Cerium(IV) ammonium nitrate is an excellent, general catalyst for the Friedlaender and Friedlaender-Borsche quinoline syntheses: Very efficient access to the antitumor alkaloid luotonin A

Article abstract of DOI:10.1021/jo900965f

(Figure Presented) The use of cerium(IV) ammonium nitrate as a catalyst of the Friedl€ander reaction allows the synthesis of polysubstituted quinoline derivatives in excellent yields, avoiding the traditional harshly basic or acidic conditions. Unlike most other previously known reagents, CAN allows double condensations and is also an excellent catalyst for the Borsche variation of the Friedlaender reaction, which has been applied to the very efficient synthesis of the antitumor alkaloid luotonin A.

Full text of DOI:10.1021/jo900965f

pubs.acs.org/joc
2
2
3
Combes,
Conrad-Limpach-Knorr,
Niementowski,
Cerium(IV) Ammonium Nitrate Is an Excellent,
General Catalyst for the Friedl €a nder and
Friedl €a nder-Borsche Quinoline Syntheses:
Very Efficient Access to the Antitumor Alkaloid
Luotonin A
3
Pfitzinger, and Friedl €a nder reactions, and also more recent
approaches.
1
b
The Friedl €a nder quinoline synthesis involves the reaction
between 2-aminoaryl aldehydes or ketones and carbonyl
compounds containing an active methylene functionality
under acidic or basic conditions. The reactions involving
the use of 2-aminobenzaldehyde allow the synthesis of
quinolines possessing an unsubstituted C-4 carbon, an im-
portant moiety that is present in many naturally occurring
quinolines, including the ones in Figure 1, but have the
problem of low stability of this reagent. This has prompted
the development of some indirect Friedl €a nder annulations
involving the use of its synthetic equivalents, such as
a
Vellaisamy Sridharan, Pascual Ribelles, M Teresa Ramos,
and J. Carlos Men ꢀe ndez*
Departamento de Quı´mica Org aꢀ nica y Farmac eꢀ utica,
Facultad de Farmacia, Universidad Complutense, 28040
Madrid, Spain
josecm@farm.ucm.es
Received May 8, 2009
2
-aminobenzyl alcohols in the presence of metallic catalysts
4
Ru, Pd, Ir, Rh, Cu, etc.), Schiff bases (known as the
(
Borsche variation of the Friedl €a nder reaction), or acetals
5
of 2-aminobenzaldehyde. While the Friedl €a nder and
Friedl €a nder-Borsche reactions allow the creation of the
quinoline moiety in a single operation, the presently known
methods still have many limitations (see below), and the
development of a mild, general, easily handled, and unex-
pensive catalyst for these important reactions remains chal-
lenging. We describe here that cerium(IV) ammonium nitrate
(
CAN) is an excellent catalyst for both the Friedl €a nder
and the Friedl €a nder-Borsche reactions that allows the
limitations inherent to previously studied catalysts to be
circumvented. It is relevant to mention that the study of
modern catalysts for the Friedl €a nder-Borsche reaction has
received very little attention in the literature.
The use of cerium(IV) ammonium nitrate as a catalyst of
the Friedl €a nder reaction allows the synthesis of polysub-
stituted quinoline derivatives in excellent yields, avoiding
the traditional harshly basic or acidic conditions. Unlike
most other previously known reagents, CAN allows
double condensations and is also an excellent catalyst
for the Borsche variation of the Friedl €a nder reaction,
which has been applied to the very efficient synthesis of
the antitumor alkaloid luotonin A.
FIGURE 1. Structures of some bioactive alkaloids containing qui-
noline structural fragments.
The quinoline ring system is found in many pharmacolo-
gically significant compounds and in some bioactive natural
products, exemplified by the natural topoisomerase I inhi-
Recently, many improved methodologies and new cata-
lysts have been developed for the Friedl €a nder annulation
that avoid the use of the traditional strongly basic condi-
1
bitors luotonin A (1) and camptothecin (2) (Figure 1). Many
methods have been developed for the construction of quino-
6-8
6
tions.
catalysts and ionic liquids have also been used for the
Apart from conventional protic acids, many other
7m
7
2
line building blocks, which include the classical Miller,
Friedl €a nder synthesis. Microwave irradiation in the presence
8
of several catalysts was also found to be effective. In spite of
*
To whom correspondence should be addressed. Phone: 34-91-3941840.
