Streamlined access to functionalized chromenes and quinolines using domino reactions of salicylic aldehydes and methyl 4-chloro-2-butynoate

Article abstract of DOI:10.1002/ejoc.201000559

Methyl 4-chloro-2-butynoate was used in a modified MoritaBaylis-Hillman reaction with salicylic aldehydes. The chlorine atom in the alkynoate moiety allows its efficient isomerization to the corresponding aliene, and remains in the adduct as a reactive site. Further one-pot derivatization leads to a variety of substituted chromenes and quinolines.

Full text of DOI:10.1002/ejoc.201000559

FULL PAPER
DOI: 10.1002/ejoc.201000559
Streamlined Access to Functionalized Chromenes and Quinolines using Domino
Reactions of Salicylic Aldehydes and Methyl 4-Chloro-2-butynoate
Davide Bello,[a] Javier Ruiz-Rodríguez,[a] Fernando Albericio,*[a,b,c] Rosario Ramón,[a] and
Rodolfo Lavilla*[a,d]
Keywords: Synthetic methods / Cyclization / Domino reactions / Nitrogen heterocycles / Isomerization
Methyl 4-chloro-2-butynoate was used in a modified Morita–
Baylis–Hillman reaction with salicylic aldehydes. The chlo-
rine atom in the alkynoate moiety allows its efficient isomeri-
zation to the corresponding allene, and remains in the adduct
as a reactive site. Further one-pot derivatization leads to a
variety of substituted chromenes and quinolines.
the inclusion of conjugated allenes in this process, showing
the viability of this structural group in the preparation of
substituted benzopyrans.[5b,6] However, in spite of reliable
synthetic access to allenyl esters,[7] their preparation re-
mains laborious because of the multistep sequences re-
quired. Furthermore, the alkynyl isomeric counterparts (i.e,
the commercially available tetrolic esters), have proven to
be unsuitable substrates, with sluggish reactions and poor
conversion yields.[8]
Introduction
Benzopyran and quinoline heterocyclic ring systems are
present in a vast number of natural products and bioactive
substances, with a wide application range.[1,2] These hetero-
cycles are privileged structures, constituting pivotal drug-
like scaffolds in medicinal chemistry, and have received
much attention.[3] Therefore, simple and direct access to
suitably functionalized precursors that may streamline the
preparation of a variety of substituted derivatives is impor-
tant in organic synthesis, with direct applications in medici-
nal chemistry. Especially appealing are methodologies lead-
ing to diverse scaffolds.[4]
Herein, we present our results in this area, and disclose
a straightforward, one-pot protocol based on a domino re-
action with salicylic aldehydes and 4-chloro-2-butynoate as
initial synthetic inputs (Scheme 1). This reaction leads to
functionalized adducts that are further derivatized to yield
a diverse set of substituted benzopyrans and quinolines, dis-
playing up to three diversity points. The process displays
similarities to the Morita–Baylis–Hillman reaction (MBH),
which has become a practical and versatile synthetic tool.
Recent developments in the field include enantioselective
versions, mechanistic studies, derivatization of the adducts
and, interestingly, the application of a new set of reac-
Scheme 1. Preparation of chromene 4a.
Results and Discussion
In the course of a different research project, we needed
tants.[5] The pioneering work of Shi has paved the way to access to compound 3, and envisaged its preparation by
treatment of salicylic aldehyde (1a) with the readily avail-
able methyl 4-chloro-2-butynoate (2a).[9] Unexpectedly, the
[a] Barcelona Science Park,
Baldiri Reixac 10–12, 08028 Barcelona, Spain
reaction furnished a mixture of 2H-chromene 4a and 4H-
Fax: +34-93-4037104
E-mail: rlavilla@pcb.ub.es
chromene 4aЈ instead (Scheme 1). Moreover, the 4H-
chromene spontaneously isomerized through a 1,3-hydroxy
shift to the 2H-isomer 4a (isolated yield 60%) either upon
chromatographic purification (SiO2) or under slight acid ca-
talysis (adventitious HCl in CDCl3), which presumably re-
flects its greater thermodynamic stability.[10] It should be
noted that on prolonged exposure to K2CO3, halohydrin 4a
slowly decomposed to give a complex mixture in which the
putative epoxide could be detected (MS evidence).
View this journal online at
[b] CIBER-BBN, Networking Centre on Bioengineering,
Biomaterials and Nanomedicine, Barcelona Science Park,
Baldiri Reixac 10, 08028 Barcelona, Spain
[c] Department of Organic Chemistry, Faculty of Chemistry,
University of Barcelona,
Martí i Franqués 1–11, 08028 Barcelona, Spain
[d] Laboratory of Organic Chemistry, Faculty of Pharmacy,
University of Barcelona,
Avda Joan XXIII sn, 08028 Barcelona, Spain
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201000559.
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Initially, experiments were carried out by pre-forming the gated, and may reflect subtle differences in the isomeriza-
sodium salt of aldehyde 1a and then slowly adding alkyno- tion and elimination reaction rates promoted by the respec-
ate 2a. We found that comparable results were obtained by tive heteroatoms.
changing the order of addition of the reagents or base to
the reaction medium. The reaction proceeded smoothly at
room temperature in acetone, N,N-dimethylformamide
(DMF) and acetonitrile (with better yields in the latter sol-
vent), but was less productive in dichloromethane or in
tetrahydrofuran (THF)/water mixtures. The base of choice
was anhydrous K2CO3 but although theoretically a catalytic
amount should have sufficed, it was determined that a slight
molar excess (1.2 equiv.) was required.
The reactivity of methyl 4-bromo-2-butynoate[11] was
then studied. Its reaction with salicylic aldehyde (1a) af-
forded the analogous chromene containing a salicyl substit-
uent at the exocyclic methylene moiety (NMR and MS evi-
dence). Interestingly, no reaction took place when methyl
3-phenylpropiolate was exposed to 1a under the usual con-
ditions. However, methyl 2-butynoate (2b) reacted slug-
gishly at reflux temperature for prolonged times to afford
chromene 4b[12] (6%, Scheme 2); when interacting with pro-
tected anthranilic aldehyde (1b),[14] the quinoline 5a[13] was
detected in trace amounts, presumably after spontaneous
elimination–hydrolysis steps.
Scheme 3. Reaction of alkynoate 2a with aldehydes 1c and 1b.
Figure 1. X-ray structure of quinoline derivative 5b.
