Synthesis of 3-amlno-8-azachromans and 3-amino-7-azabenzofurans via inverse electron demand dlels-alder reaction

Article abstract of DOI:10.1002/ejoc.200900191

The synthesis of 3-amino-8-azachromans and 3-amino-7-azabenzofurans derivatives is reported. The synthetic strategy is based on an inverse electron demand Diels-Alder approach, which employs 1,2,4-triazines that are judiciously substituted with amino alkynols. This approach permits the variation of the substituent on the aromatic core and on the amine moiety, as well as of the size of the nonaromatic ring.

Full text of DOI:10.1002/ejoc.200900191

FULL PAPER
DOI: 10.1002/ejoc.200900191
Synthesis of 3-Amino-8-azachromans and 3-Amino-7-azabenzofurans via
Inverse Electron Demand Diels–Alder Reaction
Eduard Badarau,[a,b] Franck Suzenet,*[a] Adriana-Luminita Fînaru,[b] and
¸
Gérald Guillaumet[a]
Keywords: Heterocycles / Cycloaddition / Polycycles
The synthesis of 3-amino-8-azachromans and 3-amino-7-
variation of the substituent on the aromatic core and on the
amine moiety, as well as of the size of the nonaromatic ring.
azabenzofurans derivatives is reported. The synthetic strat-
egy is based on an inverse electron demand Diels–Alder ap-
proach, which employs 1,2,4-triazines that are judiciously
substituted with amino alkynols. This approach permits the
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
Introduction
Most of the new biologically active compounds used in
drug therapy are heterocycle-based derivatives because of
the beneficial roles played by the incorporated heteroatoms
at each step of the drug’s action, from oral bioavailability
to the more favorable interactions within the specific pro-
tein target. Nitrogen and oxygen are the most widely used
heteroatoms in the construction of drug candidates. Even if
the synthesis of such heterocycles is generally more difficult
than that of their “heteroatom-free” analogues, the en-
hanced biological properties justify the effort.
Figure 1. Isosteric relationship between chroman (A/B) and aza-
chroman (C) derivatives.
One heterocycle that has proven its potential in the con-
struction of therapeutic molecules is the chroman scaffold.
Its favorable interactions with the serotoninergic,[1] dopa-
minergic,[1,2] and opioid receptors,[3] just to cite few exam-
ples, have been reported. One step further in optimizing the
discovered hits, both in terms of affinity and selectivity for
a specific target, could be achieved by increasing the
number of heteroatoms incorporated in the main skeleton.
In this paper, we report the synthesis of some analogues of
the serotoninergic 5-HT7R chroman-based ligands A (Ki =
13.4 nM)[4] and B (Ki = 5.29 nM for R = Me and Ki =
6.44 nM for R = Pr):[5] the 3-amino-8-azachroman and 3-
amino-7-azabenzofuran derivatives C (Figure 1).
The chosen synthetic route involves the construction of
the central heterocycle via a key intramolecular inverse elec-
tron demand hetero-Diels–Alder reaction between a judi-
ciously substituted 1,2,4-triazine and an alkyne. This meth-
odology has already been described in the literature, espe-
cially by Seitz.[6,7]
Previously, only simple, unsubstituted 2,3-dihydropy-
rano- or furo[2,3-b]pyridines could be accessed in studies
by Taylor[8,9] and more recently by our team.[10] The func-
tionalization on the nonaromatic ring was much less exten-
sively studied compared to the functionalization of the aro-
matic ring. There are a few examples of halogen and hy-
droxy substitution from the studies of Choi et al.[11] and
Shiotani et al.[12–14] A more recent article published by our
group explored the synthesis of 3- or 4-hydroxy deriva-
tives.[15] Using a more convergent strategy, we designed the
synthesis of 3-aminoazachromans C (Figure 1) as potential
5-HT7 ligands.
[a] Institut de Chimie Organique et Analytique, Université d’Or-
léans, UMR-CNRS 6005, UFR Sciences,
BP 6759, Rue de Chartres, 45067 Orléans Cedex 2, France
E-mail: franck.suzenet@univ-orleans.fr
[b] Centrul de Cercetare “Chimie Aplicata s¸i Inginerie de Proces”,
˘
Universitatea din Bacau,
˘
Calea Ma˘ra˘s¸esti, nr. 157, 600115 Baca˘u, Romania
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.200900191.
Eur. J. Org. Chem. 2009, 3619–3627
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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E. Badarau, F. Suzenet, A.-L. Fînaru, G. Guillaumet
FULL PAPER
Results and Discussion
First, we planned to validate the synthetic approach by
obtaining the 7-substituted azachroman derivatives follow-
ing the retrosynthetic scheme presented below. This molecu-
lar target is closely connected to the already proven stability
and reactivity of 5-substituted triazines.[15] Thus, the inter-
mediate II could be obtained by the substitution of a leav-
ing group (in this case methylsulfonyl) incorporated in the
triazine III with the alkynol IV (Scheme 1).
Scheme 2. (a) 1,3-Dimethoxybenzene or 2-bromo-1,3-dimethylben-
zene, nBuLi, THF, –78 to 25 °C, 4 h; (b) DDQ, toluene, 60 °C, 3 h;
(c) mCPBA, DCM, 0 °C to 25 °C, 3 h.
In the first case, the Garner aldehyde, a synthon widely
used in various syntheses due to its pre-existing chiral cen-
tre,[18–20] was prepared on a large scale (50 mmol) following
the procedure initially described by Garner.[21] Starting
from commercially available ,-serine, the aldehyde was
obtained after 4 steps in 55% overall yield. The Bestmann–
Ohira modification[22,23] of the Seyferth–Gilbert homologa-
tion[24,25] gave the terminal alkyne in 84% yield.[26] Finally,
acidic removal of both protective groups followed by pro-
tecting the amine as a benzyl carbamate (Cbz) gave access
to the desired amino alcohol intermediate 4 (Scheme 3).[26]
Scheme 1. Retrosynthetic analysis.
Besides the main synthetic reasons, it should be men-
tioned that following this approach, new chroman isosteres
could be obtained with the aryl substituent at a previously
unexplored position on the aromatic core, compared with
the reference molecules A and B.
Synthesis of 3-Amino-8-azachromans or 7-Azabenzofurans
ortho-Substituted to the Pyridine Nitrogen
The 5-substituted triazine intermediate III was prepared
by exploiting the relative reactivity of the different positions
of the 1,2,4-triazine ring (C5 Ͼ C6 Ͼ C3) towards organo-
metallic reagents.[16,17] Thus, the nucleophilic addition of
the aryl anion proceeded smoothly in position 5 of 3-(meth-
ylsulfanyl)-1,2,4-triazine. The aryl substituents were chosen
Scheme 3. (a) 1-Diazo-2-oxopropylphosphonate, K2CO3, MeOH,
25 °C, 12 h (84%); (b) i) TFA, MeOH, 25 °C, 2 h, ii) CbzCl,
K2CO3, dioxane, satd. NaHCO3, 25 °C, 12 h (87%).