Fax: 34-91-3941822.
1) For selected reviews of quinolines, see: (a) Michael, J. P. Nat. Prod.
this abundance of protocols, they lack generality since about
9
0% of the literature references quoted above are restricted
(
Rep. 2008, 25, 166 and previous reviews of this series. (b) Kouznetsov, V. V.;
Vargas M ꢀe ndez, L. Y.; Mel ꢀe ndez Gomez, C. M. Curr. Org. Chem. 2005, 9,
(4) For selected examples of Friedl €a nder reactions with 2-aminobenzy-
1
41. (c) Michael, J. P. Nat. Prod. Rep. 2004, 21, 650.
2) For selected recent reports, see: (a) Horn, J.; Marsden, S. P.; Nelson,
lalcohols, see: (a) Martı
´
nez, R.; Ram oꢀ n, D. J.; Yus, M. J. Org. Chem. 2008,
73, 9778.(b) Cho, C. S.; Ren, W. X. J. Organomet. Chem. 2007, 629, 4182 and
reference cited therein.
(5) For a recent example of a Friedl €a nder reaction involving derivatives
of 2-aminobenzaldehyde, see: Grillet, F.; Baumlov ꢀa , B.; Pr ꢀe vost, G.;
Constant, J.-G.; Chaumeron, S.; Bigg, D. C. H.; Greenea, A. E.; Kanazawa,
A. Bioorg. Med. Chem. Lett. 2008, 18, 2143.
(6) For a recent example of a protic acid-catalyzed Friedl €a nder reaction,
see: Ghassamipour, S.; Sardarian, A. R. Tetrahedron Lett. 2009, 50, 514.
(
A.; House, D.; Weingarten, G. G. Org. Lett. 2008, 10, 4117. (b) Wu, Y.-C.;
Liu, L.; Li, H.-J.; Wang, D.; Chen, Y.-J. J. Org. Chem. 2006, 71, 6592.
(
(
c) Denmark, S. E.; Venkatraman, S. J. Org. Chem. 2006, 71, 1668.
d) Deady, L. W.; Devine, S. M. Tetrahedron 2006, 62, 2313.
(3) For some recent improvements of the Niementowski and Pfitzinger
reactions, see: Laddha, S. S.; Bhatnagar, S. P. Arkivoc 2008, 17, 212 and
references cited therein.
DOI: 10.1021/jo900965f
r 2009 American Chemical Society
Published on Web 06/17/2009
J. Org. Chem. 2009, 74, 5715–5718 5715

Sridharan et al.
JOCNote
SCHEME 1. CAN-Catalyzed Friedl €a nder Reactions of 2-Aminophenones
to the reaction between commercially available 2-aminoaryl
ketones and active methylene carbonyl compounds and very
few deal with reactions involving 2-aminobenzaldehyde or
double reactions leading to polycyclic compounds.
TABLE 1. Synthesis of Quinoline Derivatives via CAN-Catalyzed
Friedl €a nder Annulations
reaction yield
time (h) (%) conditions
1
2
R
3
R
4
R
a
entry product R
CAN is a strong one-electron oxidant that is employed
for carbon-carbon or carbon-heteroatom bond formation
radical reactions, normally in stoichiometric quantities.