A likely mechanistic proposal that may account for the
experimental observations is shown in Scheme 4. The alky-
noate must isomerize to the allene derivative B to react with
the anionic species A, setting the stage for the conjugate
addition to afford enolate C. This step may take place with
anti stereoselectivity, with the incoming nucleophile avoid-
ing the same face as the chlorine atom, thereby exclusively
forming the E isomer. The enolate then undergoes an intra-
molecular aldol reaction with the aldehyde, giving rise to
the bicyclic intermediate D, which either readily isomerizes
to 4a (X = O), or dehydrates (X = NMs), affording 1,2-
dihydroquinoline 5b. The overall domino process comprises
the following sequence: allene formation, conjugate ad-
dition, aldol cyclization, and a final dehydration or isomer-
ization step.[6,8,15] This mechanistic hypothesis was sup-
ported by independent experiments in which, under Et3N
treatment, B was generated almost quantitatively at room
temp. in one hour, although it began to decompose rapidly;
however, when K2CO3 was used as the base, the rate of the
reaction was slower (50% after 12 h at r.t.), but the stability
Scheme 2. Methyl 2-butynoate reactions.
These results suggest the intermediacy of isomeric allene
species as the reactive inputs for this transformation, and
highlight the active role of the chloromethyl substituent,
which seems to efficiently promote the isomerization under
mild conditions. We next attempted the reaction with 5-bro-
mosalicylic aldehyde (1c), which successfully gave the corre-
sponding benzopyran 4cЈ (56%, Scheme 3). Interestingly, in
this case, we isolated the non-isomerized adduct. The
reasons for this unexpected behavior are not clear, consider-
ing Shi’s observations on this isomerization process.[6] How-
ever, this material slowly converted into 4c when exposed
to acids, which is in agreement with the greater thermo-
dynamic stability of the latter isomer, and probably means
that the isomerization step is kinetically less favored in this
series. When aldehyde 1b was treated with the chloroalk-
ynoate 2a, the 1,2-dihydroquinoline derivative 5b was ob-
tained stereoselectively (50%; Scheme 3). The structure of
this compound was confirmed by X-ray diffraction analysis
(Figure 1). The possibility of accessing functionalized quin-
olines from 2-aminobenzaldehydes through an MBH-type
reaction is noteworthy because previous approaches in-
volved the use of o-nitrobenzaldehyde precursors.[5] On the
other hand, the distinct reactivity pathways followed by the
oxygen- and nitrogen-heterocyclic systems are being investi- Scheme 4. Mechanistic proposal.
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Functionalized Chromenes and Quinolines
was higher, and subsequent treatment with salicylic alde- diversity element through the Suzuki coupling; thus, the
hyde under the standard conditions afforded 4a as expected. bromo-derivative 7c was treated with 4-tolylboronic acid
The 4-chloro-2-butynoate substrate was the compound under standard Pd-catalysis to conveniently afford adduct
of choice for this transformation because use of this sub- 9 (70%, Scheme 5).
strate balanced the reactivity toward a mild base (to gener-
ate the reactive allenoate B) at the same time as generating
stable adducts that were ready for further derivatization. In
sharp contrast, γ-unsubstituted 2-butynoates led to poor
conversion under these conditions, presumably because it
failed to provide suitable amounts of the allenoate. In this
respect, it should be noted that Shi and Cao have documen-
ted relevant examples of the direct addition of salicylic alde-
hydes and imine derivatives to activated (highly electro-
philic) alkynoates that take place without the participation
Figure 2. X-ray structure of lactam 8.
of allenoate species.[16]
In this regard, chromenes 4 and 4Ј are particularly at-
tractive systems because their polyfunctional character of-
fers the possibility of orthogonal transformations. The for-
mation of stabilized cationic species by hydroxyl group acti-
While searching for a robust and efficient route to poly-
substituted chromenes 7 and 8, we attempted a one-pot ver-
sion of the entire process, starting from the reactants 1a and
[19]
2a. Recently, the acid catalyst HBF4·SiO2
was success-
vation through acid catalysis has been recently disclosed,
and this has allowed the introduction of silyl enol ethers at
the 4-position of activated 2H-chromenes.[17] To expand the
nucleophile range, we reacted 2-methylindole with
chromene 4a in the presence of BF3·Et2O.[18] Under these
conditions, substitution at the 4-position occurred, giving
rise to adduct 6a (71%, Scheme 5). The same result was
obtained when the crude mixture of isomers 4a and 4aЈ was
employed, indicating that the 4-position in this chromene
ring is the most reactive. Analogously, treatment of bromo-
derivative 4cЈ afforded the corresponding adduct 6b (41%).
fully used in the electrophilic substitution of indoles.[20] We
explored the compatibility of this catalyst with the basic
MBH reaction system, which would allow both steps to be
performed in tandem. Thus, 2-methylindole and an excess
of HBF4·SiO2 (to quench the K2CO3 and keep an acidic
environment) were added to the reaction vessel in which
compound 4a was synthesized. Afterwards, the correspond-
ing amine and the required amount of a neutralizing base
were added to the mixture and the three-step sequence lead-
ing to substituted chromenes was successfully completed;
compounds 7a and 8 were obtained in 58% and 60% over-
all yields, respectively (Scheme 6). Similarly, phosphonate
10 (80%) was prepared by addition of neat trimethyl phos-
phite in the last step. Cyanide addition resulted in the for-
mation of a somewhat unstable adduct that decomposed
during attempts at purification.
Scheme 5. Reaction of chromene 4 with indole and amines.
Scheme 6. Tandem one-pot protocols.
Next, the functionalization of compounds 6 was carried
out with amines. Rewardingly, the reaction was selective
We then explored the derivatization of quinoline deriva-
and, whereas secondary amines cleanly afforded derivatives tive 5b, which proved to be unreactive under a variety of
7 in high yields, primary amines gave rise to the fused tricy- hydrolytic, oxidative, and reductive conditions. Reward-
clic lactam 8 with almost quantitative conversion at room ingly, upon treatment with N-bromosuccinimide (NBS), we
temperature. The structure of this latter compound was observed a clean conversion into the bromochloro-deriva-
confirmed by X-ray diffraction analysis (Figure 2), which tive 11 (70%, Scheme 7).[21] Subsequent AgNO3-mediated
also secured the assignment of the indole substitution in hydrolysis[22] afforded the corresponding quinoline aldehyde
these series. We were also able to introduce an additional 12[23] (56%). Finally, successful reaction of this compound
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F. Albericio, R. Lavilla et al.