The optimized synthesis of the second alcohol intermedi-
in connection with the biological activities of the 5-HT7 ate started from commercially available ethyl 2-aminoma-
chroman-based reference ligands A and B.[4,5] The corre- lonate. After preliminary protection of the amine moiety as
sponding aryl anions were obtained by direct ortho-met- a Cbz group, the alkylation with propargyl bromide was
alation of 1,3-dimethoxybenzene with nBuLi, or, in the case carried out on the activated CH under basic conditions.[27]
of the 1,3-dimethylphenyl substituent, via a halogen–metal Subsequently, one of the two carboxylates was hydrolysed
exchange between nBuLi and 2-bromo-1,3-dimethylben- and decarboxylated using lithium bromide and water in re-
zene. The isolated 2,5-dihydro-1,2,4-triazines 1 were rearo- fluxing DMF.[28] A last step required the reduction of the
matized to the corresponding triazines 2 by action of DDQ remaining ester moiety. Because lithium aluminium hydride
in toluene at 60 °C. The subsequent mCPBA oxidation step accomplished the reduction to the desired product with a
gave access to the sulfones 3 in very good overall yield maximum yield of 30%, a softer hydride, lithium borohyd-
(Scheme 2).
ride, was used instead, to give amino alcohol 7 in 89% yield
The synthesis of the required alcohol intermediates IV (Scheme 4).[29]
followed a different path depending on the desired final
With both key alkynol intermediates prepared, the syn-
compounds. Thus, in the case of 2,3-dihydrofuro[2,3-b] pyr- thesis was brought forward by substitution of the methyl-
idines (I, n = 0) we chose a Garner aldehyde approach, sulfonate of triazines 3 with the corresponding lithium alk-
while for the pyrano analogues (I, n = 1) we developed a oxides of 4 and 7 (Scheme 5). It is worth mentioning that
malonate approach.
preliminary attempts to carry out this reaction, conducted
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Synthesis of Chroman Isosteres
in correlation with the reference active molecules A and B,
allowed us to obtain the corresponding dialkylated com-
pounds 10a–f (Scheme 6, Table 1).[31]
Synthesis of 3-Amino-8-azachromans or 7-Azabenzofurans
meta-Substituted to the Pyridine Nitrogen
Because the proposed synthetic route was successfully
applied to the ortho-substituted derivatives, we further
planned to obtain the direct analogues of ligand A in the
Scheme 4. (a) CbzCl, BTSA, Et2O, 0 to 25 °C, 1 h (90%); (b) pro- pyridine series. Thus, for the synthesis of meta-substituted
pargyl bromide, EtONa, EtOH, 80 °C, 3 h (81%); (c) LiBr, H2O,
DMF, 155 °C, 12 h (85%); (d) LiBH4, THF, MeOH, –10 to 25 °C,
was envisaged. After the synthesis of the particularly un-
1 h (89%).
derivatives, the same synthetic approach described above
stable 3-(methylsulfonyl)-1,2,4-triazine following the proto-
cols described in the literature,[9,15] the next substitution
on the intermediates protected by the tert-butoxycarbonyl
carbamate group, gave the formation of an oxazolidinone
as a side product.
step was performed under the same conditions as for the 5-
substituted triazine (see Scheme 5). This reaction did not
provide the desired compound, but only the oxazolidinone
side product. The replacement of nBuLi with sodium hy-
dride to generate the alkoxide did not lead to any improve-
ment (Scheme 7).
Scheme 5. Synthesis of the Diels–Alder precursors.
Scheme 7. Preliminary assay for non-substituted 1,2,4-triazine.
The inverse electron demand hetero-Diels–Alder cyclo-
additions of triazine substrates were conducted under mi-
crowave irradiation, using chlorobenzene as the solvent.
Softer reaction conditions for the five-membered cycload-
dition derivatives were in agreement with published data.[15]
Subsequent carbamate hydrogenolysis[30] afforded the free
amines, which were used for the next step without further
purification. The final reductive amination step, conducted
At this stage, it seemed important to try different protect-
ing groups of the amine moiety that did not incorporate
potential leaving groups in their structures.
Thus, after the N-acetyl protection of ethyl 2-aminoma-
lonate, the synthesis of the corresponding alkynol followed
the same route as for compound 7 (see Scheme 4). With this
new protective group, the difficulties around the aromatic
nucleophilic substitution were avoided, and alkyne 11 was
isolated in 75% yield. Unfortunately, the subsequent Diels–
Alder cycloaddition gave only degradation products of the
starting material under all the different experimental condi-
tions we used: 180–220 °C as the temperature range, PhCl,
1,2-dichlorobenzene and DMF as solvents, 15 min to 1 h as
time interval (Scheme 8).
Scheme 6. (a) mw, PhCl, 200–220 °C, 1.5 h, 9a–c; (b) i) H2, Pd/C,
HCl, EtOH, 25 °C, 3 h; ii) HCHO or EtCHO, NaBH3CN,
CH3COOH, MeOH, 25 °C, 12 h, 10a–f.
Table 1. Yields for steps a and b (Scheme 6).
n
R
Yields
Step a
Step b
R1 = R2 = Me R1 = R2 = Pr
0
1
1
OMe
OMe
Me
9a, 95%
9b, 83%
9c, 73%
10a, 71%
10c, 70%
10e, 86%
10b, 40%
10d, 67%
10f, 80%
Scheme 8. Preliminary cycloaddition assays.
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E. Badarau, F. Suzenet, A.-L. Fînaru, G. Guillaumet
FULL PAPER
Similar negative results were obtained in the case of herein opens the way to the synthesis of many hetero-ana-
benzophenone imine as the protecting group. To overcome logues of compounds with already-proven biological activi-
this synthetic issue, a new modification was considered. Our ties. Our particular azachroman analogues 10a–f and 17a–b
attention was concentrated this time to the diene partner of were tested for their binding affinities with 5-HT7 receptors
the Diels–Alder cycloaddition, the 1,2,4-triazine. Starting according to the protocols described in the literature,[32] and
from the more stable 5-methyl-1,2,4-triazine[9] and N-Cbz they were found inactive. Using an analogous methodology,
alkynol 7, the SNAr and cycloaddition reactions were in this further studies are currently underway in order to obtain
case successful, and led to the desired furo- or pyranopyrid- the enantiopure derivatives. These results will be published
ines 14 (Scheme 9).
in the near future.
Experimental Section
General: Microwave-assisted reactions were carried out in a Biotage
Initiator microwave synthesis instrument equipped with a safety
pressure shutoff. 1H NMR and 13C NMR were recorded with
Bruker Avance DPX250 (250.131 MHz) and Bruker Avance II
(400 MHz) spectrometers in CDCl3, using tetramethylsilane as an
internal standard. Multiplicities were determined by the DEPT 135
sequence; chemical shifts are reported in parts per million (ppm).
