The Baylis-Hillman approach to quinoline derivatives

Article abstract of DOI:10.1039/b608592j

Baylis-Hillman reactions of 2-nitrobenzaldehydes with various activated alkenes afford adducts that undergo reductive cyclisation to quinoline derivatives. The chemo- and regioselectivity of cyclisation appears to be influenced by the choice of both the substrate and the reagent system, and competing reactions have been observed. The Royal Society of Chemistry 2006.

Full text of DOI:10.1039/b608592j

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www.rsc.org/obc | Organic & Biomolecular Chemistry
The Baylis–Hillman approach to quinoline derivatives†
Oluwole B. Familoni,‡ Phindile J. Klaas, Kevin A. Lobb, Vusumzi E. Pakade and Perry T. Kaye*
Received 16th June 2006, Accepted 5th September 2006
First published as an Advance Article on the web 25th September 2006
DOI: 10.1039/b608592j
Baylis–Hillman reactions of 2-nitrobenzaldehydes with various activated alkenes afford adducts that
undergo reductive cyclisation to quinoline derivatives. The chemo- and regioselectivity of cyclisation
appears to be influenced by the choice of both the substrate and the reagent system, and competing
reactions have been observed.
The quinoline nucleus features prominently in compounds which
exhibit medicinal properties.1 Notable amongst these are syn-
thetic antimalarials2 such as chloroquine and primaquine, fungi-
cides such as halacrinate,3 antibacterial 4-quinolones such as
ciprofloxacin and norfloxacin,4 the HIV-1 protease inhibitor
saquinavir,5 and styrylquinolines as potential HIV-1 integrase
inhibitors.6 Not surprisingly, an array of synthetic methods has
been developed to access quinoline derivatives, including the
classic Skraup, Doebner–von Miller, Conrad–Limpach and Knorr
syntheses.2,7
apparent failure21 of the reaction with 2,5-dinitrobenzaldehyde
1i is attributed to steric shielding by the nitro groups on either
side of the carbonyl moiety effectively inhibiting nucleophilic
attack by the zwitterionic Baylis–Hillman intermediate. Attention
was given to optimising the reaction conditions by varying
reactant concentrations, the catalyst and the reaction time. Under
conditions found to be optimal, a solution of 2-nitrobenzaldehyde
1a (1 eq.), ethyl acrylate 2d (1.5 eq.) and DABCO (0.05 eq.) in a
minimal volume of chloroform was stirred at room temperature for
6 days; the resulting yield of the chromatographed product 3p was
thus increased from 46% to 95%. While the yield of compound
3o was also increased from 25% to 92%, these conditions
were not equally effective across the limited range of substrates
examined, and there is clearly room for improvement in certain
cases.
Selected Baylis–Hillman products 3 were then subjected to
reduction under various conditions, in the expectation that the
resulting 2-amino analogues would undergo cyclisation to the
desired quinoline derivatives. The methods of choice, following
examination of several reducing systems, were either catalytic
hydrogenation using a 10% palladium-on-carbon catalyst or
reduction using stannous chloride dihydrate. Use of the former
reagent system is illustrated in Scheme 2, the latter in Scheme 3.
Intramolecular cyclisation of the 2-amino derivatives 5 (Scheme 2)
might be expected to proceed either via conjugate addition (Path I)
or via nucleophilic attack at the carbonyl carbon (Path II). Under
catalytic hydrogenation conditions, however, Path II appears to
be favoured, affording initially, we suggest, the “tetrahedral inter-
mediate” 7. When the substituent ‘R’ is alkyl, nucleophilic attack
followed by dehydration leads to the quinoline and quinoline-
N-oxides 8 and 9, respectively, whereas when ‘R’ is alkoxy, acyl
substitution affords the quinolone derivatives 11, 12 and 13.
Ketone precursors 3 (R5 = CO.R) thus tend to yield quinoline
derivatives, while ester precursors 3 (R5 = CO2R) afford quinolone
derivatives. The formation of quinoline-N-oxides is attributed
to early cyclisation of incompletely reduced, nucleophilic, N-
oxygenated intermediates. In three cases, hydrogenation of the
alkene moiety alone afforded compounds 10a, d and g.