FULL PAPER
added and the resulting mixture was stirred at r.t. for 6 h. 2-Meth-
ylindole (1.5 equiv.) was then added, followed by HBF4·SiO2 (until
ca. pH 3),[26] and the resulting mixture was stirred for an additional
5 h. Triethylamine (until ca. pH 11) was then added to the mixture,
followed by the corresponding primary or secondary amine
(2.0 equiv.), and the resulting mixture was stirred overnight.
with 4-methoxyphenyl hydrazine to obtain the pyridazinone
adduct 13 (69%) demonstrated the feasibility of this ap-
proach to reach this biologically important scaffold.[24]
Methyl
2-(Chloromethyl)-2-hydroxy-2H-chromene-3-carboxylate
(4a): Salycylaldehyde (1a, 442 mg, 3.62 mmol, 1.0 equiv.) and
methyl 4-chlorobut-2-ynoate (2a, 528 mg, 3.98 mmol, 1.1 equiv.)
were dissolved in acetonitrile (10 mL) and K2CO3 (600 mg,
4.34 mmol, 1.2 equiv.) was added. The resulting mixture was stirred
at r.t. for 5 h. The solids were removed by filtration and the re-
sulting solution was concentrated under reduced pressure. The resi-
due was adsorbed onto silica gel and purified by flash chromatog-
raphy on silica gel (hexane/ethyl acetate) to give 4a as a yellow,
Scheme 7. Post-condensation reactions of quinoline 5b.
1
waxy solid (552 mg, 60%). H NMR (400 MHz, CDCl3): δ = 7.75
(s, 1 H), 7.39–7.35 (m, 1 H), 7.28–7.25 (m, 1 H), 7.04–7.00 (m, 2
H), 4.30 (d, J = 11.2 Hz, 1 H, CH2), 4.07 (d, J = 11.2 Hz, 1 H,
CH2), 3.88 (s, 3 H, OCH3) ppm. 13C NMR (101 MHz, CDCl3): δ
= 165.60, 152.58, 137.29, 133.15, 129.24, 122.36, 121.80, 118.20,
Conclusions
116.81, 98.28, 52.57, 49.28 ppm. IR (thin film): ν
= 3032.7 (w),
˜
max
We have developed a practical and versatile approach to
polysubstituted 4H-chromenes and quinolines, based on the
participation of 4-chloro-2-butynoate in a modified MBH-
type reaction.[25] This complex cascade process can be ap-
plied in one-pot sequences to streamline the preparation of
these derivatives.
2949.5 (w), 2847.0 (w), 1706.8 (s), 1629.9 (m), 1578.6 (w), 1489.0
(m), 1431.3 (m), 1278.0 (w), 1220.0 (s), 1104.6 (m), 1053.4 (s) cm–1.
HRMS: calcd. for C12H12ClO4 [M + H]+ 255.0419; found 255.0424;
calcd. for C12H10ClO3 [M – OH]+ 237.0313; found 237.032; calcd.
for C12H11O4 [M – Cl]+ 219.0652; found 219.066.
Methyl 6-Bromo-2-(chloromethyl)-4-hydroxy-4H-chromene-3-carb-
oxylate (4cЈ): 5-Bromo-2-hydroxybenzaldehyde (1c; 1.0 g,
4.97 mmol, 1.0 equiv.) and methyl 4-chlorobut-2-ynoate (2a;
983 µL, 7.45 mmol, 1.5 equiv.) were dissolved in acetonitrile
(10 mL) and K2CO3 (690 mg, 4.97 mmol, 1.0 equiv.) was added.
The resulting mixture was stirred at r.t. for 6 h. The solids were
removed by filtration and the resulting solution was concentrated
under reduced pressure. The residue was adsorbed onto silica gel
and purified by silica gel flash chromatography (hexane/ethyl acet-
ate) to give 4cЈ as a yellow, waxy solid (922 mg, 56%). 1H NMR
(400 MHz, CDCl3): δ = 7.58 (d, J = 2.4 Hz, 1 H), 7.47 (dd, J =
8.7, 2.4 Hz, 1 H), 7.06 (d, J = 8.7 Hz, 1 H), 5.62 (s, 1 H), 4.12 (d,
J = 4.0 Hz, 1 H, CH2), 3.94 (d, J = 4.1 Hz, 1 H, CH2), 3.77 (s, 3
H, OCH3) ppm. 13C NMR (100 MHz, CDCl3): δ = 164.16, 155.71,
150.18, 134.04, 132.48, 120.71, 119.44, 115.62, 102.41, 54.43, 51.59
Experimental Section
General: Chemicals were purchased and used without further puri-
fication. Room temp. refers to a temperature of 25 °C. Analytical
thin layer chromatography (TLC) was carried out on pre-coated
Merk silica gel 60 F254 plates and visualized under a UV lamp. 1H
NMR spectra were recorded with a Varian Mercury 400 (400 MHz)
instrument using internal deuterium lock and CDCl3 as a solvent
(unless otherwise indicated). The chemical shift (δ) are given in
units of parts per million (ppm) relative to tetramethylsilane (TMS;
δ = 0.00 ppm). The multiplicity of each signal is indicated by: s
(singlet), br. s (broad singlet), d (doublet), t (triplet), td (triplet of
doublets), dd (doublet of doublets), ddd (doublet of doublet of
doublets), m (multiplet), or br. m (broad multiplet). Coupling con-
stants (J) are quoted in Hz and are recorded to the nearest 0.1 Hz.
13C NMR spectra were recorded with a Varian Mercury 400
(101 MHz) instrument using internal deuterium lock and proton
decoupling. The chemical shift data for each signal are given as δ
in units of ppm relative to TMS (δ = 0.00 ppm). 31P NMR spectra
were recorded with a Varian Inova 300 (121.4 MHz) instrument
using proton decoupling and internal deuterium lock. The chemical
shift data for each signal are given as δ in units of ppm relative to
an external standard of 85% H3PO4. IR spectra were recorded with
a Thermo Nicolet Nexus spectrometer as thin films between KBr
discs. Absorption maxima are reported in wavenumbers (cm–1). In-
tensities of the maxima are quoted as: strong (s), medium (m), or
weak (w). High Resolution Mass Spectrometry (HRMS) was per-
formed by the University of Barcelona Mass Spectrometry Service.
Flash Column chromatography was carried out on silica gel as indi-
cated, under a positive pressure of compressed air.
ppm. IR (KBr): ν
= 3429 (w, br), 2951 (m), 2853 (w), 1715 (s),
˜
max
1634 (m), 1479 (s), 1228 (s), 1056 (m) cm–1. HRMS: calcd. for
C12H9BrClO3 [M – HO]+ 314.9418; found 314.9417.