Coupling constants are reported in units of Hertz [Hz]. Infrared
(IR) spectra were recorded with a Perkin–Elmer Paragon 1000 PC
FTIR using NaCl films or KBr pellets. Low-resolution mass spec-
tra (MS) were recorded with a Perkin–Elmer SCIEX AOI 300 spec-
trometer. High-resolution mass spectra were recorded with a Q-Tof
micro Waters spectrometer. Melting points were determined in
open capillary tubes and are uncorrected. Flash chromatography
was performed on Merck 40–70 nM (230–400 mesh) silica gel un-
der nitrogen pressure. Thin-layer chromatography (TLC) was car-
ried out on Merck silica gel 60 F254 precoated plates. Visualization
was made with ultraviolet light (λ = 254 nm) and, if necessary, an
ethanolic solution of potassium permanganate. Reactions requiring
anhydrous conditions were performed under nitrogen. Toluene and
tetrahydrofuran were freshly distilled from sodium/benzophenone
under argon prior to use. Dichloromethane was distilled from cal-
cium hydride under argon prior to use.
Scheme 9. (a) mCPBA, DCM, 0 °C to 25 °C, 1 h (67%); (b) 7,
nBuLi, THF, –78 °C to 25 °C, 2 h; (c) i) for n = 0: PhCl, 180 °C,
1 h, ii) for n = 1: PhCl, 220 °C, 1.5 h.
The resulting cycloadducts 14 were halogenated with
bromine in refluxing methanol.[9] The bromo derivatives
were subsequently engaged in a Suzuki coupling reaction
with 1,3-dimethylphenylboronic acid to afford compounds
16. A further hydrogenation step followed by a reductive
amination step led to the final compounds 17 (Scheme 10).
Synthesis of 5-Aryl-3-(methylsulfonyl)-1,2,4-triazines 3
5-(2,6-Dimethoxyphenyl)-3-(methylsulfanyl)-2,5-dihydro-1,2,4-tri-
azine (1a): At –78 °C and under nitrogen, n-butyllithium (1.6  in
THF, 75.6 mL, 121 mmol) was added to a solution of 1,3-dimeth-
oxybenzene (14.40 mL, 110 mmol) in anhydrous THF (140 mL).
The mixture was vigorously stirred for 1 h at 0 °C and two ad-
ditional hours at room temp. before adding slowly a solution of 3-
(methylsulfanyl)-1,2,4-triazine (20 g, 157.3 mmol) in anhydrous
THF (20 mL). After the complete consumption of the starting ma-
terial, the reaction was quenched with satd. NaCl (100 mL), and
then extracted with ethyl acetate (3ϫ100 mL). The organic layer
was dried with MgSO4, evaporated, and purified by silica gel col-
umn chromatography (petroleum ether/ethyl acetate, 8:2) to give
Scheme 10. (a) Br2, NaHCO3, MeOH, 65 °C, 1–3 h; (b) Pd-
(PPh3)4, 1,3-dimethylphenylboronic acid, toluene, EtOH, 110 °C,
24 h; (c) i) H2, Pd/C, HCl 1 , EtOH, 25 °C, 12 h; ii) HCHO,
NaBH3CN, CH3COOH, MeOH, 25 °C, 24 h.
the desired compound 1a; yield 21.94 g (75%); white solid; m.p.
1
141–143 °C. IR (KBr): ν = 3284, 2928, 1599, 1250 cm–1. H NMR
˜
(250 MHz, CDCl3, 25 °C): δ = 7.29 (br. s, 1 H), 7.26 (t, J = 8.4 Hz,
1 H), 6.72 (d, J = 1.4 Hz, 1 H), 6.60 (d, J = 8.4 Hz, 2 H), 5.10 (d,
J = 1.4 Hz, 1 H), 3.80 (s, 6 H), 2.41 (s, 3 H) ppm. 13C NMR
(62.9 MHz, CDCl3, 25 °C): δ = 159.1 (C), 152.9 (C), 143.0 (CH),
129.5 (CH), 116.6 (C), 104.7 (2 CH), 56.1 (2 CH3), 50.2 (CH),
14.1 (CH3) ppm. MS: m/z = 266 [M + H]+. HRMS: calcd. for
C12H15N3O2S 266.0963, found 266.0951.
Conclusions
In conclusion, in the present article we designed the syn-
thesis of 3-amino-2,3-dihydrofuro- and 3,4-dihydro-2H-
pyrano[2,3-b]pyridines by applying the inverse electron de-
mand Diels–Alder cycloaddition methodology. For this key
step, we also emphasized the differences of reactivity of a
few triazine substrates in correlation with the protecting
5-(2,6-Dimethylphenyl)-3-(methylsulfanyl)-2,5-dihydro-1,2,4-triazine
(1b): To
a stirred solution of 2-bromo-1,3-dimethylbenzene
(10.1 mL, 75.49 mmol) in anhydrous THF (150 mL) under nitro-
group of the amine moiety. The synthetic route exposed gen, n-butyllithium (1.5  in THF, 54.5 mL, 81.78 mmol) was
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Synthesis of Chroman Isosteres
added at –78 °C. After 45 min at –78 °C, a solution of 3-(methylsul-
fanyl)-1,2,4-triazine (8.0 g, 62.91 mmol) in anhydrous THF
(10 mL) was added via cannula over 15 min. The reaction mixture
was stirred for 45 min at –78 °C, warmed slowly to room tempera-
ture over 1.5 h, and subsequently quenched with 10% NaHCO3
(100 mL). The layers were separated, the water layer was extracted
with ethyl acetate (3ϫ100 mL), the combined organic layers dried
with MgSO4, and the solvent was removed under reduced pressure.
The crude product was purified by column chromatography (petro-
leum ether/ethyl acetate, 8:2) to afford compound 1b; yield 12.66 g
J = 8.5 Hz, 2 H), 3.78 (s, 6 H), 3.46 (s, 3 H) ppm. 13C NMR
(62.9 MHz, CDCl3, 25 °C): δ = 166.6 (C), 158.6 (C), 158.0 (C),
153.9 (CH), 133.8 (CH), 111.4 (C), 104.4 (2 CH), 56.2 (2 CH3),
39.8 (CH3) ppm. MS: m/z = 296.5 [M + H]+. HRMS: calcd. for
C12H13N3O4S 296.0705, found 296.0714.
5-(2,6-Dimethylphenyl)-3-(methylsulfonyl)-1,2,4-triazine (3b): Yield
5.17 g (87%); yellow solid; m.p. 146–148 °C. IR (KBr): ν = 3000,
˜
1543, 1327, 1138, 764 cm–1. 1H NMR (250 MHz, CDCl3, 25 °C): δ
= 9.40 (s, 1 H), 7.34 (t, J = 7.6 Hz, 1 H), 7.19 (d, J = 7.6 Hz, 2 H),
3.53 (s, 3 H), 2.17 (s, 6 H) ppm. 13C NMR (62.9 MHz, CDCl3,
25 °C): δ = 166.9 (C), 162.4 (C), 152.9 (CH), 136.4 (C), 132.4 (C),
131.0 (CH), 128.8 (2 CH), 39.8 (CH3), 20.5 (2 CH3) ppm. MS: m/z
= 264.0 [M + H]+. HRMS: calcd. for C12H13N3O2S 264.0807,
found 264.0820.