As part of our ongoing research into applications of the
Baylis–Hillman reaction in the construction of benzannulated
heterocycles,8 we reported, in a preliminary communication,9
the synthesis of quinoline, quinoline-N-oxide and 2-quinolone
derivatives from 2-nitrobenzaldehyde—an approach which ob-
viates use of the relatively inaccessible 2-aminobenzaldehydes
required in the Friedlander synthesis. Numerous applications
of Baylis–Hillman methodology in the preparation of quinoline
derivatives have since been reported.10–20 In this paper, we discuss:
the results of our studies into the generality of the Baylis–Hillman
approach to quinoline derivatives; competing reactions; and the
interconversion of the quinoline and quinoline-N-oxide products.
An extensive range of 2-nitrophenyl Baylis–Hillman adducts
3a–r (Scheme 1), required as potential precursors for the targeted
quinoline derivatives, were prepared by reacting the nitroben-
zaldehydes 1a–i with the activated alkenes 2a–f in the presence of
the nucleophilic catalyst, DABCO. Electron-releasing substituents
(e.g., hydroxy or alkoxy, as in compounds 1c, d, f and g) may
be expected to decrease electrophilicity and, hence, reactivity
at the aldehydic carbonyl carbon while (additional) electron-
withdrawing substituents (e.g., nitro, as in compounds 1h and 1i)
should enhance reactivity. However, the disparate yields observed
for the corresponding sets of products [3c (33%); 3d (24%); 3f
(73%); 3g (60%); 3j (90%) and 3m (14%)] and [3k (ca. 0%)21 and
3o (25%)] are hardly consistent with such expectations and may
well reflect the importance of steric, kinetic and thermodynamic
factors in a reaction that has been shown to be reversible.22 The
While product selectivity on reduction with stannous chloride
dihydrate also appears to be substrate-dependent, the pattern is
rather different. Under these conditions (Scheme 3), ketone pre-
cursors 3 (R5 = CO.R) favour conjugate addition and dehydration
or, more likely, concerted SNꢀ displacement of the hydroxyl group,
to give the N-hydroxydihydroquinolines 14; ester precursors
Department of Chemistry, Rhodes University, Grahamstown, 6140, South
Africa
† Electronic supplementary information (ESI) available: Analytical data
for compounds 33, 3d, 17, 3e, 3g, 3i, 3j, 3m, 3q, 3r, 8b, 9b, 8c, 9c, 8d, 10d,
8e, 9e, 8g, 10g, 9h, 8h, 12l, 13l, 11l, 12n, 13n, 19, 18, 14a, 14h, 15p, 20q and
20r. See DOI: 10.1039/b608592j
‡ Present address: Department of Chemistry, University of Lagos.
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Scheme 1
Scheme 2
3 (R5 = CO2R) behave similarly but cyclisation affords the
dihydroquinoline derivatives 15. Stannous chloride presumably
not only serves to reduce the nitro group but also to coordinate
with the hydroxyl group, thus facilitating cyclisation via the SN
pathway.
Given the formation of both quinolines and quinoline-N-oxides
on catalytic hydrogenation of ketone precursors (Scheme 2),
methods for interconverting these products were explored. Treat-
ment of 2,3-dimethylquinoline 8a with m-chloroperbenzoic acid
(MCPBA) in chloroform23 afforded the corresponding N-oxide
ꢀ
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major product (60%) being the bis-MVK adduct 17 (Scheme 5).
