,
after extraction of the reaction mixtures, it appeared that
nitric acid-mediated reactions also produced products in
relatively lower yields. Optimization of the concentration
of nitric acid and yield of the product was attempted in
various cases. But no definite conclusions or optimization
could be drawn from these studies, except that the
progress of the reactions with multiple components has
been observed in the TLC plate under different acid
concentrations. Notably, the reaction proceeds (Table 3,
entry 5) with bismuth nitrate in the presence of potas-
sium carbonate (20 mol %). With a higher proportion of
potassium carbonate (50 mol %), the rate of the reaction
becomes very slow, and a considerable amount of starting
materials is recovered after the reaction is terminated.
This suggests that there might be a complexation role
for bismuth nitrate apart from its acidity, so that acidity
may not be the only factor underlying the success of this
reaction. To get more specific knowledge, IR and NMR
studies were conducted with carbamate and phenyl
propynyl ketone (Table 4, entry 3) in the presence and
a
b
Reaction was completed within 10-15 h. For the preparation
c
of 23, 25, 26 and 27, see ref 7. For the preparation of 24, see:
Wabnitz, T., C.; Spencer, J . B. Tetrahedron Lett. 2002, 43, 389.
and afford products in high yield. In general, the reac-
tions took place at the 3-position of the indole ring when
this position was unoccupied. When the 3-position was
occupied by a methyl group, the reaction took place at
3 3
absence of bismuth nitrate in CD CN and CDCl . IR
C
2
positions (Table 3, entries 9 and 12).
Bism u th Nitr a te-Ca ta lyzed Ad d ition of Ca r ba m -
analysis of the mixture showed no changes at all. But it
was reported that acetonitrile solution of this carbamate
and scandium triflate produced a large shift in the
a tes to En on es. While amines and thiols are moderately
nucleophilic, carbamates are very weakly nucleophilic.
Therefore, the various acid catalysts that are successfully
employed in Michael reactions with amines and thiols
have failed to produce products with carbamates. Inter-
estingly, indium chloride, which was the best catalyst for
the indole addition reaction, failed to produce any desired
compounds with carbamates or unsaturated ketones in
frequency.7 On the other hand, the C and H NMR
study also indicated no changes of the chemical shift of
the carbamate or ketone (acceptor) in the presence or
absence of bismuth nitrate (10 mol %), whereas a large
shift was documented when scandium triflate was the
catalyst. This clearly suggested that the mode of inter-
action of the bismuth-mediated process is different from
that using oxophilic scandium triflate or indium salts as
the catalyst.
13
1
7
a previous study. Most of the conventional Lewis acids
showed lower reactivity, and the isolated yield of the
products was very low. The most fascinating reaction was
the conjugate addition reaction of carbamates with
To confirm the critical role of bismuth nitrate in this
reaction, other salts were tested. Ferric nitrate, zinc
nitrate, copper sulfate, sodium nitrate, and ferric chloride
proved to be completely ineffective, indicating the critical
role of bismuth nitrate in this reaction. However, bismuth
trichloride produced product in lower yield (Table 4, entry
3, 20%). The failure of these salts to promote an effective
Michael reaction indicates their inability to produce
sufficient amounts of acids or a precise coordinating
complex (although not observed under the conditions of
the experiments) that is critical for the success of this
type of reaction. Therefore, we believe that bismuth
nitrate has unique characteristics as a catalyst in Michael
reactions.
7
enones, which is mediated by platinum salt. The success
of this method depended on the choice of solvents: less
polar solvents gave inferior results, while polar solvents
gave excellent results. However, the use of solvents such
as DMSO, DMF, and THF did not result in a reaction.
We were delighted to discover that our bismuth nitrate-
catalyzed method was also applicable with carbamates
as the reactive partners. Reaction of carbamates with
enones proceeded under identical conditions without the
bias of any solvents in high yield (Table 4, entries 1-6).