(86%); yellow solid; m.p. 119–121 °C. IR (KBr): ν = 3392, 3014,
˜
1610, 1420, 1142, 756 cm–1. 1H NMR (250 MHz, CDCl3, 25 °C): δ
= 8.15 (s, 1 H), 7.06–7.19 (m, 3 H), 6.75 (d, J = 1.0 Hz, 1 H), 4.88
(d, J = 1.0 Hz 1 H), 2.45 (s, 3 H), 2.34 (s, 6 H) ppm. 13C NMR
(62.9 MHz, CDCl3, 25 °C): δ = 152.8 (C), 142.6 (CH), 137.4 (C),
135.8 (C), 129.3 (2 CH), 127.8 (CH), 55.5 (C), 21.1 (2 CH3), 13.9
(CH3) ppm. MS: m/z = 234.5 [M + H]+. HRMS: calcd. for
C12H15N3S 234.1065, found 234.1077.
Benzyl (1-Hydroxybut-3-yn-2-yl)carbamate (4): A solution of tert-
butyl
4-ethynyl-2,2-dimethyl-oxazolidine-3-carboxylate
(2 g,
8.88 mmol; for its preparation see Meffre et al.[26]) in methanol
(8 mL) was slowly poured into TFA (40 mL) at 25 °C. After 2 h of
vigorous stirring, the reaction mixture was coevaporated with Et2O
(3ϫ50 mL; never to dryness). Dioxane (40 mL) and satd. NaHCO3
(40 mL) were added, and the pH was adjusted to 8 by addition of
solid NaHCO3. Subsequently, potassium carbonate (1.6 g,
11.54 mmol) and benzyl chloroformate (1.52 mL, 10.66 mmol)
were added, and the mixture was stirred overnight. The reaction
was quenched by addition of water (50 mL), the aqueous layer was
extracted with AcOEt (3ϫ100 mL), the combined organic extracts
were dried with MgSO4 and the solvent was removed under re-
duced pressure. The crude amino alcohol was purified by flash col-
umn chromatography (petroleum ether/ethyl acetate, 5:5); yield
General Procedure for the Preparation of Triazines 2a and 2b: DDQ
(45.23 mmol) was added to a suspension of the corresponding 2,5-
dihydro-1,2,4-triazine 1a or 1b (36 mmol) in toluene (300 mL). The
reaction mixture was heated at 60 °C for 2 h, cooled to room tem-
perature, and poured into satd. K2CO3 (200 mL). The layers were
separated, and the aqueous layer was extracted with DCM
(3ϫ200 mL). The combined organic layers were dried with
MgSO4, and the solvent was removed under reduced pressure. The
crude product was purified by column chromatography (petroleum
ether/ethyl acetate, 7:3) to afford the corresponding triazines 2a and
2b.
5-(2,6-Dimethoxyphenyl)-3-(methylsulfanyl)-1,2,4-triazine
(2a):
1.87 g (87%); white solid; m.p. 60–62 °C. IR (KBr): ν = 3287, 2954,
˜
Yield 8.08 g (85%); yellow solid; m.p. 102–104 °C. IR (KBr): ν =
˜
1
2108, 1700, 1538, 1252, 1035, 752, 696 cm–1. H NMR (250 MHz,
1
2931, 1600, 1258, 1128 cm–1. H NMR (250 MHz, CDCl3, 25 °C):
CDCl3, 25 °C): δ = 7.30–7.38 (m, 5 H), 5.37–5.38 (m, 1 H), 5.12 (s,
2 H), 4.58–4.62 (m, 1 H), 3.74 (t, J = 6.1 Hz, 2 H), 2.44 (t, J =
6.1 Hz, 1 H), 2.35 (d, J = 2.4 Hz, 1 H) ppm. 13C NMR (62.9 MHz,
CDCl3, 25 °C): δ = 156.0 (C), 136.1 (C), 128.7 (CH), 128.4 (2 CH),
128.3 (2 CH), 80.6 (C), 72.9 (CH), 67.4 (CH2), 65.3 (CH2), 45.7
(CH) ppm. MS: m/z = 220.5 [M + H]+, 242.0 [M + Na]+. HRMS:
calcd. for C12H13NO3 242.0793, found 242.0799.
δ = 8.89 (s, 1 H), 7.38 (t, J = 8.5 Hz, 1 H), 6.63 (d, J = 8.5 Hz, 2
H), 3.75 (s, 6 H), 2.68 (s, 3 H) ppm. 13C NMR (62.9 MHz, CDCl3,
25 °C): δ = 173.3 (C), 158.4 (C), 155.1 (C), 147.9 (CH), 132.3 (CH),
112.8 (C), 104.3 (2 CH), 56.1 (CH3), 14.1 (CH3) ppm. MS: m/z =
264.0 [M + H]+. HRMS: calcd. for C12H13N3O2S 264.0807, found
264.0803.
5-(2,6-Dimethylphenyl)-3-(methylsulfanyl)-1,2,4-triazine (2b): Yield
7.91 g (95%); yellow solid; m.p. 82–84 °C. IR (KBr): ν = 3010,
˜
Synthesis of the Amino Alcohol Intermediate 7
1
1530, 1239, 784, 756 cm–1. H NMR (250 MHz, CDCl3, 25 °C): δ
Diethyl 2-[(Benzyloxycarbonyl)amino]-2-(prop-2-ynyl)malonate (5):
= 8.85 (s, 1 H), 7.25 (dd, J = 6.7, 8.4 Hz, 1 H), 7.11 (apparent d,
J = 7.3 Hz, 2 H), 2.65 (s, 3 H), 2.10 (s, 6 H) ppm. 13C NMR
(62.9 MHz, CDCl3, 25 °C): δ = 173.9 (C), 159.1 (C), 146.3 (CH),
135.7 (C), 133.8 (C), 129.7 (CH), 128.1 (2 CH), 20.2 (2 CH3), 13.8
(CH3) ppm. MS: m/z = 232.5 [M + H]+. HRMS: calcd. for
C12H13N3S 232.0908, found 232.0919.
Diethyl
2-[(benzyloxycarbonyl)amino]malonate[27]
(12 g,
38.79 mmol) was added to a solution of sodium ethanolate (1 ,
40.7 mL, 40.73 mmol) at room temperature. After 30 min of vigor-
ous stirring at room temperature, propargyl bromide (80% in tolu-
ene, 4.6 mL, 42.67 mmol) was added, and the reaction mixture was
refluxed for 3 h. The solvent was evaporated, and the residue was
hydrolyzed with satd. NaCl (30 mL). The aqueous phase was ex-
tracted with AcOEt (3ϫ100 mL), the combined organic layers
were dried with MgSO4, and the solvent was removed under re-
duced pressure. Subsequent purification of the crude alkylation de-
rivative by flash column chromatography (petroleum ether/ethyl
acetate, 9:1) yielded the desired alkyne 5; yield 11.49 g (80%); col-
General Procedure for the Preparation of Methyl Sulfones 3a and
3b: To a solution of the corresponding 3-(methylsulfanyl)-1,2,4-tri-
azine 2a or 2b (22.5 mmol) in anhydrous DCM (100 mL), mCPBA
(45 mmol) was added in portions at 0 °C over 10 min. The reaction
mixture was stirred for 1 h at room temp., and the resulting suspen-
sion was filtered. The filtrate was washed with saturated solutions
of sodium hydrogen carbonate (2ϫ70 mL) and sodium thiosulfate
(2ϫ100 mL). The organic layer was dried with MgSO4, the solvent
was removed in vacuo, and the crude product was purified by flash
column chromatography (petroleum ether/ethyl acetate, 5:5) to give
the corresponding sulfone 3a and 3b.