Shi et al.25 have reported the formation of similar adducts
in DABCO- or 4-(dimethylamino)pyridine (DMAP)-catalysed
reactions of certain arylaldehydes with MVK, and noted that
the yields of the adducts could be enhanced by increasing the
concentration of MVK. Interestingly, however, Shi et al.25 found
(in line with our own observations) that 2-nitrobenzaldehyde 1a
failed to afford the bis-MVK adduct, the sole product being the
normal Baylis–Hillman adduct 3a. It seems that the presence of
the 3-methoxy group is a critical factor in the formation of the bis-
MVK adduct 17, and detailed mechanistic and theoretical studies
are now being undertaken to explore substituent effects on these
transformations. The formation of the MVK dimer 16 in Baylis–
Hillman reactions involving MVK is well known.26
Catalytic hydrogenation of the bis-MVK adduct 17 gave a
mixture of the acyclic diketone 18 (43%) and the quinoline
derivative 19 (7%). The latter product arises from tandem (in
uncertain order!) reduction of the nitro group, cyclisation via
condensation of the resulting amino group with the unconjugated
ketone, hydrogenation of the conjugated alkene and dehydration
to afford the aromatic quinoline. Simple catalytic hydrogenation
of the conjugated alkene moiety in the substrate 17 would account
for the formation of the dominant, acyclic product 18; similar
Scheme 3
9a in 78% yield, while the N-oxide 9a was readily converted to
the quinoline 8a in 79% yield on treatment with phosphorus
tribromide in N,N-dimethylformamide (DMF).24 In order to
demonstrate “direct” syntheses of either the quinoline or the
quinoline-N-oxide derivatives from the Baylis–Hillman precursor
3a, crude mixtures of both products were treated (i) with PBr3
to afford the quinoline 8a in 86% yield; and (ii) with MCPBA to
afford the quinoline-N-oxide 9a in 85% yield (Scheme 4).
A number of unexpected side reactions have also been observed.
Thus, reaction of 8-methoxy-2-nitrobenzaldehyde 1d with MVK
2a afforded the Baylis–Hillman product 3d in only 24% yield, the
Scheme 4
Scheme 5
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hydrogenation of the alkene moiety in the Baylis–Hillman adducts
3a, d and g has already been noted (Scheme 2). However, catalytic
hydrogenation of the cyano- and phenylsulfonyl derivatives, 3q and
3r respectively, results in reduction of both the alkene and the nitro
moieties (presumably in that order) to afford the corresponding
acyclic systems 20 as the sole products.
Mat GCQ mass spectrometer and high-resolution (EI) mass
spectra on a VG70-SEQ double-focusing magnetic sector spec-
trometer (Cape Technikon Mass Spectrometry unit or Department
of Chemistry, University of the Witwatersrand). The general
synthetic procedures are illustrated by the following examples.
In summary, it is apparent that, while competing reactions
have been observed, cyclisation of the initial Baylis–Hillman
adducts 3 provides convenient access to a range of quinoline
derivatives and that significant chemoselectivity can be achieved
by judicious choice of the reactants and reagent systems. Thus,
catalytic hydrogenation of ketone precursors 3 (R5 = CO.R;
Scheme 6) yields quinolines 8 and quinoline-N-oxides 9 via
nucleophilic carbonyl addition and dehydration, whereas ester
precursors 3 (R5 = CO2R) afford quinolone derivatives 11–13
via acyl substitution. Reduction with SnCl2·2H2O, on the other
hand, favours cyclisation via conjugate addition to give 1,2-
dihydropyridine derivatives 14 or 15. However, it should be noted
that, in most cases, reaction conditions have not been optimised
and it is likely that product yields, in general, could be improved.
4-Hydroxy-3-methylene-4-(2-nitrophenyl)butan-2-one 3a
A solution of 2-nitrobenzaldehyde 1a (10.0 g, 66.0 mmol), methyl
vinyl ketone 2a (6.99 g, 99.0 mmol), DABCO (0.37 g, 3.3 mmol)
in CHCl3 (2 mL) was stirred in a stoppered flask at room
temperature for 7 days. The solvent was evaporated from the
resulting mixture in vacuo, and the crude product was purified
by flash chromatography on silica [using EtOAc–hexane (1 : 3)]
to afford, as yellow-brown crystals, 4-hydroxy-3-methylene-4-(2-
nitrophenyl)butan-2-one 3a (11.2 g, 75%), mp 79.5–82.5 ◦C (lit.17
◦
94–95 C)27 (Found, M+: 221.06672. Calc. for C11H11NO4: M,
221.06881); mmax(KBr)/cm−1 3361 (OH) and 1665 (C O); dH 2.34
=
(3H, s, CH3), 3.29 (1H, br s, OH), 5.77 and 6.15 (2H, 2 × s, CH2)
and 6.20 (1H, s, CH), 7.43 (1H, t, J 7.2 Hz, 4ꢀ-H), 7.62 (1H, t, J
7.2 Hz, 5ꢀ-H), 7.74 (1H, d, J 8.0 Hz, 6ꢀ-H) and 7.92 (1H, d, J 8.0 Hz,
3ꢀ-H); dC 26.4 (C-1), 67.9 (C-4), 124.6, 126.8, 128.9, 129.3, 133.8,
=
=
136.4, 148.1 and 148.9 (C CH2 and Ar–C) and 199.8 (C O); m/z
Experimental
221 (M+, 0.2%) and 43 (100).