(E)-Methyl 2-(Chloromethylene)-1-(methylsulfonyl)-1,2-dihydroquin-
oline-3-carboxylate (5b): N-Mesyl 2-aminobenzaldehyde (1b;
398 mg, 2.0 mmol, 1.0 equiv.) and methyl 4-chlorobut-2-ynoate
(292 mg, 2.2 mmol, 1.1 equiv.) were dissolved in acetonitrile
(10 mL) and K2CO3 (332 mg, 2.4 mmol, 1.2 equiv.) was added. The
resulting mixture was heated to reflux with stirring for 16 h. The
solids were then removed by filtration, the resulting solution was
concentrated under reduced pressure and the residue was adsorbed
onto silica and purified by flash chromatography on silica gel (hex-
ane/ethyl acetate), to give 5b as a colorless solid (310 mg, 50%). 1H
NMR (400 MHz, CDCl3): δ = 7.69 (d, J = 8.1 Hz, 1 H), 7.45–7.36
(m, 3 H), 7.32 (td, J = 7.5, 1.1 Hz, 1 H), 6.60 (s, 1 H), 3.91 (s, 3
H, OCH3), 2.75 (s, 3 H, SO2CH3) ppm. 13C NMR (101 MHz,
CDCl3): δ = 165.84, 137.14, 134.46, 131.01, 129.14, 129.03, 127.33,
126.08, 125.89, 125.53, 124.30, 52.95, 37.73 ppm. IR (thin film):
General One-Pot Procedure for the Synthesis of 4H-Chromene De-
rivatives 7 and 8: Salicylaldehyde 1 (1.0 equiv.) and methyl 4-chlo-
robut-2-ynoate (2a; 1.1 equiv.) were dissolved in acetonitrile (0.1 
with respect to the aldehyde component), K2CO3 (1.2 equiv.) was
ν
= 3090.4 (w), 3007.1 (w), 2943.1 (w), 1718.7 (s), 1553.0 (w),
˜
max
1348.0 (s), 1252.0 (m), 1207.1 (m), 1066.2 (m), 950.9 (m) cm–1.
HRMS: calcd. for C13H13ClNO4S [M + H]+ 314.0254; found
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Functionalized Chromenes and Quinolines
314.0248; calcd. for C12H10ClNO2 [M – SO2CH2]+ 235.0394; found
235.0393.
Method 2: Compound 7a was prepared according to the general
one-pot procedure, using salicylaldehyde 1a (200 mg, 1.64 mmol,
1.0 equiv.), methyl 4-chlorobut-2-ynoate 2a (239 mg, 1.80 mmol,
1.1 equiv.), 2-methylindole (322 mg, 2.46 mmol, 1.5 equiv.) and N-
ethyl piperazine (416 µL, 3.28 mmol, 2.0 equiv.). The crude product
was purified by flash chromatography on silica gel (dichlorometh-
ane/methanol) affording 7a (426 mg, 58% overall yield with respect
Methyl 2-(Chloromethyl)-4-(2-methyl-1H-indol-3-yl)-4H-chromene-
3-carboxylate (6a): Method 1: Compound 4a (75 mg, 0.29 mmol,
1.0 equiv.) was dissolved in anhydrous dichloromethane (2 mL) un-
der an atmosphere of argon. The mixture was cooled to –78 °C,
BF3·EtO2 (40 µL, 0.32 mmol, 1.1 equiv.) was added and the re-
sulting mixture was stirred at –78 °C for 5 min, then 2-methylindole
(46.3 mg, 0.35 mmol, 1.2 equiv.) was added and the mixture was
warmed to r.t. and stirred overnight. The mixture was washed with
satd. aq. sodium hydrogen carbonate (3 times), dried with Na2SO4
and concentrated under reduced pressure. The resulting residue was
adsorbed onto silica gel and purified by flash chromatography on
silica gel (hexane/ethyl acetate) to give 6a as a pale-brown solid
(76 mg, 71%).
1
to salicylaldehyde 1a). H NMR (400 MHz, CDCl3): δ = 7.92 (s, 1
H, NH), 7.36 (d, J = 7.9 Hz, 1 H), 7.19 (d, J = 7.9 Hz, 1 H), 7.12–
6.99 (m, 3 H), 6.98–6.86 (m, 3 H), 5.40 (s, 1 H, 4-H), 3.89 (d, J =
13.5 Hz, 1 H, CH2), 3.70 (d, J = 13.5 Hz, 1 H, CH2), 3.55 (s, 3 H,
OCH3), 2.88–2.77 (br. m, 4 H), 2.74–2.62 (br. m, 4 H), 2.58 (q, J
= 7.3 Hz, 2 H, CH2-Me), 2.45 (s, 3 H, C-CH3), 1.17 (t, J = 7.3 Hz,
3 H, CH2-CH3) ppm. 13C NMR (101 MHz, CDCl3): δ = 167.80,
156.29, 149.53, 135.33, 131.70, 129.53, 127.59, 127.52, 124.70,
124.11, 121.00, 119.43, 118.45, 116.27, 116.06, 110.47, 108.81,
57.25, 52.64, 52.40, 52.32, 51.59, 32.17, 12.01, 11.40 ppm. IR (thin
Method 2: Compound 4a (667 mg, 2.6 mmol, 1.0 equiv.) then 2-
methylindole (515 mg, 3.9 mmol, 1.5 equiv.) were dissolved in ace-
tonitrile, HBF4·SiO2 (100 mg) was added and the resulting mixture
was stirred for 6 h. The mixture was then filtered and the solvent
was removed under reduced pressure. The resulting residue was ad-
sorbed onto silica gel and purified by flash chromatography on
silica gel (hexane/ethyl acetate) to give 6a as a pale-brown solid
film): ν
= 3391.5 (w, br.), 3173.7 (w), 3045.5 (w), 2936.6 (m),
˜
max
2802.1 (m), 1706.8 (s), 1649.1 (w), 1585.0 (m), 1489.0 (m), 1328.8
(w), 1213.5 (s), 1047.0 (m) cm–1. HRMS: calcd. for C27H32N3O3
[M + H]+ 446.2438; found 446.2445.