1
2
3
4
5
6
7
8
9
0
1
6a
6a
6a
6a
6b
6b
6c
6c
6d
6e
6f
6g
6h
6i
6j
6k
6l
6m
6n
6o
6p
6q
6r
6r
H
CH
CH
CH
CH
CH
3
3
3
3
3
CH
CH
CH
3
3
3
3
CO
CO
CO
CO
2
2
2
2
2
Et
Et
Et
Et
Et
10
10
8
8
8
13
8
13
16
6
6
9
7
6
6
4
4
50
89
63
98
83
91
83
88
97
97
98
92
90
98
92
94
97
96
98
98
98
89
50
62
A
B
C
D
D
D
D
D
D, E
D
D
D
D
D, E
D
D
D, E
D
D
H
H
H
H
H
H
H
H
H
9
CH
Because of its many advantages such as low cost, air and
water stability, and low toxicity, Nair, one of the main
contributors to CAN chemistry, has stated that the main
n
Pr CO
n
CH3 Pr CO Et
2
CH
CH3 CH3 COPh
CH
Ph CH
3
CH
3
COPh
9
a
goal to be achieved in this field is its use as a catalyst.
Indeed, the Lewis acidity of CAN has recently allowed many
synthetically important organic transformations using cata-
3
-(CH
2
)
3
-
1
1
3
3
3
3
CO
CO
2
Et
Et
Cl Ph CH
Ph CH
Cl Ph CH
2
1
0
lytic amounts of the reagent to be carried out, and if this
chemistry continues to be successfully implemented, CAN
will become an alternative to the hygroscopic and highly
expensive lanthanide triflate Lewis acids.
12
H
COPh
COPh
13
14
15
16
H
H
Cl Ph
Cl Ph -(CH ) -
H
H
Ph -(CH
Ph
2
)
3
-
n
Pr CO
Pr CO
2
Et
Et
n
2
Our investigation started with an optimization study for the
reaction between 2-aminoacetophenone (3a) and ethyl aceto-
acetate (4a) in the presence of a catalytic amount of CAN
17
18
2
3
t
COS Bu
CH
Ph CH
3
CH
3
3
3
6
COS Bu 2.5
t
19
20
21
22
t
COS Bu 2.5
Cl Ph CH
D
(Scheme 1 and Table 1, entries 1-4), which established that
H
H
H
H
Ph -(CH
Ph -(CH
Ph -(CH
Ph -(CH
2
2
2
2
)
)
)
)
4
-
-
8
8
8
24
D, E
D, E
D
the best conditions involved 15 mol % of CAN in refluxing
ethanol. Subsequently, we applied the optimized conditions to
a variety of 2-aminoaryl ketones (3) and active methylene
compounds (4), which furnished diversely substituted quino-
line derivatives 6, presumably with enaminones 5 as inter-
mediates, since anilines and active methylene compounds are
known to give enaminones in the presence of CAN, even at
5
23
2
10
-
-
4
10
D
a
Conditions: (A) 5 mol % of CAN, rt; (B) 5 mol % of CAN, reflux;
C) 15 mol % of CAN, rt; (D) 15 mol % of CAN, reflux; (E) 1.5 equiv of 4
was used.
(
while 16 h was required for cyclopentanone (entry 9) to
achieve quantitative yield. In contrast to 2-aminoacetophe-
nones, 2-aminobenzophenone derivatives were more reactive
1
1
room temperature. Yields of 91% and 88% were obtained
for compounds 6b and 6c after a 13 h reflux (entries 6 and 8),
(entries 10-20) and gave the expected products in excellent
(
7) (a) De, S. K.; Gibbs, R. A. Tetrahedron Lett. 2005, 46, 1647. (b) Yang,
yields and shorter reaction times. The reaction of 2-amino-
benzophenone with cyclohexanone and cycloheptanone pro-
ceeded well, while cyclododecanone was less reactive and gave
only 62% yield after a 24 h reflux (entries 21-24).
Due to the existence of very little literature precedent for
the catalysis by Lewis acids of double Friedl €a nder processes,
we treated two 2-aminobenzophenones and 1,2-cyclo-
hexanedione, in a 2:1 ratio, under our previously determined
optimal conditions. These three-component reactions led to
fast and efficient double annulations that afforded com-
pounds 7, derived from the pentacyclic dibenzo[b, j][1,10]-
phenanthroline system, in 85-90% yields after 2 h
D.; Jiang, K.; Li, J.; Xu, F. Tetrahedron 2007, 63, 7654. (c) Rodrigues, L. M.;
Francisco, C. S.; Oliveira-Campos, A. M. F.; Salaheldin, A. M. Synth.