MeltingpointsweredeterminedusingaKofler hot-stageapparatus
and are uncorrected. 400 MHz 1H and 100 MHz 13C NMR
spectra were recorded on Bruker AMX400 or AVANCE 400 MHz
spectrometers at 303 K in CDCl3 (or, where specified, in DMSO-
d6), and calibrated using solvent signals. Infrared spectra were
recorded on a Perkin Elmer FT-IR spectrum 2000 spectrometer.
Low-resolution (EI) mass spectra were obtained on a Finnigan-
Catalytic hydrogenation of 4-hydroxy-3-methylene-4-
(2-nitrophenyl)butan-2-one 3a
4-Hydroxy-3-methylene-4-(2-nitrophenyl)butan-2-one 3a (1.00 g,
4.50 mmol) was dissolved in ethanol (50 mL), 10% Pd–C catalyst
(0.16 g) was added, and the reaction mixture was stirred vigorously
Scheme 6
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under hydrogen at atmospheric pressure for 1.5 hours. The solvent
was evaporated in vacuo, and the crude product was dissolved
in CH2Cl2, dried (anhyd. MgSO4) and finally purified by flash
chromatography on silica [elution with hexane–EtOAc (3 : 1)] to
afford three fractions.
Interconversion of quinolines and quinoline-N-oxides
2,3-Dimethylquinoline 8a. To stirred solution of the
a
quinoline-N-oxide 9a (0.27 g, 1.6 mmol) and DMF (8 mL) at room
temperature under nitrogen was added PBr3 (0.69 mL, 2.4 mmol),
and the stirring was continued for 1 hour. The reaction mixture was
poured into a mixture of satd. aq. NaHCO3 (40 mL) and ice (10 g)
and the resulting mixture extracted with EtOAc (3 × 20 mL). The
extracts were combined, washed with satd. aq. NaHCO3 (10 mL)
and brine (10 mL), dried over anhydrous MgSO4 and filtered. The
solvent was evaporated in vacuo to give the quinoline 8a in 79%
yield.
Fraction 1. As light yellow crystals, 2,3-dimethylquinoline 8a31
◦
(0.13 g, 14%), mp 69–70 C (Found, M+: 157.08826. Calc. for
C11H11N: M, 157.08915); mmax(KBr)/cm−1 1663 (N C); dH 2.42
=
and 2.67 (6H, 2 × s, 2 × CH3), 7.43 (1H, t, J 7.6 Hz, 6-H), 7.58
(1H, t, J 7.6 Hz, 7-H), 7.68 (1H, d, J 8.0 Hz, 5-H), 7.80 (1H, s, 4-H)
and 7.99 (1H, d, J 8.0 Hz, 8-H); dC 19.7 and 24.2 (2 × CH3), 124.9,
125.8, 126.8, 128.4, 128.5, 130.4, 135.8, 146.2 and 159.1 (Ar–C);
m/z 157 (M+, 100%).
6-Hydroxy-2,3-dimethylquinoline 8c. The general procedure
described for the conversion of the quinoline-N-oxide 9a to 2,3-
dimethylquinoline 8a was followed, using 6-hydroxy-2,3-dimethyl-
quinoline-N-oxide 9c (0.22 g, 1.13 mmol), DMF (8 mL) and PBr3
(0.49 mL, 1.72 mmol) to give the quinoline 8c in 70% yield.