Methyl
4-(2-Methyl-1H-indol-3-yl)-2-(pyrrolidin-1-ylmethyl)-4H-
chromene-3-carboxylate (7b): Compound 6a (160 mg, 0.45 mmol,
1.0 equiv.) was dissolved in acetonitrile (7 mL), pyrrolidine
(126 µL, 1.36 mmol, 3.0 equiv.) was added and the resulting mix-
ture was stirred at r.t. for 20 h. The solvent was removed under
reduced pressure and the resulting residue was adsorbed onto silica
gel and purified by flash chromatography on silica gel (hexane/ethyl
acetate) furnishing compound 7b in quantitative yield (175 mg). 1H
NMR (400 MHz, CDCl3): δ = 8.08 (s, 1 H, NH), 7.42 (d, J =
7.8 Hz, 1 H), 7.17 (d, J = 7.9 Hz, 1 H), 7.10–6.99 (m, 3 H), 6.99–
6.94 (m, 2 H), 6.92–6.86 (m, 1 H), 5.42 (s, 1 H, 4-H), 4.07 (d, J =
13.5 Hz, 1 H, CH2), 3.82 (d, J = 13.5 Hz, 1 H, CH2), 3.55 (s, 3 H,
OCH3), 2.77 (d, J = 3.9 Hz, 4 H, CH2-CH2-N), 2.42 (s, 3 H, C-
CH3), 1.82 (s, 4 H, CH2-CH2-N) ppm. 13C NMR (100 MHz,
CDCl3): δ = 167.80, 157.61, 149.58, 135.26, 131.60, 129.42, 127.56,
127.46, 124.55, 124.18, 120.91, 119.40, 118.50, 116.28, 116.26,
110.33, 107.73, 54.67, 54.25, 51.46, 32.04, 23.78, 11.94 ppm. IR
1
(523 mg, 55%). H NMR (400 MHz, CDCl3): δ = 7.73 (br. s, 1 H,
NH), 7.42 (d, J = 7.79 Hz, 1 H), 7.20 (d, J = 7.79 Hz, 1 H), 7.14–
6.91 (m, 6 H), 5.42 (s, 1 H, 4-H), 4.83 (d, J = 11.3 Hz, 1 H, CH2),
4.74 (d, J = 11.3 Hz, 1 H, CH2), 3.60 (s, 3 H, OCH3), 2.43 (s, 3 H,
C-CH3) ppm. 13C NMR (101 MHz, CDCl3): δ = 166.86, 155.41,
149.39, 135.16, 132.00, 129.58, 127.83, 127.61, 125.07, 123.73,
121.18, 119.76, 118.38, 116.18, 116.14, 110.44, 108.16, 51.97, 40.91,
31.99, 12.07 ppm. IR (thin film): νmax = 3391.5 (s, br.), 2949.5 (w),
˜
2911.0 (w), 1719.6 (s), 1698.7 (s), 1614.5 (w), 1586.4 (m), 1558.3
(s), 1431.8 (m), 1337.0 (m), 1217.6 (s), 1101.7 (m), 1056.0 (m), 926.5
(w) cm–1. HRMS: calcd. for C21H22ClN2O3 [M + NH4]+ 385.1313;
found 385.1321.
Methyl 6-Bromo-2-(chloromethyl)-4-(2-methyl-1H-indol-3-yl)-4H-
chromene-3-carboxylate (6b): Compound 4cЈ (760 mg, 2.40 mmol,
1.0 equiv.) then 2-methylindole (331 mg, 2.52 mmol, 1.05 equiv.)
were dissolved in acetonitrile, HBF4·SiO2 (80 mg) was added and
the resulting mixture was stirred for 6 h. The mixture was then
filtered and the solvent removed under reduced pressure. The re-
sulting residue was adsorbed onto silica gel and purified by flash
chromatography on silica gel (hexane/ethyl acetate) to give 6b as a
yellow solid (413 mg, 41%). 1H NMR (400 MHz, CDCl3): δ = 7.83
(s, 1 H, NH), 7.38 (d, J = 7.8 Hz, 1 H), 7.23 (m, J = 8.7, 2.4 Hz,
2 H), 7.02 (m, 4 H), 5.37 (s, 1 H, 4-H), 4.82 (d, J = 11.4 Hz, 1 H,
CH2), 4.73 (m, 1 H, CH2), 3.61 (s, 3 H, OCH3), 2.44 (s, 3 H, C-
CH3) ppm. 13C NMR (100 MHz, CDCl3) δ = 166.43, 155.14,
148.50, 135.18, 132.19, 132.10, 130.92, 127.35, 125.83, 121.35,
119.88, 118.19, 118.03, 117.33, 115.45, 110.50, 107.99, 52.03, 40.65,
(KBr): νmax = 3399 (m), 3054 (w), 2951 (m), 1713 (s), 1458 (s), 1217
˜
(s), 1189 (m), 1054 (m) cm–1. HRMS: calcd. for C25H27N2O3 [M +
H]+ 403.2022; found 403.2014.
Methyl 6-Bromo-4-(2-methyl-1H-indol-3-yl)-2-(morpholinomethyl)-
4H-chromene-3-carboxylate (7c): Compound 6b (410 mg,
0.92 mmol, 1.0 equiv.) was dissolved in acetonitrile (6 mL), K2CO3
(140 mg, 1.01 mmol, 1.1 equiv.) followed by morpholine (88 µL,
1.01 mmol, 1.1 equiv.) were added and the resulting mixture was
stirred at r.t. for 16 h. The solvent was removed under reduced
pressure and the resulting residue was adsorbed onto silica gel and
purified by flash chromatography on silica gel (hexane/ethyl acet-
ate) to give 7c as a yellow solid (410 mg, 90%). 1H NMR
(400 MHz, CDCl3): δ = 8.02 (s, 1 H, NH), 7.34 (d, J = 7.9 Hz, 1
H), 7.24–7.16 (m, 2 H), 7.09–7.02 (m, 2 H), 7.00–6.92 (m, 2 H),
5.37 (s, 1 H, 4-H), 3.82 (d, J = 13.5 Hz, 1 H, CH2), 3.73 (m, 5 H),
3.57 (s, 3 H, OCH3), 2.66 (dd, J = 7.1, 3.7 Hz, 4 H, CH2-CH2-N),
2.45 (s, 3 H, C-CH3) ppm. 13C NMR (100 MHz, CDCl3): δ =
167.39, 156.10, 148.63, 135.31, 132.11, 131.69, 130.66, 127.21,
126.20, 121.21, 119.57, 118.28, 118.10, 116.91, 115.41, 110.47,
31.94, 12.08 ppm. IR (KBr): ν
= 3400 (s, br.), 3056 (w), 2951
˜
max
(m), 2917 (m), 2855 (w), 1713 (s), 1649 (s) cm–1. HRMS: calcd. for
C21H17BrClNNaO3 [M + Na]+ 467.9978; found 467.9971.