Th e Role of Bism u th Nitr a te. The success of bis-
muth nitrate-mediated conjugate reactions prompted us
to investigate the mechanistic process. Catalytic amounts
2
112 J . Org. Chem., Vol. 68, No. 6, 2003

Bismuth Nitrate-Catalyzed Versatile Michael Reactions
Con clu sion
3-(N-Th iom or p h olin o)-1-p h en ylbu ta n -1-on e (5): yield
08 mg, 79%; mp 88-90 °C; IR (neat) 2961, 2913, 2813, 1680,
3
-
1 1
In summary, Michael reactions of various organic
compounds with moderate to low nucleophilicities have
been successfully carried out in the presence of a catalytic
amount of bismuth nitrate. In contrast to the existing
methods using many acidic catalysts, this method is very
general, simple, high-yielding, environmentally friendly,
and oxygen and moisture tolerant. However, the promot-
ing role of bismuth nitrate in this reaction is not under-
stood at this time. Further exploration of the scope of
addition reactions with complex structures of biological
significance is in progress.
1596, 1580, 1449, 1409, 1376, 1350 cm ; H NMR (300 MHz,
CDCl
3
) δ 1.08 (d, J ) 6 Hz, 3 H, CH
.78-2.91 (m, 5 H, 2 × CH and 1 H), 3.24 (dd, J
) 15.0 Hz, 1 H, CH ), 3.29-3.34 (m, 1 H, CH ), 7.44-7.59
3
), 2.58 (m, 4 H, CH
2
),
2
J
(
1
2
1
) 5.4 Hz,
2
2
2
1
3
m, 3 H, ArH), 7.91-7.94 (m, 2 H, ArH); C NMR (75 MHz) δ
5.5, 28.8, 42.6, 51.4, 58.3, 128.4, 128.9, 133.2, 137.8, 200.0.
Anal. Calcd for C14 19NSO (249.378): C, 67.43; H, 7.68; N,
.62. Found: C, 67.07; H, 7.23; N, 5.40.
-(N-Im id a zolo)-1-p h en ylbu ta n -1-on e (6): yield 202 mg,
69%; IR (neat) 3356, 3113, 2979, 2936, 1681, 1597, 1580, 1499,
H
5
3
-
1
1
1449, 1411, 1366, 1288 cm ; H NMR (300 MHz, CDCl
.61 (d, J ) 6 Hz, 3 H, CH ), 3.33 (dd, J ) 6.6 Hz, J ) 17.4
Hz, 1 H, CH ), 3.49 (dd, J ) 6.6 Hz, J ) 17.4 Hz, 1 H, CH ),
.93-5.04 (m, 1 H, CH), 7.0 (d, J ) 15 Hz, 2 H, ArH), 7.44-
.48 (m, 2 H, ArH), 7.59-7.61 (m, 2 H, ArH), 7.87-7.90 (m, 2
H, ArH); C NMR (75 MHz) δ 21.8, 46.4, 49.1, 127.9, 128.7,
3
) δ
1
3
1
2
2
1
2
2
4
7
Exp er im en ta l Section
1
3
Gen er a l Meth od s. All solvents and reagents were obtained
from commercial sources and used without purification. Reac-
tions were monitored by TLC using precoated silica gel
aluminum plates containing a fluorescence indicator. Chemical
1
7
33.6,, 136.3, 196.3. Anal. Calcd for C13
2.87; H, 6.59; N, 13.07. Found: C, 72.40; H, 6.12; N, 12.99.
-(N-Im id a zolo)-cycloh exa n -1-on e (7): yield 225 mg,
14 2
H N O (214.268): C,
3
-1
1
66%; IR (neat) 3383, 2955, 2127, 1704, 1659, 1501, 1415 cm ;
shifts of H NMR spectra were given in parts per million with
1
H NMR (300 MHz, CDCl
m, 2 H, CH ), 2.35-2.48 (m, 3 H, CH
CH ), 4.37-4.44 (m, 1 H, CH), 6.99 (m, 1 H, ArH), 7.09 (m, 1
H, ArH), 7.57 (brs, 1 H, ArH); C NMR (75 MHz) δ 22.2, 32.8,
0.8, 49.1, 55.9, 117.1, 130.1, 135.5, 207.0. Anal. Calcd for
O (164.208): C, 65.83; H, 7.37; N, 17.06. Found: C,
5.54; H, 7.23; N, 16.96.