orless oil. IR (NaCl): ν = 3424, 3288, 2983, 2115, 1745, 1496, 1306,
˜
1042, 700 cm–1. 1H NMR (250 MHz, CDCl3, 25 °C): δ = 7.30–7.36
(m, 5 H), 6.37 (br. s, 1 H), 5.11 (s, 2 H), 4.25 (q, J = 7.1 Hz, 4 H),
3.28 (d, J = 2.3 Hz, 2 H), 1.99 (t, J = 2.5 Hz, 1 H), 1.23 (t, J =
7.1 Hz, 6 H) ppm. 13C NMR (62.9 MHz, CDCl3, 25 °C): δ = 166.6
(C), 154.5 (C), 136.2 (C), 128.6 (CH), 128.3 (CH), 128.1 (CH), 78.2
(C), 71.7 (CH), 67.2 (CH2), 65.8 (C), 63.1 (2 CH2), 24.4 (CH2),
14.0 (2 CH3) ppm. MS: m/z = 370.0 [M + Na]+. HRMS: calcd. for
C18H21NO6 370.1267, found 370.1249.
5-(2,6-Dimethoxyphenyl)-3-(methylsulfonyl)-1,2,4-triazine
(3a):
Yield 5.13 g (77%); yellow solid; m.p. 126–128 °C. IR (KBr): ν =
˜
2938, 1598, 1537, 1376, 1263, 1134, 760 cm–1. 1H NMR (250 MHz,
CDCl3, 25 °C): δ = 9.42 (s, 1 H), 7.44 (t, J = 8.5 Hz, 1 H), 6.66 (d,
Eur. J. Org. Chem. 2009, 3619–3627
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3623

E. Badarau, F. Suzenet, A.-L. Fînaru, G. Guillaumet
FULL PAPER
Ethyl 2-[(Benzyloxycarbonyl)amino]pent-4-ynoate (6): Lithium bro-
13C NMR (62.9 MHz, CDCl3, 25 °C): δ = 165.0 (C), 158.4 (C),
mide (6.41 g, 61.12 mmol) and water (2.2 mL, 122.23 mmol) were 158.3 (C), 155.5 (C), 147.9 (CH), 136.1 (C), 132.5 (CH), 128.5 (2
added to a solution of diester 5 (19.3 g, 55.56 mmol) in DMF CH), 128.2 (CH), 128.1 (2 CH), 112.3 (C), 104.2 (2 CH), 79.9 (C),
(120 mL). The reaction mixture was refluxed overnight, and after 72.8 (CH), 69.1 (CH2), 67.2 (CH2), 56.0 (CH3), 42.8 (CH) ppm.
the complete conversion of the starting material, the solvent was
evaporated. The residue was hydrolyzed with 100 mL of satd.
NaCl, and the aqueous layer was extracted with ethyl acetate
(3ϫ150 mL). The combined organic layers were dried with
MgSO4, and the solvent was removed under reduced pressure.
Flash chromatography over silica gel (petroleum ether/ethyl acetate,
9:1) afforded the corresponding monoester 6; yield 13.21 g (85%);
MS: m/z = 435.5 [M + H]+, 457.5 [M + Na]+. HRMS: calcd. for
C23H22N4O5 435.1668, found 435.1659.
Benzyl {1-[5-(2,6-Dimethoxyphenyl)-1,2,4-triazin-3-yloxy]pent-4-yn-
2-yl}carbamate (8b): Yield 2.25 g (87%); yellow oil. IR (NaCl): ν
˜
1
= 3298, 2946, 2118, 1718, 1599, 1515, 1255, 1110 cm–1. H NMR
(250 MHz, CDCl3, 25 °C): δ = 8.96 (s, 1 H), 7.39 (t, J = 8.5 Hz, 1
H), 7.30–7.34 (m, 5 H), 6.63 (d, J = 8.5 Hz, 2 H), 5.44 (d, J =
8.7 Hz, 1 H), 5.09 (s, 2 H), 4.76–4.82 (m, 1 H), 4.57–4.64 (m, 1 H),
4.28–4.37 (m, 1 H), 3.75 (s, 6 H), 2.67–2.70 (m, 2 H), 2.01 (t, J =
2.6 Hz, 1 H) ppm. 13C NMR (62.9 MHz, CDCl3, 25 °C): δ = 165.0
(C), 158.4 (C), 155.8 (C), 147.9 (CH), 136.3 (C), 132.5 (CH), 128.6
(2 CH), 128.2 (CH), 128.1 (2 CH), 112.3 (C), 104.2 (2 CH), 79.7
(C), 71.3 (CH), 68.0 (CH2), 67.0 (CH2), 56.0 (2 CH3), 48.9 (CH),
21.6 (CH2) ppm. MS: m/z = 449.5 [M + H]+, 471.5 [M + Na]+.
HRMS: calcd. for C24H24N4O5 471.1644, found 471.1643.
white solid; m.p. 45–47 °C. IR (KBr): ν = 3366, 3234, 2983, 2123,
˜
1728, 1524, 1214, 1061, 747 cm–1. 1H NMR (250 MHz, CDCl3,
25 °C): δ = 7.31–7.36 (m, 5 H) 5.65 (d, J = 7.3 Hz, 1 H), 5.13 (s, 2
H), 4.52 (dt, J = 4.7, 8.9 Hz, 1 H), 4.19–4.28 (m, 2 H), 2.77 (dd, J
= 2.5, 4.1 Hz, 2 H), 2.03 (t, J = 2.6 Hz, 1 H), 1.29 (t, J = 7.1 Hz,
3 H) ppm. 13C NMR (62.9 MHz, CDCl3, 25 °C): δ = 170.3 (C),
155.7 (C), 136.2 (C), 128.6 (CH), 128.3 (CH), 128.2 (CH), 78.4 (C),
71.9 (C), 67.2 (CH2), 62.0 (CH2), 52.4 (CH), 22.9 (CH2), 14.3 (CH3)
ppm. MS: m/z = 298.0 [M + Na]+. HRMS: calcd. for C15H17NO4
298.1055, found 298.1057.
Benzyl {1-[5-(2,6-Dimethylphenyl)-1,2,4-triazin-3-yloxy]pent-4-yn-2-
yl}carbamate (8c): Yield 1.98 g (82%); Yellow oil. IR (NaCl): ν =
˜
3410, 2954, 2248, 1724, 1536, 1066, 734 cm–1. 1H NMR (250 MHz,
CDCl3, 25 °C): δ = 8.94 (s, 1 H), 7.29–7.35 (m, 6 H), 7.15 (d, J =
7.6 Hz, 2 H), 5.50 (d, J = 5.4 Hz, 1 H), 5.11 (s, 2 H), 4.78 (dd, J =
5.4, 10.8 Hz, 1 H), 4.64 (dd, J = 5.4, 10.8 Hz, 1 H), 4.30–4.42 (m,
1 H), 2.68–2.71 (m, 2 H), 2.12 (s, 6 H), 2.05 (t, J = 2.6 Hz, 1 H)
ppm. 13C NMR (62.9 MHz, CDCl3, 25 °C): δ = 165.1 (C), 162.5
(C), 155.7 (C), 146.2 (CH), 136.2 (C), 135.7 (C), 133.6 (C), 129.8
(2 CH), 128.5 (2 CH), 128.1 (2 CH), 79.4 (C), 71.5 (CH), 68.2
(CH2), 66.9 (CH2), 48.6 (CH), 21.5 (CH2), 20.2 (2 CH3) ppm. MS:
m/z = 417 [M + H]+, 439.5 [M + Na]+. HRMS: calcd. for
C24H24N4O3 439.1746, found 439.1730.