Commun. 2008, 38, 4369. (d) Pasha, M. A.; Jayashankara, V. P.; Mahammed,
K. A. Indian J. Chem. 2008, 47B, 1160. (e) Enugala, R.; Nuvvula, S.; Kotra,
V.; Varala, R.; Adapa, S. R. Heterocycles 2008, 75, 2523. (f) Niknam, K.;
Zolfigol, M. A.; Dehghani, A. Heterocycles 2008, 75, 2513. (g) Das, B.;
Krishnaiah, M.; Laxminarayana, K.; Nandakumar, D. Chem. Pharm. Bull.
2
008, 56, 1049. (h) Yadav, J. S.; Reddy, B. V. S.; Sreedhar, P.; Rao, R. S.;
Nagaiah, K. Synthesis 2004, 2381. (i) Arcadi, A.; Chiarini, M.; Di Giuseppe,
S.; Marinelle, F. Synlett 2003, 203. (j) Wu, J.; Xia, H.-G.; Gao, K. Org.
Biomol. Chem. 2006, 4, 126. (k) Varala, R.; Enugala, R.; Adapa, S. R.
Synthesis 2006, 3825. (l) Zhang, L.; Wu, J. Adv. Synth. Catal. 2007, 349, 1047.
(
m) Zhou, T.; Lin, J.-L.; Chen, Z.-C. Lett. Org. Chem. 2008, 5, 47. (n) Jiang,
B.; Dong, J.-J.; Jin, Y.; Du, X.-L.; Xu, M. Eur. J. Org. Chem. 2008, 2693.
o) Wang, H.-M.; Hou, R.-S.; Cheng, H.-T.; Chen, L.-C. Heterocycles 2009,
8, 487.
8) For a recent example, see: Thomae, D.; Perspicace, E.; Hesse, S.;
Kirsch, G.; Seck, P. Tetrahedron 2008, 64, 9309.
9) For reviews of CAN-promoted synthetic transformations, see:
a) Nair, V.; Balagopal, L.; Rajan, R.; Mathew, J. Acc. Chem. Res. 2004,
7, 21. (b) Nair, V.; Deepthi, A. Chem. Rev. 2007, 107, 1862.
10) For examples of CAN-catalyzed reactions, taken from our work,
see: (a) Sridharan, V.; Maiti, S.; Men ꢀe ndez, J. C. Chem.;Eur. J. 2009, 15,
565. (b) Sridharan, V.; Men ꢀe ndez, J. C. Org. Lett. 2008, 10, 4303.
c) Sridharan, V.; Avenda n~ o, C.; Men ꢀe ndez, J. C. Tetrahedron 2007, 63,
73. For proof of the Lewis acidity of CAN, see: (d) Maulide, N.; Vanherck,
J.-C.; Gautier, A.; Mark oꢀ , I. E. Acc. Chem. Res. 2007, 40, 381.
11) Sridharan, V.; Avenda n~ o, C.; Men ꢀe ndez, J. C. Synlett 2007, 881.
(
7
(
Scheme 2). The framework of compounds 7 is of interest
(
1
2
because of its chelating properties.
(
Our initial attempts to synthesize quinolines with an
unsubstituted C-4 position using the challenging 2-amino-
benzaldehyde were complicated by the isolation of a side
product 8, arising from a diastereoselective four-component
(
3
(
4
(
6
´
(12) Moya, S. A.; Guerrero, J.; Rodrıguez-Nieto, F. J.; Wolcan, E.; Feliz,
M. R.; Baggio, R. F.; Garland, M. T. Helv. Chim. Acta 2005, 88, 2842.
(
5
716 J. Org. Chem. Vol. 74, No. 15, 2009

Sridharan et al.
JOCNote
SCHEME 2. CAN-Catalyzed Double Friedl €a nder Reactions of
SCHEME 4. CAN-Catalyzed Friedl €a nder-Borsche Reactions
2
-Aminobenzophenones
SCHEME 3. CAN-Catalyzed Four-Component Synthesis of 8
deduced from the large chemical shift value for the proton γ
with respect to the pyridine nitrogen, which is characteristic
1
5
for 1,8-phenanthroline derivatives, and corresponds to the
generation of the most conjugated intermediate.