Fraction 2. As reddish-brown oil, 4-hydroxy-3-methyl-4-(2-
nitrophenyl)butan-2-one 10a (0.108 g, 8%) (lit.26 not detailed);
mmax(KBr)/cm−1 3390 (OH) and 1715 (C O); dH 1.18 (3H, d, J
=
7.2 Hz, CH3CH), 2.12 (3H, s, CH3CO), 3.09 (1H, m, 3-H), 3.83
(1H, br s, OH), 5.39 (1H, d, J 6.0 Hz, 4-H), 7.43 (1H, t, J 7.2 Hz,
5ꢀ-H), 7.61 (1H, t, J 7.6 Hz, 4ꢀ-H), 7.67 (1H, d, J 6.8 Hz, 3ꢀ-H) and
7.91 (1H, d, J 8.4 Hz, 6ꢀ-H); dC 14.6 (CH3CH), 30.3 (CH3CO),
51.9 (C-3), 71.4 (C-4), 124.5, 128.5, 128.7, 133.3, 137.4 and 139.9
2,3-Dimethylquinoline-N-oxide 9a. To a stirred solution of 2,3-
dimethylquinoline 8a (0.1 g, 0.6 mmol) in CHCl3 (0.6 mL) was
added MCPBA (0.11 g, 0.64 mmol) portionwise during 3 min at
room temperature. The mixture was stirred for 24 hours, following
which, excess MCPBA was destroyed (as indicated by wet starch-
iodide paper) by the addition of solid Na2S2O5. m-Chlorobenzoic
acid was precipitated from the solution as the potassium salt by the
addition, with stirring, of solid K2CO3. The solids were removed
by filtration, and the solvent was removed from the filtrate in vacuo
to give a yellow solid. lH NMR analysis revealed the presence of
some unreacted starting material, and further MCPBA (0.1 g) was
added and the mixture stirred for another 24 hours. After work-
up, 2,3-dimethylquinoline-N-oxide 9a was obtained as a yellow
powder (0.09 g, 78%).
=
(Ar–C) and 213.5 (C O).
Fraction 3. As brown crystal◦s, 2,3-dimethylquinoline-N-oxide
9a9 (0.59 g, 66%), mp 123–125 C (Found, M+: 173.08338. Calc.
for C11H11NO: M, 173.08406); mmax(KBr)/cm−1 1650 (N C) and
=
1318 (N–O); dH 2.45 and 2.68 (6H, 2 × s, 2 × CH3), 7.45 (1H, s,
4-H), 7.51 (1H, t, J 7.6 Hz, 6-H), 7.63 (1H, t, J 7.6 Hz, 7-H), 7.68
(1H, d, J 8.0 Hz, 5-H) and 8.68 (1H, d, J 8.8 Hz, 8-H); dC 14.7
and 20.2 (2 × CH3), 119.6, 125.1, 127.1, 127.7, 128.1, 129.2, 130.8,
139.9 and 146.4 (Ar–C); m/z 173 (M+, 70%) and 156 (100).
Selective in situ oxygenation and deoxygenation reactions
Stannous chloride reduction of methyl 3-hydroxy-2-methylene-3-
(2-nitrophenyl)propanoate 3l
A mixture of 3-hydroxy-2-methylene-3-(2-nitrophenyl)butan-2-
one 3a (0.50 g, 2.3 mmol) and 10% Pd–C catalyst (40 mg) in
methanol (40 mL) was subjected to hydrogenation (following the
general method) for 3 h. The catalyst was filtered off and the
solvent evaporated from the filtrate in vacuo. The residue was
dissolved in CH2Cl2, dried (anhydrous MgSO4), and the solvent
evaporated in vacuo to afford, as a brown oil, a mixture of
2,3-dimethylquinoline 8a and 2,3-dimethylquinoline-N-oxide 9a
(0.41 g).