-(Bu tylth iol)cycloh exa n -1-on e (9): yield 282 mg, 73%;
IR (neat) 2956, 2931, 2871, 1710, 1447, 1420, 1379, 1342, 1314,
3
) δ 1.78 (m, 1 H, CH), 2.09-2.15
respect to TMS, and the coupling constant J was measured in
Hz. Data are reported as follows: chemical shifts, multiplicity
(
2
2
), 2.74-2.80 (m, 2 H,
2
(
s ) singlet, d ) doublet, t ) triplet, q ) quartet, m )
1
3
1
multiplet). H NMR spectra were recorded in CDCl
3
using
4
tetramethylsilane as an internal standard. IR spectra of neat
-
1
9 12 2
C H N
compounds were expressed as wavenumbers (cm ).
Exp er im en ta l P r oced u r es. For a small-scale reaction, the
following procedure was followed. Bismuth nitrate (100 mg,
6
3
0
1
.2 mmol) was added to a mixture of dibenzylamine (200 mg,
.36 mmol) and ketone (200 mg, 1.36 mmol) in dichloro-
-
1 1
1
3
276, 1220, 1175 cm ; H NMR (300 MHz, CDCl
H, CH ), 1.42 (m, 2 H, CH ), 1.55 (m, 2 H, CH ), 1.72 (m, 2
), 2.13 (m, 2 H, CH ), 2.35 (m, 3 H, CH and CH), 2.55
t, J ) 6 Hz, 2 H, CH ), 2.70 (m, 1 H, CH), 3.10 (m, 1 H, CH);
C NMR (75 MHz) δ 13.9, 22.4, 24.6, 30.6, 32.0, 32.1, 41.3,
3.1, 48.6, 209.2. Anal. Calcd for C10 18SO (186.319): C, 64.46;
H, 9.74. Found: C, 64.08; H, 9.65.
-(Bu tylth iol)-4-m eth ylp en ta n -2-on e (10): yield 271 mg,
1%; IR (neat) 3417, 2930, 2873, 1709, 1464, 1378, 1355, 1196,
3
) δ 0.92 (t,
3
2
2
methane (2 mL). Dichloromethane was then removed under
reduced pressure, and the reaction mixture was kept at room
temperature for the specific time as indicated in Tables 1-4.
Dichloromethane (20 mL) was added to the reaction mixture,
and it was filtered through filter paper to remove bismuth
H, CH
2
2
2
(
2
1
3
4
H
3
nitrate. The filtrate was washed with saturated NaHCO (2
4
×
10 mL) and brine solution (1 × 10 mL) and dried over Na
2
-
7
1
SO
4
. The extracts were then concentrated, and the crude
-
1 1
174, 1122 cm ; H NMR (300 MHz) δ 0.92 (t, J ) 7.16, 3 H,
), 1.35-1.50 (m, 8 H, 2 × CH and CH ) 1.57 (q, 2 H, CH ),
.19 (s, 3 H, CH ), 2.51(t, J ) 7.16, 2 H, CH ), 2.68, (s, 2 H,
); C NMR (75 MHz) δ 14.0, 22.2, 28.1, 28.8, 31.9, 32.6,
20SO (188.335): C, 63.77;
H, 10.70. Found: C, 63.58; H, 10.25.
product was purified using flash chromatography on silica gel
column eluent 30% EtOAc-70% in hexane as the eluent to
give pure compound. An identical procedure was followed in
other cases as described in Tables 1-4. The yield of the
products was almost identical when the same amount of
methanol, ethanol, diethyl ether, acetonitrile, and toluene was
used as the solvent instead of dichloromethane.