To further validate our protocol, we decided to apply it to
the synthesis of the naturally occurring cytotoxic alkaloid
luotonin A (1), which is of considerable interest because of its
ability to stabilize the binary complex between human DNA
reaction between three molecules of 2-aminobenzaldehyde
and a molecule of ethanol. This was confirmed by conduct-
ing the reaction in the absence of the active methylene
substrate. Although the unstable hydroxy analogue of 8 is
a known compound, which is obtained in low yield via the
trimerization of 2-aminobenzaldehyde in the presence of
1
6
and topoisomerase I. Following its first total synthesis
1
7
by Ganesan, a number of routes have been developed for
1
the synthesis of luotonin A and its analogues. Some of
8
1
3
these methods involve the use of the Friedl €a nder reaction as a
acids, our synthesis of compound 8 is noteworthy for its
mildness and excellent yield (Scheme 3). Although 8 may be
of interest because of its structural relationship with Tr o€ ger’s
base, which has multiple applications in supramolecular
chemistry that have led to a surge of interest in its analo-
1
key step to generate the quinoline framework from the
9
2
known compound 12 and 2-aminobenzaldehyde or its
0
synthetic equivalents. However, the reported conditions,
1
9a
such as Triton B (ethanol, reflux, 2 h, 36%) and p-tolue-
1
9b
1
4
nesulfonic acid (xylene, reflux, 20 h, 30%), gave very poor
yields. Derivatives of luotonin A have also been synthesized
by using the Friedl €a nder reaction, and here again the yields
gues, we needed to suppress its formation in order to
optimize our quinoline synthesis. To this end, we applied
the Borsche modification of the Friedl €a nder reaction, using
N-(2-aminobenzylidene)-4-methylaniline (9) as a 2-amino-
benzaldehyde equivalent. Treatment of mixtures of imine 9
and carbonyl compounds 4 in the presence of 15 mol % of
CAN under our previously established conditions furnished
the desired quinolines 10 in excellent yields (Scheme 4). Our
first experiments confirmed the feasibility of preparing sim-
ple quinoline systems unsubstituted at C-4 (compounds
1
9c
were poor (32-36%). With this precedent in mind, we
applied our conditions to the cyclocondensation between 12
and 2-aminobenzaldehyde and found that the reaction was
complete in 1.5 h and gave 66% of luotonin A, along with a
small amount of compound 8. The fact that the expected
Friedl €a nder product is the major one contrasts with the
results obtained in our initial studies with simple ketones
as substrates. This different behavior can be explained
through the expected higher reactivity of the carbonyl group
in compound 12, due to the presence of a neighboring
electron-withdrawing substituent, leading to a shorter reac-
tion time. Use of the Borsche protocol afforded 82% of
luotonin A from compound 12 and imine 9 (Scheme 5).
1
0a-c). We also carried out the synthesis of tetrahydroacri-
dines from imine 9 and cyclohexanone or 1,3-cyclohexane-
diones, the latter of which afforded only monocondensation
derivatives 10e,f, even when excess imine was used. These
reactions are completely regioselective, and proceeded via
the most stable conjugated enaminone, as proved by HMBC
correlations. Double condensations were possible for both
1
,2-cyclohexanedione and 1,4-cyclohexanedione, which
(15) Majewicz, T. G.; Caluwe, P. J. Org. Chem. 1975, 40, 3407.
(16) Cinelli, M. A.; Morrell, A.; Dexheimer, T. S.; Scher, E. S.; Pommier,
Y.; Cushman, M. J. Med. Chem. 2008, 51, 4609.
(17) Wang, H.; Ganesan, A. Tetrahedron Lett. 1998, 39, 9097.
furnished products 10g (related to 7) and 10h, the latter of
which is interesting because its skeleton is almost unknown in
the literature. The proposed angular structure for 10h was
(
18) For a review, see: Ma, Z.; Hano, Y.; Nomura, T. Heterocycles 2005,
5, 2203.