Methyl
2-[(4-Ethylpiperazin-1-yl)methyl]-4-(2-methyl-1H-indol-3-
yl)-4H-chromene-3-carboxylate (7a): Method 1: Compound 6a
(200 mg, 0.54 mmol, 1.0 equiv.) was dissolved in acetonitrile
(8 mL), N-ethyl piperazine (145 µL, 1.14 mmol, 2.1 equiv.) was
added and the resulting mixture was stirred at r.t. for 20 h. The
solvent was removed under reduced pressure and the resulting resi-
due was adsorbed onto silica gel and purified by flash chromatog-
raphy on silica gel (dichloromethane/methanol) to furnish 7a in
quantitative yield (240 mg).
108.65, 67.21, 57.69, 53.79, 51.61, 32.10, 11.94 ppm. IR (KBr): ν
˜
max
= 3395 (s, br.), 2952 (s), 2855 (s), 1714 (s), 1476 (s) cm–1. HRMS:
calcd. for C25H26BrN2O4 [M + H]+ 497.1076; found 497.1068.
2-Butyl-9-(2-methyl-1H-indol-3-yl)-2,3-dihydrochromeno[3,2-c]-
pyrrol-1(9H)-one (8): Compound 8 was prepared according to the
Eur. J. Org. Chem. 2010, 5373–5379
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5377

F. Albericio, R. Lavilla et al.
FULL PAPER
general one-pot procedure, using salicylaldehyde (1a; 100 mg,
0.82 mmol, 1.0 equiv.), 4-chlorobut-2-ynoate (2a; 120 mg,
0.90 mmol, 1.1 equiv.), 2-methylindole (161 mg, 1.23 mmol,
1.5 equiv.), and n-butylamine (162 µL, 1.64 mmol, 2.0 equiv.). The
crude product was purified by flash chromatography on silica gel
(dichloromethane/methanol) to afford 8 (182 mg, 60% overall yield
with respect to salicylaldehyde 1a). 1H NMR (400 MHz, [D6]-
DMSO): δ = 10.77 (s, 1 H, NH), 7.23–7.14 (m, 3 H), 7.05–6.96 (m,
2 H), 6.92 (d, J = 7.8 Hz, 1 H), 6.86 (t, J = 7.2 Hz, 1 H), 6.70 (t,
J = 7.3 Hz, 1 H), 5.09 (s, 1 H, 9-H), 4.21 (d, J = 18.2 Hz, 1 H,
CH2), 4.14 (d, J = 18.2 Hz, 1 H, CH2), 3.31 (s, 3 H, C-CH3), 3.29–
3.20 (m, 1 H), 3.20–3.11 (m, 1 H), 1.47–1.31 (m, 2 H), 1.23–1.11
(m, 2 H), 0.81 (t, J = 7.3 Hz, 3 H, -CH2-CH3) ppm. 13C NMR
(101 MHz, [D6]DMSO): δ = 168.67, 160.52, 150.19, 135.12, 132.18,
130.84, 127.83, 126.78, 124.81, 124.52, 119.65, 118.16, 116.99,
7.90 (s, 1 H, NH), 7.41 (d, J = 7.8 Hz, 1 H), 7.19 (d, J = 7.9 Hz, 1
H), 7.12–7.06 (m, 1 H), 7.05–6.99 (m, 2 H), 6.99–6.94 (m, 2 H),
6.93–6.88 (m, 1 H), 5.42 (d, J = 4.5 Hz, 1 H, 4-H), 3.90 (ddd, J =
22.2, 14.7, 0.8 Hz, 1 H, CH2), 3.78 (d, J = 10.9 Hz, 3 H, P-OCH3),
3.76 (d, J = 10.9 Hz, 3 H, P-OCH3), 3.61–3.50 (m, 4 H), 2.42 (s, 3
H, C-CH3) ppm. 13C NMR (101 MHz, CDCl3): δ = 167.60 (d,
JC–P = 3.2 Hz), 152.52 (d, JC–P = 12.7 Hz), 149.45, 135.31, 132.03,
129.68, 127.62, 127.59, 124.91, 124.23, 120.86, 119.41, 118.36,
116.06 (d, JC–P = 3.2 Hz), 115.88, 110.46, 107.78 (d, JC–P = 9.8 Hz),
53.16 (d, JC–P = 6.6 Hz), 53.15 (d, JC–P = 6.5 Hz), 51.67, 31.91 (d,
JC–P = 1.7 Hz), 29.88 (d, JC–P = 136.6 Hz), 11.86 ppm. 31P NMR
(121 MHz, CDCl ): δ = 26.21 ppm. IR (thin film): ν
= 3256.9
˜
3
max
(m, br.), 2994.3 (w), 2049.5 (m), 2853.4 (m), 1693.9 (s), 1655.5 (m),
1450.5 (w), 1335.2 (w), 1213.5 (s), 1104.6 (w), 1047.0 (s) cm–1.
HRMS: calcd. for C23H25NO6P [M + H]+ 442.1414; found
116.41, 112.93, 110.48, 107.77, 47.23, 40.32, 30.02, 28.19, 19.39, 442.1418; calcd. for C23H24NNaO6P [M + Na]+ 464.1233; found
13.55, 11.54 ppm. IR (thin film): ν
= 3269.7 (m, br.), 3052.0 464.1233.
˜
max
(w), 2955.9 (w), 2917.4 (w), 2859.8 (w), 1696.2 (m), 1668.6 (s),
1650.1 (s), 1557.9 (s), 1456.5 (s), 1392.2 (m), 1251.3 (w), 1078.3 (m)
cm–1. HRMS: calcd. for C24H25N2O2 [M + H]+ 373.1911; found
373.1913.