For a relatively large-scale reaction (5-10 g), a different
experimental procedure was adopted. If one of the reactants
was liquid, the experiment was conducted without using
solvent. However, if the reaction mixture was a very thick
slurry, the addition of a small amount (1 g of the substrates/1
mL solvent) of any of the above solvents was necessary for
the success of the reaction. However, care should be taken
when mixing these reactants with solid bismuth nitrate (20
mol %) with vigorous stirring. When the reaction was over
CH
3
3
2
2
2
3
2
1
3
CH
2
4
3.6, 55.0, 207.2. Anal. Calcd for C10H
3-(5-Cya n o-3-in d olyl)-1-p h en ylbu ta n -1-on e (12): yield
07 mg, 78%; mp 136-139 °C; IR (neat) 3335, 2964, 2218,
3
1
(
-1 1
676, 1618, 1597, 1579, 1472, 1448, 1355, 1279 cm ; H NMR
300 MHz, CDCl
3
) δ 1.46 (d, J ) 6 Hz, 3 H, CH
)16.5 Hz, 1 H, CH ) 3.41 (dd, J
), 3.77-3.88 (m, 1 H, CH), 7.14 (d, J ) 3 Hz
3
), 3.27 (dd, J
1
)
7.8 Hz, J
6.5 Hz, 1 H, CH
2
2
1
) 6 Hz, J )
2
1
1
8
2
1
2
H, ArH), 7.40-7.56 (m, 5 H, ArH), 7.91-7.94 (m, 2 H, ArH),
.01 (s, 1 H, ArH), 8.3 (brs, 1 H, NH); 13C NMR (75 MHz) δ
1.8, 27.3, 46.6, 102.7, 112.5, 121.2, 122.7, 122.8, 125.3, 126.6,
28.4, 129.0, 133.5, 137.4, 138.5, 199.5. Anal. Calcd for
C H N O (288.350): C, 79.14; H, 5.59; N, 9.71. Found: C,
19 16 2
8.99; H, 5.75; N, 9.50.
(TLC, approximately 2-24 h), during the next step it was
7
necessary to extract the reaction mixture with dichloromethane
as described above. There was no difference in yield when the
reactions were performed under these experimental conditions.
3-(5-Ben zyloxy-3-in d olyl)-1-p h en ylp r op a n -1-on e (13):
yield 363 mg, 72%; IR (neat) 3410, 2961, 1677, 1623, 1579,
-
1
1
3
-(N-Diben zyla m in o)-1-p h en ylbu ta n -1-on e (4): yield
1480, 1449, 1374, 1279 cm ; H NMR (300 MHz, CDCl
1.4 1 (d, 6 Hz, 3 H, CH ), 3.18 (dd, J ) 8.7 Hz, J ) 16.5 Hz,
1 H, CH ) 3.39 (dd, J ) 5.0 Hz, J ) 16.5 Hz, 1 H, CH ), 3.70-
3.81 (m, 1 H, CH), 5.08 (s, 2 H, OCH ), 6.90-6.94 (m, 2 H,
3
) δ
2
1
95 mg, 75%; IR (neat) 3364, 2800, 1673, 1624, 1597, 1579,
3
1
2
524, 1494, 1448, 1363, 1330, 1291, 1218 cm-1; 1H NMR (300
2
1
2
2
MHz, CDCl
Hz, J ) 14.3 Hz, 1 H, CH
Hz, 1 H, CH ), 3.43-3.54 (m, 3 H, CH and CH
2 Hz, 2 H, CH ), 7.19-7.29 (m, 12 H, ArH), 7.35 (m, 1 H,
ArH), 7.81 (m, 2 H, ArH); C NMR (75 MHz) δ 14.9, 43.7,
3
) δ 1.13 (d, J ) 6 Hz, 3 H, CH
3
), 2.85 (dd, J
) 5.8 Hz, J
), 3.69 (d, J )
1
) 8.3
2
ArH), 7.15-7.55 (m, 10 H, ArH), 7.90-7.93 (m, 3 H, ArH and
NH); 13C NMR (75 MHz) δ 20.8, 26.9, 46.3, 70.9, 102.8, 111.9,
112.7, 121.0, 121.1, 126.6, 127.6, 127.7, 128.1, 128.2, 128.4,
128.5, 131.8, 132.9, 137.2, 137.6, 152.8, 199.8. Anal. Calcd for
C H23NO (369.464): C, 81.27; H, 6.27; N, 3.79. Found: C,
25 2
81.07; H, 6.33; N, 3.67.
2
2
), 3.25 (dd, J
1
2
) 14.3
2
2
1
2
1
3
5
1
1.4, 53.4, 53.6, 54.0, 127.2, 127.4, 128.6, 128.7, 128.8, 128.9,
29.0, 133.2, 137.4, 140.3, 140.8, 199.9. Anal. Calcd for C24
H
25
-
NO (343.47): C, 83.93; H, 7.34; N, 4.08. Found: C, 83.48; H,
.08; N, 4.02.