19) For the use of the Friedl €a nder reaction in the synthesis of luotonin A
6
(
and analogues, see: (a) Kelly, T. R.; Chamberland, S.; Silva, R. A.
Tetrahedron Lett. 1999, 40, 2723. (b) Ma, Z.-Z.; Hano, Y.; Nomura, T.;
Chen, Y.-J. Heterocycles 1999, 51, 1593. (c) Dallavalle, S.; Merlini, L.;
Beretta, G. L.; Tinelli, S.; Zunino, F. Bioorg. Med. Chem. Lett. 2004, 14,
5757.
(
13) (a) Skuratowicz, J. S.; Madden, I. L.; Busch, D. H. Inorg. Chem.
977, 16, 1721. (b) Taylor, L. T.; Busch, D. H. Inorg. Chem. 1969, 8, 1366. (c)
McGeachin, S. G. Can. J. Chem. 1966, 44, 2323.
14) For a review, see: Dolensky, B.; Elguero, J.; Kr ꢀa l, V.; Pardo, C.;
Valık, M. Adv. Heterocycl. Chem. 2007, 93, 1.
1
(
´
(20) Molina, P.; T ꢀa rraga, A.; Gonz ꢀa lez-Tejero, A. Synthesis 2000, 1523.
J. Org. Chem. Vol. 74, No. 15, 2009 5717

Sridharan et al.
JOCNote
SCHEME 5. CAN-Catalyzed Synthesis of Luotonin A
-1
(neat) 3069.7, 2962.9, 1726.4, 1587.5, 1454.6, 1233.5, 1055.2 cm ;
1
H NMR (CDCl
7.2 Hz, 3H), 1.82-1.91 (m, 2H), 2.67 (s, 3H), 2.90-2.96 (m,
H), 4.51 (q, J = 7.2 Hz, 2H), 7.55 (td, J = 8.2, 1.3 Hz, 1H), 7.73
td, J = 8.2, 1.3 Hz, 1H), 8.02 (dd, J = 8.4, 0.8 Hz, 1H), 8.06 (dd,
3
, 250 MHz) δ 1.05 (t, J = 7.4 Hz, 3H), 1.47 (t, J
=
2
(
1
3
J = 8.4, 0.8 Hz, 1H); C NMR (CDCl
3
, 63 MHz) δ 14.7, 16.2,
3.5, 39.8, 62.1, 124.4, 126.2, 126.7, 128.3, 129.9, 130.3, 141.8,
47.6, 158.4, 169.8. Anal. Calcd for C H NO : C, 74.68; H,
2
1
7
1
6
19
2
.44; N, 5.44. Found: C, 74.37; H, 7.57; N, 5.59.
,7-Dihydrodibenzo[b,j][1,10]phenanthroline (10g). Starting
from 1,2-cyclohexanedione (80 mg, 0.72 mmol) and compound
6
9
1
(300 mg, 1.44 mmol), a yield of 179 mg (88%) of compound
2
1
0g, as a brown solid, was obtained. Mp 177-179 °C (lit. mp
-
1 1
In conclusion, we have developed a mild, environmentally
friendly, and very efficient protocol for the Friedl €a nder and
Friedl €a nder-Borsche reactions under CAN catalysis, avoid-
ing the need for harsh basic or acidic conditions and allowing
double condensations. This method significantly increases
the scope of the traditional one and has led to an exception-
ally general synthesis of polysubstituted and polycyclic
quinoline derivatives in excellent yields. It has also led to a
much improved synthesis of the alkaloid luotonin A, which
can be readily adapted to the preparation of luotonin
analogues modified at the quinoline structural fragment in
order to contribute to the study of structure-activity rela-
tionships in this family of antitumor agents.