Benzyl (1-Hydroxypent-4-yn-2-yl)carbamate (7): Lithium borohyd-
ride (1.52 g, 69.74 mmol) was added by portions to a solution of
ester 6 (6.4 g, 23.25 mmol) in anhydrous THF (90 mL) at –10 °C,
followed by the addition of anhydrous methanol (20 mL). The reac-
tion mixture was allowed to return to room temperature over
30 min, and the solvent was evaporated. Water (80 mL) was added
to the resulting residue, and after the complete hydrolysis of the
hydride, the aqueous layer was extracted with AcOEt (3ϫ100 mL).
The organic layer was dried with MgSO4, the solvent was removed
in vacuo, and the crude product was purified by flash column
chromatography (petroleum ether/ethyl acetate, 5:5) to give the de-
sired alcohol 7; yield 4.89 g (89%); white solid; m.p. 66–68 °C. IR
General Procedure for the Preparation of Cycloadducts 9a–c: The
corresponding compound 8a–c (1.11 mmol) was dissolved in chlo-
robenzene (5 mL) and heated at 200–220 °C under microwave irra-
diation for 1.5 h. The solvent was removed in vacuo, and the resi-
due was purified by flash chromatography (petroleum ether/ethyl
acetate, 4:6) to afford the corresponding cycloaddition derivatives
9a–c.
(KBr): ν = 3409, 3300, 2950, 2128, 1714, 1536, 1232, 1061,
˜
741 cm–1. 1H NMR (250 MHz, CDCl3, 25 °C): δ = 7.34 (s, 5 H),
5.43 (d, J = 8.3 Hz, 1 H), 5.09 (s, 2 H), 3.82–3.90 (m, 1 H), 3.63–
3.78 (m, 2 H), 3.03 (br. s, 1 H), 2.48 (d, J = 3.8 Hz, 2 H), 2.02 (t,
J = 2.6 Hz, 1 H) ppm. 13C NMR (62.9 MHz, CDCl3, 25 °C): δ =
156.4 (C), 136.2 (C), 128.6 (CH), 128.3 (CH), 128.2 (CH), 80.1 (C),
71.1 (CH), 67.0 (CH2), 63.4 (CH2), 51.2 (CH), 21.1 (CH2) ppm.
MS: m/z = 256.5 [M + Na]+. HRMS: calcd. for C13H15NO3 Benzyl {6-(2,6-Dimethoxyphenyl)-2,3-dihydrofuro[2,3-b]pyridin-3-
256.0950, found 256.0941.
yl}carbamate (9a): Yield 0.43 g (95%); white solid; m.p. 68–70 °C.
IR (KBr): ν = 3320, 2964, 1712, 1602, 1472, 1250, 1110, 753 cm–1.
˜
Synthesis of the ortho-Substituted Derivatives
1H NMR (250 MHz, CDCl3, 25 °C): δ = 7.68 (d, J = 7.4 Hz, 1 H),
7.35 (m, 5 H), 7.28 (t, J = 8.4 Hz, 1 H), 6.89 (d, J = 7.4 Hz, 1 H),
6.60 (d, J = 8.4 Hz, 2 H), 5.45–5.50 (m, 1 H), 5.28–5.33 (m, 1 H),
5.13 (s, 2 H), 4.72–4.80 (m, 1 H), 4.33–4.39 (m, 1 H), 3.70 (s, 6 H)
ppm. 13C NMR (62.9 MHz, CDCl3, 25 °C): δ = 167.9 (C), 158.1
(C), 155.8 (C), 154.8 (C), 136.2 (C), 134.6 (CH), 129.9 (CH), 128.7
(2 CH), 128.4 (CH), 128.2 (2 CH), 119.7 (CH), 118.5 (C), 116.6
(C), 104.2 (2 CH), 75.9 (CH2), 67.2 (CH2), 56.1 (2 CH3), 51.8 (CH)
ppm. MS: m/z = 407.0 [M + Na]+.
General Procedure for the Preparation of Triazines 8a–c: Under ni-
trogen atmosphere, n-butyllithium (1.5  in THF, 5.78 mmol) was
slowly added at –78 °C to a solution of the corresponding alcohol
(5.5 mmol) in anhydrous THF (60 mL). After 40 min at –78 °C, a
solution of the corresponding triazine (6.70 mmol) in anhydrous
THF (25 mL) was added. The mixture was stirred for 45 min at
–78 °C and 1 h at –30 °C, before it was quenched at low tempera-
ture with 5% NaHCO3. The aqueous layer was separated and ex-
tracted with AcOEt (3ϫ100 mL). The combined organic layers
were dried with MgSO4, the solvent was evaporated, and the crude
product was purified by flash chromatography (petroleum ether/
ethyl acetate, 5:5) to give the derivatives 8a–c.
Benzyl {7-(2,6-Dimethoxyphenyl)-3,4-dihydro-2H-pyrano[2,3-b]pyr-
idin-3-yl}carbamate (9b): Yield 0.41 g (88%); white solid; m.p. 167–
169 °C. IR (KBr): ν = 3338, 2942, 1715, 1602, 1472, 1248, 1111,
˜
755 cm–1. 1H NMR (250 MHz, CDCl3, 25 °C): δ = 7.41 (d, J =
7.5 Hz, 1 H), 7.33 (br. s, 5 H), 7.27 (t, J = 8.4 Hz, 1 H), 6.91 (d, J
= 7.5 Hz, 1 H), 6.59 (d, J = 8.4 Hz, 2 H), 5.39 (d, J = 6.4 Hz, 1
H), 5.10 (s, 2 H), 4.27 (br. s, 3 H), 3.70 (s, 6 H), 3.11 (d, J = 16.6 Hz,
Benzyl {1-[5-(2,6-Dimethoxyphenyl)-1,2,4-triazin-3-yloxy]but-3-yn-
2-yl}carbamate (8a): Yield 1.65 g (69%); white solid; m.p. 54–56 °C.
IR (KBr): ν = 3304, 2946, 2121, 1717, 1600, 1520, 1226, 1108, 1025,
˜
768 cm–1. 1H NMR (250 MHz, CDCl3, 25 °C): δ = 8.97 (s, 1 H), 1 H), 2.84 (d, J = 16.6 Hz, 1 H) ppm. 13C NMR (62.9 MHz,
7.39 (t, J = 8.4 Hz, 1 H), 7.31–7.32 (m, 5 H), 6.63 (d, J = 8.4 Hz,
2 H), 5.63 (d, J = 7.0 Hz, 1 H), 5.09 (s, 2 H), 4.99–5.04 (m, 1 H),
4.63–4.76 (m, 2 H), 3.74 (s, 6 H), 2.33 (d, J = 2.4 Hz, 1 H) ppm.