3-(5-Ben zyloxy-6-m eth oxy-3-in d olyl)-1-p h en ylbu ta n -1-
on e (14): yield 377 mg, 69%; IR (neat) 3410, 1679, 1481, 1313,
7
J . Org. Chem, Vol. 68, No. 6, 2003 2113

Srivastava and Banik
1
199 cm-1; 1H NMR (300 MHz, CDCl
H, CH ), 3.17 (dd, J ) 8.8 Hz, J ) 16.2 Hz, 1 H, CH
dd, J ) 4.9 Hz, J ) 16.2 Hz, 1 H, CH ), 3.66-3.72 (m, 1 H,
CH), 3.87 (s, 3 H, OMe), 5.14 (s, 2 H, OCH ), 6.84-6. 86 (m, 2
H, ArH), 7.09 (s, 1 H, ArH) 7.24-7.30 (m, 3 H, ArH), 7.42-
.49 (m, 5 H, ArH), 7.88-7.91 (m, 3 H, 2 ArH and 1 NH); 13
NMR (75 MHz) δ 18.2, 27.0, 46.3, 53.4, 71.9, 72.2, 95.2, 104.9,
3
) δ 1.37 (d, J ) 6 Hz, 3
), 3.29
(300 MHz, CDCl
H, CH ), 2.25 (s, 3 H, CH
3.37 (m, 1 H, CH), 6.91-7.16 (m, 2 H, ArH), 7.29-7.32 (m, 1
3
) δ 1.89-1.96 (m, 2 H, CH
2
), 2.13-2.18 (m, 2
3
1
2
2
2
3
), 2.50-2.66 (m, 4 H, 2 x CH
2
), 3.38-
(
1
2
2
1
3
2
H, ArH), 7.51 (d, J ) 6 Hz, 1 H, ArH), 7.80 (brs, 1 H, NH); C
NMR (75 MHz) δ 8.8, 25.8, 31.9, 36.8, 41.7, 47.6, 107.1, 110.8,
118.7, 119.7, 121.9, 129.5, 135.5, 136.3, 210.8. Anal. Calcd for
C H17NO (227.307): C, 79.26; H, 7.54; N, 6.16. Found: C,
15
79.19; H, 7.58; N, 6.01.
7
C
1
1
18.8, 119.0, 121.0, 127.5, 127.6, 127.8, 128.0, 128.3, 128.5,
28.6, 131.4, 133.1, 136.8, 137.2, 137.6, 143.4, 147.7, 199.8.
4-(5-Cya n o-3-in d olyl)bu ta n -2-on e (20): yield 467 mg,
76%; mp 108-112 °C; IR (neat) 3338, 2919, 2218, 1706, 1619,
Anal. Calcd for C26
Found: C, 78.01; H, 6.12; N, 3.31.
-(5-Cya n o-3-in d olyl)-3-m eth ylp en ta n -2-on e (15): yield
74 mg, 56%; mp 128-130 °C; IR (neat) 3336, 2969, 2219,
3
H25NO (399.490): C, 78.17; H, 6.31; N, 3.51.
-
1
1
1473, 1434, 1359, 1230 cm ; H NMR (300 MHz, CDCl
2.16 (s, 3 H, COCH ), 2.84 (t, J ) 6 Hz, 2 H, CH
) 6 Hz, 2 H, CH ), 7.11-7.12 (m, 1 H, ArH), 7.41-7.42 (m, 2
13
3
) δ
4
3
2
), 3.02 (t, J
2
1
2
-
1
1
698, 1618, 1471, 1356, 1232, 1170 cm ; H NMR (300 MHz,
) δ 0.96 (d, J ) 6 Hz, 3 H, CH ), 1.32 (d, J ) 6 Hz, 3 H,
), 2.19 (s, 3 H, COCH ), 2.90-2.95 (m, 1 H, CH), 3.27-
H, ArH), 7.90 (brs, 1 H, ArH), 8.29 (brs, 1 H, NH); C NMR
CDCl
CH
3
3
(75 MHz) δ 102.8, 112.4, 116.6, 121.1, 124.1, 124.8, 125.3,
127.5, 127.5, 129.2, 131.3, 138.2. Anal. Calcd for C13H N O
12 2
(212.252): C, 73.56; H, 5.70; N, 13.20. Found: C, 73.29; H,
5.48; N, 13.11.