To
a solution of methyl 3-hydroxy-2-methylene-3-(2-nitro-
phenyl)propanoate 3l (1.19 g, 5.0 mmol) was added a solution
of SnCl2·2H2O (5.64 g, 25 mmol) in MeOH (10 mL). The resulting
mixture was stirred at 70 ◦C for 5 h and then, after cooling, poured
into ice, basified (pH 7–8) using aq. NaHCO3, and extracted
repeatedly with EtOAc. The combined organic extracts were
washed (satd. aq. NaCl) and dried (anhyd. Na2SO4). Evaporation
of the solvent in vacuo afforded the crude product, which was
purified by flash chromatography on silica [elution with hexane–
EtOAc (1 : 3)] to give methyl 1,2-dihydroquinoline-3-carboxylate
15l, as an off-white powder (0.47 g, 50%), mp 175–177 ◦C
(Found M+: 189.07852. C11H11NO2 requires M, 189.07898); dH
3.55 (3H, s, CH3), 4.56 (2H, s, CH2), 7.21 (1H, m, Ar–H), 7.45
(1H, m, Ar–H), 7.47 (1H, m, Ar–H), 7.55 (1H, d, Ar–H), 7.87
(1H, s, 4-H) and 12.27 (1H, br s, NH); dC 59.0 (CH3), 69.3 (C-2),
Formation of 2,3-dimethylquinoline-N-oxide 9a from the mixture
of 8a and 9a. To a stirred solution of the foregoing mixture
(0.135 g) of 2,3-dimethylquinoline 8a and 2,3-dimethylquinoline-
N-oxide 9a in CHCl3 (0.5 mL) was added MCPBA (0.107 g),
portionwise, over 15 minutes at room temperature. The mixture
was stirred for 24 hours, before excess MCPBA was destroyed
by the addition of solid Na2S2O5. m-Chlorobenzoic acid was
precipitated from solution as the potassium salt by the addition of
solid K2CO3. The solids were removed by filtration and the filtrate
dried (MgSO4); the solvent was removed in vacuo to give, as yellow
crystals, 2,3-dimethylquinoline-N-oxide 9a (0.116 g, 85%)
=
115.8, 120.0, 122.6, 127.6, 129.9, 130.0, 136.3 and 137.6 (C CH
+
=
and Ar–C) and 163.2 (C O); m/z 189 (M , 18%) and 159 (100).
Compounds 3b,28 3d,29 3f,17 3h,17 3l,17 3n,15 3o,30 3p,17 8b,31
8d,32 8g,33 8h,34 9a,35 9h,36 12l,37 12n,38 13l39 and 13n40 have also
been reported by other researchers; data for compound 9a were
also reported in our preliminary communication.9 Analytical data
for other products are provided as Electronic Supplementary
Information (ESI)†.
Formation of 2,3-dimethylquinoline 8a from the mixture of 8a
and 9a. A mixture (0.125 g) of 2,3-dimethylquinoline 8a and
2,3-dimethylquinoline-N-oxide 9a in DMF (3 mL) was stirred
at room temperature. PBr3 (0.2 mL, 0.7 mmol) was added and
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stirring continued for 1 hour. The mixture was poured into satd.
aq. NaHCO3, and the resulting mixture extracted with EtOAc
(3 × 20 mL). The extracts were combined, washed with satd.
aq. NaHCO3 and brine, dried (anhyd. MgSO4) and filtered. The
solvent was removed from the filtrate in vacuo to give, as yellow
crystals, 2,3-dimethylquinoline 8a (0.107 g, 86%).
15 D. K. O’Dell and K. M. Nicholas, Tetrahedron, 2003, 59(6), 747–754.
16 K. Y. Lee and J. N. Kim, Bull. Korean Chem. Soc., 2002, 23(7), 939–940.
17 D. Basavaiah, R. M. Reddy, N. S. Kumaragurubaran and D. S. Sharada,
Tetrahedron, 2002, 58(19), 3693–3697.
18 J. N. Kim, H. S. Kim, J. H. Gong and Y. M. Chung, Tetrahedron Lett.,
2001, 42(47), 8341–8344.
19 J. N. Kim, K. Y. Lee, H.-S. Ham, H. R. Kim and E. K. Ryu, Bull.
Korean Chem. Soc., 2001, 22(2), 135–136.
20 J. N. Kim, K. Y. Lee, H. S. Kim and T. Y. Kim, Org. Lett., 2000, 2(3),
343–345.
Acknowledgements
21 The attempted Baylis–Hillman reaction using ethyl vinyl ketone 2b and
2,6-dinitrobenzaldehyde 1i afforded only a trace amount of material,
the 1H NMR spectrum of which was consistent with the desired product
3k.
The authors thank the National Research Foundation (NRF) for
bursaries (to P. J. K. and V. E. P.) and Rhodes University and the
NRF (GUN no. 2047288) for generous financial support.
22 E. Ciganek, Org. React., 1997, 51, 206.
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24 D. H. Bremmer, A. D. Dunn, K. A. Wilson, K. R. Sturrock and G.
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