185 °C); IR (neat) 1601.2, 1494.7 cm ; H NMR (CDCl , 250
MHz) δ 3.30 (s, 4H), 7.59 (td, J = 7.0, 1.2 Hz, 2H), 7.75 (td, J =
7.0, 1.5 Hz, 2H), 7.84 (dd, J = 8.0, 1.0 Hz, 2H), 8.12 (s, 2H), 8.49
3
1
3
(
d, J = 8.5 Hz, 2H); C NMR (CDCl
27.7, 128.8, 129.4, 131.4, 133.0, 135.1, 148.6, 152.8. Anal. Calcd
for C H N : C, 85.08; H, 5.00; N, 9.92. Found: C, 84.79; H,
3
, 63 MHz) δ 29.1, 127.2,
1
2
0
14
2
5
.16; N, 9.71.
Luotonin A (1). Method A: Starting from compound 12
22
(120 mg, 0.60 mmol) and 2-aminobenzaldehyde (73 mg, 0.60
mmol), a yield of 112 mg (66%) of luotonin A was obtained,
as a pale brown solid. Method B: Starting from compound 12
(110 mg, 0.55 mmol) and compound 9 (77 mg, 0.37 mmol),
a yield of 86.4 mg (82%) of luotonin A was obtained, as a pale
2
0
2
2
brown solid. Mp 253 °C dec (lit. mp 252 °C dec); IR (neat)
052.1, 2929.1, 1678.6, 1629.6, 1606.6, 1467.0, 1359.1, 1326.8
3
-
1 1
cm ; H NMR (CDCl
.1, 1.1 Hz, 1H), 7.74 (td, J = 7.9, 1.1 Hz, 1H), 7.86-7.93
(m, 2H), 8.01 (dd, J = 8.0, 1.0 Hz, 1H), 8.17 (d, J = 7.7 Hz, 1H),
3
, 250 MHz) δ 5.40 (s, 2H), 7.62 (td, J =
Experimental Section
8
General Procedure for the CAN-Catalyzed Friedl €a nder and
Friedl €a nder-Borsche Reactions. A solution of the suitable
1
3
8.46-8.54 (m, 3H); C NMR (CDCl , 63 MHz) δ 47.7, 121.7,
126.9, 127.6, 128.4, 128.9, 129.2, 129.8, 131.1, 132.0, 135.0,
149.7, 149.8, 151.6, 152.9, 161.1. Anal. Calcd for C H -
3
N O: C, 75.78; H, 3.89; N, 14.73. Found: C, 75.47; H, 4.08;
N, 14.39.
3
2
-aminoketone, aldehyde, or imine (2 mmol) and active methy-
lene compound (2 to 4 mmol), together with CAN (15 mol %),
in ethanol (5 mL) was refluxed for the time periods specified
in Table 1 and in the Supporting Information. After comple-
tion of the reaction (TLC), the mixture was cooled, diluted
1
8
11
with CH
dried (anhydrous Na
2
Cl
2
, washed with water followed by brine, and
SO ). The solvent was evaporated under
Acknowledgment. We thank In ꢀe s Prieto for experimental
assistance and MCINN (grant CTQ2006-10930) and UCM-
CAM (Grupos de Investigaci oꢀ n, grant 920234) for financial
support.
2
4
reduced pressure and the crude reaction mixture was purified
by silica column chromatography eluting with a suitable
petroleum ether-ethyl acetate mixture. Characterization data
for some representative cases are given below, and data
for all other compounds can be found in the Supporting
Information.
Ethyl 4-Methyl-2-propylquinoline-3-carboxylate (6b). Start-
ing from o-aminoacetophenone (270 mg, 2.0 mmol) and ethyl
3-oxohexanoate (316 mg, 2.0 mmol), a yield of 468 mg (91%) of
compound 6b was obtained, as a colorless viscous liquid. IR
Supporting Information Available: Experimental proce-
dures and spectra of all final products. This material is available
free of charge via the Internet at http://pubs.acs.org.
(
(
21) Thummel, R. P.; Lefoulon, F. J. Org. Chem. 1985, 50, 666.
22) Ma, Z.-Z.; Hano, Y.; Nomura, T.; Chen, Y.-J. Heterocycles 1997,
46, 541.
5
718 J. Org. Chem. Vol. 74, No. 15, 2009