Methyl 2-(Bromochloromethyl)quinoline-3-carboxylate (11): Com-
pound 5b (100 mg, 0.33 mmol, 1.0 equiv.) was dissolved in acetoni-
trile (2 mL), N-bromosuccinimide (118 mg, 0.69 mmol, 2.1 equiv.)
was added and the resulting mixture was stirred at r.t. for 2 h. The
solvent was removed under reduced pressure and the crude mixture
was purified by flash chromatography on silica gel (hexane/ethyl
Methyl
4-(2-Methyl-1H-indol-3-yl)-2-(morpholinomethyl)-6-(p-
tolyl)-4H-chromene-3-carboxylate (9): Compound 7c (110 mg,
0.23 mmol, 1.0 equiv.), 4-methyl boronic acid (88 mg, 0.57 mmol,
2.5 equiv.), and Pd(PPh3)4 (26 mg, 0.023 mmol, 0.01 equiv.) were
placed in a Schlenk tube under an atmosphere of argon. N,N-Di-
methylformamide (3 mL) and aq. Na2CO3 (2 , 912 µL,
1.82 mmol, 8.0 equiv.) were added and the resulting mixture was
heated to 150 °C for 24 h. The mixture was then filtered through
Celite, the solvent was removed under reduced pressure and the
residue was adsorbed onto silica gel and purified by flash
chromatography on silica gel (hexane/ethyl acetate), furnishing 9 as
1
acetate), affording 11 as a colorless solid (73 mg, 70%). H NMR
(400 MHz, CDCl3): δ = 8.87 (s, 1 H, 4-H), 8.27 (dd, J = 8.5, 0.7 Hz,
1 H), 8.20 (s, 1 H, -CHClBr), 7.93 (d, J = 8.1 Hz, 1 H), 7.90 (ddd,
J = 8.5, 7.0, 1.3 Hz, 1 H), 7.67 (ddd, J = 8.5, 7.0, 1.3 Hz, 1 H),
4.04 (s, 3 H, OCH3) ppm. 13C NMR (100 MHz, CDCl3): δ =
165.74, 155.53, 148.88, 141.50, 132.93, 129.91, 128.86, 128.72,
127.04, 119.60, 55.90, 53.26 ppm. IR (thin film): νmax = 3064.8 (m,
˜
br.), 2949.5 (m), 1777.2 (w), 1706.7 (s), 1649.1 (w), 1431.3 (w),
1284.0 (w), 1162.3 (s), 1060.0 (w), 848.4 (w) cm–1. HRMS: calcd.
for C12H10BrClNO2 [M + H]+ 313.9578; found 313.9577; calcd. for
C12H9ClNO2 [M – Br]+ 234.0316; found 234.0320.
1
a colorless solid (79 mg, 70%). H NMR (400 MHz, CDCl3): δ =
7.70 (s, 1 H, NH), 7.35 (d, J = 7.8 Hz, 1 H), 7.25–7.17 (m, 3 H),
7.11 (d, J = 7.9 Hz, 1 H), 7.08–7.03 (m, 4 H), 6.95 (t, J = 7.5 Hz,
1 H), 6.89 (t, J = 7.4 Hz, 1 H), 5.38 (s, 1 H, 4-H), 3.80 (d, J =
13.5 Hz, 1 H, CH2), 3.70–3.62 (m, 5 H), 3.50 (s, 3 H, OCH3), 2.64–
Methyl 2-Formylquinoline-3-carboxylate (12): Compound 11
(180 mg, 0.57 mmol, 1.0 equiv.) was dissolved in a methanol/water
mixture (3:1, 4 mL) and silver nitrate (290 mg, 1.7 mmol,
3.0 equiv.) was added. The resulting mixture was heated to reflux
for 2 h, then cooled to r.t., concentrated under reduced pressure
and a mixture of ethyl acetate and satd. aq. ammonium chloride
was added. The layers were separated and the aqueous layer was
extracted with ethyl acetate (ϫ3). The combined organic layers
were dried with Na2SO4, concentrated under reduced pressure and
the residue was purified by flash chromatography on silica gel (hex-
2.54 (m, 4 H), 2.40 (s, 3 H, C-CH3), 2.25 (s, 3 H, C-CH3) ppm. 13
C
NMR (100 MHz, CDCl3): δ = 167.78, 156.57, 148.98, 137.80,
137.72, 136.99, 135.34, 131.54, 129.54, 127.89, 127.54, 126.90,
126.31, 124.35, 121.11, 119.54, 118.65, 116.64, 116.18, 110.36,
108.79, 67.35, 57.84, 53.85, 51.59, 32.39, 21.25, 12.12 ppm. IR (thin
film): ν
= 3405 (w), 2949 (w), 2855 (w), 1713 (m), 1489 (s),
˜
max
1212 (s), 1115 (m) cm–1. HRMS: calcd. for C32H33N2O4 [M + H]+
509.2440; found 509.2441.
1
ane/ethyl acetate) to give 12 as a colorless solid (69 mg, 56%). H
Methyl 2-[(Dimethoxyphosphoryl)methyl]-4-(2-methyl-1H-indol-3-
yl)-4H-chromene-3-carboxylate (10): Compound 10 was prepared
using a modified version of the general one-pot procedure. Salicyl-
aldehyde (1a; 250 mg, 2.05 mmol, 1.0 equiv.) and methyl 4-chlo-
robut-2-ynoate (2a; 300 mg, 2.25 mmol, 1.1 equiv.) were dissolved
in acetonitrile (20 mL), K2CO3 (340 mg, 2.46 mmol, 1.2 equiv.) was
added and the resulting mixture was stirred at r.t. for 6 h. 2-Meth-
ylindole (402 mg, 3.08 mmol, 1.5 equiv.) was then added, followed
by HBF4·SiO2 (amount required to reach ca. pH 3), and the re-
sulting mixture was stirred for an additional 6 h. The mixture was
treated with solid NaHCO3 (500 mg) and the solids were removed
by filtration, the mixture was concentrated under reduced pressure
and the residue was redissolved in neat P(OMe)3. The resulting
solution was heated to reflux overnight, then concentrated under
reduced pressure and the resulting residue was adsorbed onto silica
gel and purified by flash chromatography on silica gel (dichloro-
methane/methanol) to afford 10 (722 mg, 80% overall yield with
respect to salicylaldehyde 1a). 1H NMR (400 MHz, CDCl3): δ =
NMR (400 MHz, CDCl3): δ = 10.40 (s, 1 H, CHO), 8.60 (s, 1 H,
4-H), 8.29 (d, J = 8.0 Hz, 1 H), 7.95 (d, J = 7.9 Hz, 1 H), 7.90
(ddd, J = 8.1, 7.0, 1.4 Hz, 1 H), 7.74 (ddd, J = 8.1, 7.0, 1.4 Hz, 1
H), 4.02 (s, 3 H, OCH3) ppm. 13C NMR (100 MHz, CDCl3): δ =
191.79, 167.16, 151.47, 148.20, 138.74, 132.40, 130.66, 129.97,
128.61, 128.04, 124.64, 53.30 ppm. IR (thin film): ν
= 3052.0
˜
max
(w), 2949.5 (m), 2834.2 (w), 1731.6 (m), 1713.2 (s), 1553.0 (m),
1431.3 (m), 1245.6 (s), 1207.1 (m), 1123.8 (w), 1066.2 (s) cm–1.