3
3
3
1
.32 (m, 1 H, CH), 7.13 (d, J ) 2.7 Hz, 1 H, ArH), 7.43 (d, J )
.2 Hz, 2 H, Ar H), 8.02 (brs, 1 H, ArH), 8.4 (brs, 1 H, NH);
C NMR (75 MHz) δ 16.3, 20.3, 29.0, 34.2, 52.9, 102.8, 112.6,
20.7, 123.8, 125.2, 125.4, 126.9, 138.4, 213.1. Anal. Calcd for
1
3
4-(5-Ben zyloxy-3-in d olyl)bu ta n -2-on e (21): yield 603
mg, 71%; IR (neat) 3407, 3032, 2915, 1705, 1624, 1582, 1482,
1
C
7
-
1 1
15
H
16
N
2
O (240.306): C, 74.97; H, 6.71; N, 11.66. Found: C,
4.61; H, 6.52; N, 11.43.
-(5-Ben zyloxy-6-m eth oxy-3-in d olyl)-3-m eth ylp en ta n -
-on e (16): yield 522 mg, 73%; IR (neat) 3374, 2963, 1700,
1374, 1292, 1197 cm ; H NMR (300 MHz, CDCl
3 H, CH ), 2.78-2.83 (t, J ) 9 Hz, 2 H, CH ), 2.97-3.02 (t, J
) 6 Hz, 2 H, CH ) 5.12 (s, 2 H, OCH ), 6.91-6.94 (m, 2 H,
3
) δ 2.13 (s,
3
2
4
2
2
2
1
0
ArH), 7.10 (d, J ) 2.4, 1 H, ArH), 7.22-7.41 (m, 6 H, ArH),
7.48 (m, 2 H, ArH), 7.80 (brs, 1 H, NH); C NMR (75 MHz) δ
-
1
1
13
632, 1547, 1480, 1313 cm ; H NMR (300 MHz, CDCl
.89 (d, J ) 6 Hz, 3 H, CH ), 1.22 (d, J ) 6 Hz, 3 H, CH ), 2.07
), 2.73-2.83 (m, 1 H, CH), 3.10-3.18 (m, 1 H,
CH), 3.91 (s, 3 H, COCH ), 5.18 (s, 2 H, OCH ) 6.82 (d, J )
.4 Hz, 1 H, ArH), 6.88 (s, 1 H, ArH), 7.27-7.48 (m, 4 H, ArH),
.48-7.50 (m, 2 H, ArH) 7.84 (brs, 1 H, NH); 13C NMR (75
3
) δ
3
3
19.7, 30.4, 44.3, 71.4, 102.8, 112.2, 113.28, 115.3, 122.7, 127.9,
128.0, 128.1, 128.9, 131.2, 138.0, 153.5, 209.1. Anal. Calcd for
C H19NO (293.366): C, 77.79; H, 6.53; N, 4.77. Found: C,
19 2
(s, 3 H, COCH
3
3
2
2
7
77.39; H, 6.34; N, 4.61.
4-(3-Met h yl-2-in d olyl)bu t a n -2-on e (22): yield 262 mg,
-1
MHz) δ 15.9, 19.6, 29.4, 34.1, 53.3, 56.3, 72.4, 95.0, 105.6,
45%; IR (neat) 3407, 2400, 1714, 1605, 1455, 1360, 1166 cm ;
1
1
1
19.2, 119.5, 119.7, 127.6, 127.6, 128.4, 131.3, 137.7, 143.4,
47.9, 213.5. Anal. Calcd for C22 (351.446): C, 75.19;
H NMR (300 MHz, CDCl
3
) δ 2.16 (s, 3 H, CH
3
), 2.23 (s, 3 H,
H
25NO
3
CH
CH
3
), 2.82 (t, J ) 6.6 Hz, 2 H, CH ), 2.98 (t, J ) 6.6 Hz, 2 H,
2
H, 7.17; N, 3.98. Found: C, 74.98; H, 7.12; N, 3.85.