CDCl3, 25 °C): δ = 159.7 (C), 158.1 (C), 155.8 (C), 152.0 (C), 139.6
(CH), 136.3 (C), 129.6 (CH), 128.6 (2 CH), 128.2 (3CH), 120.5
(CH), 118.4 (C), 112.2 (C), 104.0 (2 CH), 68.8 (CH2), 66.9 (CH2),
3624
www.eurjoc.org
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 3619–3627

Synthesis of Chroman Isosteres
56.0 (2 CH3), 43.7 (CH), 31.0 (CH2) ppm. MS: m/z = 421.5 [M +
= 2938, 1606, 1471, 1248, 1110, 749 cm–1. 1H NMR (250 MHz,
CDCl3, 25 °C: δ = 7.45 (d, J = 7.5 Hz, 1 H), 7.27 (t, J = 8.4, 1 H),
6.89 (d, J = 7.5 Hz, 1 H), 6.60 (d, J = 8.4 Hz, 2 H), 4.48–4.54 (m,
1 H), 3.99–4.09 (m, 1 H), 3.71 (s, 6 H), 2.77–3.02 (m, 3 H), 2.41 (s,
6 H) ppm. 13C NMR (62.9 MHz, CDCl3, 25 °C): δ = 160.4 (C),
158.2 (C), 151.5 (C), 139.1 (CH), 129.5 (CH), 119.8 (CH), 118.8
(C), 113.4 (C), 104.1 (2 CH), 68.2 (CH2), 57.1 (CH), 56.0 (2 CH3),
42.8 (2 CH3), 29.2 (CH2) ppm. MS: m/z = 315.5 [M + H]+. HRMS:
calcd. for C18H22N2O3 315.1471, found 315.1460.
H]+. HRMS: calcd. for C24H24N2O5 421.1763, found 421.1778.
Benzyl {7-(2,6-Dimethylphenyl)-3,4-dihydro-2H-pyrano[2,3-b]pyr-
idin-3-yl}carbamate (9c): Yield 0.31 g (71%); white solid; m.p. 65–
67 °C. IR (KBr): ν = 3332, 3018, 1710, 1572, 1536, 1244, 755 cm–1.
˜
1H NMR (250 MHz, CDCl3, 25 °C): δ = 7.46 (d, J = 7.5 Hz, 1 H),
7.35 (m, 5 H), 7.16 (dd, J = 6.3, 8.6 Hz, 1 H), 7.06 (d, J = 7.4 Hz,
2 H), 6.84 (d, J = 7.5 Hz, 1 H), 5.27 (d, J = 5.3 Hz, 1 H), 5.12 (s,
2 H), 4.29–4.38 (m, 3 H), 3.17 (dd, J = 3.8, 16.7 Hz, 1 H), 2.88
(dd, J = 3.8, 16.7 Hz, 1 H), 2.07 (s, 6 H) ppm. 13C NMR
(62.9 MHz, CDCl3, 25 °C): δ = 160.0 (C), 157.6 (C), 155.8 (C),
140.1 (CH), 139.9 (C), 136.2 (C), 135.9 (C), 128.7 (2 CH), 128.4
(CH), 128.3 (2 CH), 127.8 (CH), 127.5 (2 CH), 119.0 (CH), 112.1
(C), 69.1 (CH2), 67.2 (CH2), 43.8 (CH), 31.1 (CH2), 20.4 (2 CH3)
ppm. MS: m/z = 389.5 [M + H]+. HRMS: calcd. for C24H24N2O3
389.1865, found 389.1856.
7-(2,6-Dimethoxyphenyl)-3-(dipropylamino)-3,4-dihydro-2H-pyrano-
[2,3-b]pyridine (10d): Yield 0.07 g (67%); yellowish oil. IR (NaCl):
1
ν = 2962, 1602, 1472, 1248, 1111, 752 cm–1. H NMR (250 MHz,
˜
CDCl3, 25 °C): δ = 7.45 (d, J = 7.5 Hz, 1 H), 7.26 (t, J = 8.4 Hz,
1 H), 6.87 (d, J = 7.5 Hz, 1 H), 6.60 (d, J = 8.4 Hz, 1 H), 4.43 (dd,
J = 2.9, 10.5 Hz, 1 H), 4.01 (dd, J = 2.9, 10.5 Hz, 1 H), 3.71 (s, 6
H), 3.26 (ddd, J = 3.6, 9.9, 19.3 Hz, 1 H), 2.88 (d, J = 8.4 Hz, 1
H), 2.53 (t, J = 7.4 Hz, 4 H), 1.47 (sext., J = 7.4 Hz, 4 H), 0.89 (t,
J = 7.4 Hz, 6 H) ppm. 13C NMR (62.9 MHz, CDCl3, 25 °C): δ =
160.6 (C), 158.3 (C), 151.4 (C), 139.2 (CH), 129.5 (CH), 119.5
(CH), 118.9 (C), 114.4 (C), 104.1 (2 CH), 68.4 (CH2), 56.1 (2 CH3),
52.9 (CH), 52.8 (2 CH2), 28.0 (CH2), 21.9 (2 CH2), 11.8 (2 CH3)
ppm. MS: m/z = 371.5 [M + H]+. HRMS: calcd. for C22H30N2O3
371.2335, found 371.2330.
General Procedure for the Preparation of Triazines 10a–f: To a solu-
tion of the protected amines 9a–c (0.5 mmol) in ethanol (10 mL)
was added 10% Pd/C (0.02 g), and hydrogen was bubbled through
the suspension for 15 min at room temperature. 1N HCl (0.5 mmol)
was added, and the reaction mixture was stirred under hydrogen
atmosphere until the complete consumption of the starting material
(10 h). The mixture was filtered through Celite, diluted with satd.
K2CO3 (25 mL), and extracted with DCM (3ϫ50 mL). The sepa-
rated organic layers were dried with MgSO4, and the solvent was
evaporated to give the free amines, which were used without further
purification.
3-(Dimethylamino)-7-(2,6-dimethylphenyl)-3,4-dihydro-2H-pyrano-
[2,3-b]pyridine (10e): Yield 0.07 g (86%); white solid; m.p. 76–78 °C.
1
IR (KBr): ν = 2958, 1604, 1572, 1466, 1254, 752 cm–1. H NMR
˜
(250 MHz, CDCl3, 25 °C): δ = 7.47 (d, J = 7.4 Hz, 1 H), 7.14 (dd,
J = 6.2, 8.2 Hz, 1 H), 7.04 (d, J = 8.2 Hz, 2 H), 6.79 (d, J = 7.4 Hz,
1 H), 4.51–4.58 (m, 1 H), 4.03–4.11 (m, 1 H), 2.76–3.03 (m, 3 H),
2.42 (s, 6 H), 2.06 (s, 6 H) ppm. 13C NMR (62.9 MHz, CDCl3,
25 °C): δ = 160.6 (C), 157.0 (C), 140.2 (C), 139.6 (CH), 136.0 (C),
127.7 (CH), 127.4 (2 CH), 118.2 (CH), 113.5 (C), 68.5 (CH2), 57.0
(CH), 42.8 (2 CH3), 29.1 (CH2), 20.4 (2 CH3) ppm. MS: m/z =
283.5 [M + H]+. HRMS: calcd. for C18H22N2O 283.1810, found
283.1820.