HRMS: calcd. for C12H10NO3 [M + H]+ 216.0655; found 216.0659;
calcd. for C12H9NNaO3 [M + Na]+ 238.0475; found 238.0473.
2-(4-Methoxyphenyl)pyridazino[4,5-b]quinolin-1(2H)-one
(13):
Compound 12 (34 mg, 0.16 mmol, 1.0 equiv.) was dissolved in an-
hydrous ethanol (1 mL) under an atmosphere of argon in the pres-
ence of activated 4 Å molecular sieves. 4-Methoxyphenylhydrazine
(26 mg, 0.19 mmol, 1.2 equiv.) was added and the resulting mixture
was stirred for 3 h at r.t., after which time conversion into the corre-
sponding hydrazone was complete. Fuming acetic acid (45 µL,
5378
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 5373–5379

Functionalized Chromenes and Quinolines
[4] For a recent result, see: S. K. Ko, H. J. Jang, E. Kim, S. B.
Park, Chem. Commun. 2006, 2962–2964, and references cited
therein.
[5] For recent reviews, see: a) D. Basavaiah, A. J. Rao, T. Satyana-
rayana, Chem. Rev. 2003, 103, 811–891; b) G.-N. Ma, J.-J. Ji-
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13, 3701–3706.
0.79 mmol, 5.0 equiv.) was added and the resulting mixture was
heated to reflux overnight. The mixture was then filtered, the sol-
vent was removed under reduced pressure and the residue was
taken up in ethyl acetate/satd. aq. sodium hydrogen carbonate. The
layers were separated and the aqueous layer was extracted with
ethyl acetate (ϫ3). The combined organic layers were dried with
Na2SO4, concentrated under reduced pressure, and the residue was
purified by flash chromatography on silica gel (hexane/ethyl acet-
ate) to give 13 (33 mg, 69%). 1H NMR (400 MHz, CDCl3): δ =
9.37 (s, 1 H, 4-H), 8.65 (s, 1 H, 10-H), 8.30 (d, J = 8.7 Hz, 1 H),
8.14 (d, J = 8.3 Hz, 1 H), 7.98 (ddd, J = 8.3, 6.8, 1.3 Hz, 1 H), 7.75
(t, J = 8.3 Hz, 1 H), 7.61 (d, J = 9.0 Hz, 2 H), 7.04 (d, J = 9.0 Hz,
2 H), 3.88 (s, 3 H, OCH3) ppm. 13C NMR (100 MHz, CDCl3): δ
= 159.43, 159.24, 151.51, 145.42, 140.69, 137.95, 134.75, 133.39,
130.15, 129.65, 128.94, 128.78, 127.09, 121.97, 114.34, 55.80 ppm.
[7] B. J. Cowen, S. J. Miller, Chem. Soc. Rev. 2009, 38, 3102–3116,
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[10] Preliminary calculations (geometry optimization by molecular
mechanics, semiempirical and DFT methods) indicate that
compound 4a is more stable than the corresponding isomer 4aЈ
by around 23 kJ/mol.
[11] H. B. Henbest, E. R. H. Jones, I. M. S. Walls, J. Chem. Soc.
1950, 3646–3650.
IR (thin film): ν
= 3051.7 (w), 2949.5 (w), 2917.4 (w), 2840.6
˜
max
(w), 1661.9 (s), 1610. (m), 1501.8 (w), 1495.4 (m), 1091.8 (s) cm–1.
HRMS: calcd. for C18H14N3O2 [M + H]+ 304.1081; found
304.1082; calcd. for C18H13N3NaO2 [M + Na]+ 326.0900; found
326.0901.
[12] J. Andrieux, C. Vidal, G. Adam, M. Plat, D. Molho, Bull. Soc.
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47, 4365–4368; b) The use of unprotected anthranilic aldehyde
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8637–8640.
CCDC-788117 (for 5b) and -788116 (for 8) contain the supplemen-
tary crystallographic data for this paper. These data can be ob-
tained free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
Supporting Information (see also the footnote on the first page of
1
this article): H and 13C NMR spectra of all new compounds.
[18] For a related reaction upon xanthylium ions, see: R. Deschner,
U. Pindur, J. Heterocycl. Chem. 1984, 21, 1485–1488.
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3521–3525.
Acknowledgments
This work was supported by Dirección General de Investigación
Ciencia y Técnica (DGICYT) (project BQUCTQ2009-07758), Ge-
neralitat de Catalunya (project 2009SGR 1024), Barcelona Science
Park and Cooperación Internacional, Chile (Proyecto Fondecyt
1080132). Grupo Ferrer (Barcelona, Spain) is thanked for financial
support.
[20] B. P. Bandgar, A. V. Patil, V. T. Kamble, ARKIVOC 2007, 16,
252–259.
[21] For alternative access to related quinoline derivatives through
a Friedländer annulation, see: D. S. Bose, M. Idrees, N. M.
Jakka, J. V. Rao, J. Comb. Chem. 2010, 12, 100–110.
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Xu, J. Org. Chem. 2008, 73, 7361–7364.
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701–726.
[2] C. H. McAteer, M. Balasubramanian, M. Murugan in Compre-
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mon, Oxford, 2008, vol. 7, pp. 309–336.
[3] a) K. C. Nicolaou, J. A. Pfefferkorn, H. J. Mitchell, A. J.
Roecker, S. Barluenga, G. Q. Cao, R. L. Affleck, J. E. Lillig, J.
Am. Chem. Soc. 2000, 122, 9954–9967; b) V. V. Kouznetsov,
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199–201.
[23] G. K. Jnaneshwara, N. S. Shaikh, N. V. Bapat, V. H.
Deshpande, J. Chem. Res., Synop. 2000, 34–35.
[24] Around 237,000 substances with this core are listed in
SciFinder (2010), most being in biomedical patents.
[25] Although in this study only two salicylic aldehydes and one
anthranilic aldehyde have been used, taking into account the
reactivity precedents on related MBH-type reactions, we be-
lieve the methodology has a general application range, includ-
ing substrates with different substituents and substitution pat-
terns on the aromatic ring.
[26] The HBF4·SiO2 reagent was prepared accordingly to a litera-
ture procedure, see: A. K. Chakraborti, R. Gulhane, Tetrahe-
dron Lett. 2003, 44, 3521–3525.
Received: April 22, 2010
Published Online: August 16, 2010
Eur. J. Org. Chem. 2010, 5373–5379
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5379