-(5-Cya n o-3-in d olyl)-4-m eth ylp en ta n -2-on e (17): yield
2
), 7.05-7.11 (m, 2 H, ArH), 7.25-7.27 (m, 1 H, ArH), 7.45-
13
4
7.48 (d, J ) 9 Hz, 1 H, ArH), 8.29 (brs, 1 H, NH); C NMR
-
1 1
3
13 mg, 64%; IR (neat) 3339, 2219, 1695, 1472, 1350 cm ; H
NMR (300 MHz, CDCl ) δ 1.54 (s, 6 H, 2 CH ) 1.84 (s, 3 H,
COCH ), 2.95 (s, 2 H, CH ), 7.06 (d, J ) 2.4 Hz, 1 H, ArH),
(75 MHz) δ 8.7, 19.7, 30.4, 44.0, 107.0, 110.7, 118.4, 119.2,
3
3
121.5, 129.3, 134.6, 135.5, 209.7. Anal. Calcd for C13H15NO
3
2
(201.269): C, 77.58; H, 7.51; N, 6.96. Found: C, 77.39; H, 7.59;
N, 6.71.
7
1
1
.40 (d, J ) 3 Hz, 2 H, ArH), 8.14 (brs, 1 H, ArH), 8.60 (brs,
13
H, NH); C NMR (75 MHz) δ 28.9, 31.9, 34.2, 54.7, 102.3,
4-(N-Oxa zolid in yl)-4-m eth ylp en ta n -2-on e (28): yield
230 mg, 61%; IR (neat) 3451, 2980, 2920, 1728, 1539, 1483,
12.4, 120.8, 122.8, 124.6, 124.6, 125.2, 126.2, 138.8, 208.1.
-
1
1
Anal. Calcd for C15
1.66. Found: C, 74.65; H, 6.53; N, 11.55.
-(5-Cya n o-3-in d olyl)cycloh exa n -1-on e (18): yield 391
mg, 79%; IR (neat) 3324, 2940, 2218, 1698, 1617, 1472, 1429,
H
16
N
2
O (240.306): C, 74.97; H, 6.71; N,
1415, 1365, 1247, 1173 cm ; H NMR (300 MHz, CDCl
1.43 (s, 6 H, 2 x CH ), 2.13 (s, 3 H, CH ), 3.14 (s, 2 H, CH
3.68 (m, 2 H, CH ), 4.23 (m, 2 H, CH
26.4, 31.3, 43.7, 50.3, 53.6, 61.4, 157.1, 207.1. Anal. Calcd for
9 3
C H15NO (185.223): C, 58.36; H, 8.16; N, 7.56. Found: C,
3
) δ
),
); C NMR (75 MHz) δ
1
3
3
1
2
3
3
2
2
344, 1224, 1344, 1224 cm-1; H NMR (300 MHz, CDCl
.92-2.05 (m, 3 H), 2.23-2.30 (m, 1 H), 2.43-2.48 (m, 2 H,
), 2.64-2.68 (m, 1 H, CH), 2.76-2.77 (m, 1 H) 3.43-3.48
1
) δ
1
1
CH
3
58.13; H, 7.99; N, 7.09.
2
Ack n ow led gm en t. We gratefully acknowledge the
partial funding support received for this research project
from The University of Texas. We are thankful for NIH
Cancer Center Support Grant No. 5-P30-CA16672-25,
in particular, the shared resources of the Pharmacology
and Analytical Center Facility.
(
m, 1 H, CH), 7.03 (q, 1 H, ArH), 7.44 (d, 2 H, J ) 1.2 Hz,
13
ArH), 7.98 (brs, 1 H, ArH), 8.51 (brs, 1 H, NH); C NMR (75
MHz) δ 25.0, 32.1, 35.9, 41.8, 48.1, 102.9, 112.6, 120.8, 123.1,
1
14 2
25.1, 125.5, 126.4, 138.5, 211.6. Anal. Calcd for C15H N O
(
5
238.290): C, 75.61; H, 5.92; N, 11.76. Found: C, 75.47; H,
.58; N, 11.71.
-(3-Meth yl-2-in d olyl)cycloh exa n -1-on e (19): yield 260
3
-1 1
mg, 55%; IR (neat) 3407, 2940, 1702, 1463, 1344 cm ; H NMR
J O026550S
2
114 J . Org. Chem., Vol. 68, No. 6, 2003