To a solution of the corresponding previously obtained primary
amines (0.30 mmol) in methanol (5 mL) was added the correspond-
ing aldehyde (2.40 mmol) and sodium borohydride (2.40 mmol).
The pH of the reaction was adjusted to 6 by addition of acetic acid,
and the mixture was stirred for 24 h at room temp. before being
poured into 1  NaOH (10 mL). The aqueous phase was extracted
with DCM (3ϫ30 mL), the organic layer was dried with MgSO4,
and the solvents were evaporated in vacuo. The final dialkylated
compounds 10a–f were isolated by flash chromatography (DCM/
MeOH, 95:5).
7-(2,6-Dimethylphenyl)-3-(dipropylamino)-3,4-dihydro-2H-pyrano-
[2,3-b]pyridine (10f): Yield 0.08 g (80%); yellow oil. IR (NaCl): ν =
˜
2962, 1600, 1567, 1462, 1244, 1027, 754 cm–1. 1H NMR (250 MHz,
CDCl3, 25 °C): δ = 7.46 (d, J = 7.4 Hz, 1 H), 7.14 (dd, J = 6.2,
8.6 Hz, 1 H), 7.05 (d, J = 7.4 Hz, 2 H), 6.77 (d, J = 7.4 Hz, 1 H),
4.46 (dd, J = 3.0, 10.4 Hz, 1 H), 4.05 (t, J = 10.4 Hz, 1 H), 3.20–
3.32 (m, 1 H), 2.90 (d, J = 8.6 Hz, 2 H), 2.51–2.57 (m, 4 H), 2.06
(s, 6 H), 1.48 (sext., J = 7.3 Hz, 4 H), 0.89 (t, J = 7.3 Hz, 6 H)
ppm. 13C NMR (62.9 MHz, CDCl3, 25 °C): δ = 160.8 (C), 156.7
(C), 140.2 (C), 139.7 (CH), 136.0 (C), 127.7 (CH), 127.4 (2 CH),
117.9 (CH), 114.4 (C), 68.6 (CH2), 52.8 (CH, 2 CH2), 28.0 (CH2),
21.9 (2 CH2), 20.3 (2 CH3), 11.8 (2 CH3) ppm. MS: m/z = 339.5 [M
+ H]+. HRMS: calcd. for C22H30N2O 339.2436, found 339.2424.
6-(2,6-Dimethoxyphenyl)-3-(dimethylamino)-2,3-dihydrofuro[2,3-b]-
pyridine (10a): Yield 0.06 g (71%); white solid; m.p. 151–153 °C. IR
(KBr): ν = 2938, 1598, 1250, 1110, 753 cm–1. 1H NMR (250 MHz,
˜
CDCl3, 25 °C): δ = 7.67 (d, J = 7.4 Hz, 1 H), 7.28 (d, J = 8.4 Hz,
1 H), 6.87 (d, J = 7.4 Hz, 1 H), 6.61 (d, J = 8.4 Hz, 2 H), 4.57–
4.62 (m, 1 H), 4.46–4.51 (m, 2 H), 3.71 (s, 6 H), 2.29 (s, 6 H) ppm.
13C NMR (62.9 MHz, CDCl3, 25 °C): δ = 168.5 (C), 158.2 (C),
154.0 (C), 135.2 (CH), 129.7 (CH), 118.9 (CH), 115.9 (C), 104.2 (2
CH), 70.4 (CH2), 64.7 (CH), 56.1 (2 CH3), 40.8 (2 CH3) ppm. MS:
m/z = 301.5 [M + H]+. HRMS: calcd. for C17H20N2O3 301.1552,
found 301.1551.
Synthesis of the meta-Substituted Derivatives
6-(2,6-Dimethoxyphenyl)-3-(dipropylamino)-2,3-dihydrofuro[2,3-b]-
pyridine (10b): Yield 0.04 g (40%); colorless oil. IR (NaCl): ν =
˜
5-Methyl-3-methylsulfonyl-1,2,4-triazine (12): Under inert atmo-
2923, 2360, 1703, 1587, 1471, 1250, 1106, 973 cm–1 1H NMR
.
sphere,
5-methyl-3-(methylsulfanyl)-1,2,4-triazine
(1.5 g,
(400 MHz, CDCl3, 25 °C): δ = 7.63 (d, J = 7.3 Hz, 1 H), 7.28 (t, J
= 8.4 Hz, 1 H), 6.84 (d, J = 7.3 Hz, 1 H), 6.61 (d, J = 8.4 Hz, 2
H), 4.73–4.77 (m, 1 H), 4.48–4.56 (m, 2 H), 3.72 (s, 6 H), 2.38–2.51
(m, 4 H), 1.42–1.51 (m, 4 H), 0.87 (t, J = 7.3 Hz, 6 H) ppm. 13C
NMR (100.7 MHz, CDCl3, 25 °C) δ = 168.6 (C), 158.3 (C), 153.5
(C), 134.9 (CH), 129.6 (CH), 119.1 (C), 118.9 (CH), 117.7 (C),
104.2 (2 CH), 71.5 (CH2), 61.5 (CH), 56.2 (2 CH3), 52.8 (2 CH2),
21.8 (2 CH2), 11.9 (2 CH3) ppm. MS: m/z = 357.0 [M + H]+.
HRMS: calcd. for C21H28N2O3 357.2178, found 357.2183.
10.62 mmol; for its preparation see Taylor et al.[9]) was dissolved in
anhydrous DCM (70 mL). The reaction mixture was cooled to 0 °C
and treated with mCPBA (70%, 5.76 g, 23.37 mmol). The mixture
was allowed to return to room temperature over 15 min and then
stirred for an additional hour. The suspension was rapidly filtered
through a sintered glass funnel, and the filtrate was evaporated
under reduced pressure (never to dryness!). Diethyl ether was added
to the resulting wet solid and, after 2–3 min of slowly stirring under
inert atmosphere, the precipitated sulfone was filtered through a
7-(2,6-Dimethoxyphenyl)-3-(dimethylamino)-3,4-dihydro-2H-pyrano- sintered glass funnel (if necessary, another precipitation step could
[2,3-b]pyridine (10c): Yield 0.07 (70%); yellowish oil. IR (NaCl): ν be conducted after the evaporation of the recovered filtrate); yield
˜
Eur. J. Org. Chem. 2009, 3619–3627
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3625

E. Badarau, F. Suzenet, A.-L. Fînaru, G. Guillaumet
FULL PAPER
1.39 g (67%); orange solid; m.p. 66–68 °C. IR (KBr): ν = 3034,
2.43 (s, 3 H) ppm. 13C NMR (62.9 MHz, CDCl3, 25 °C): δ = 159.5
(C), 156.4 (C), 155.8 (C), 140.1 (CH), 136.2 (C), 128.7 (2 CH),
128.4 (CH), 128.2 (2 CH), 117.7 (CH), 110.7 (C), 69.0 (CH2), 67.1
˜
1548, 1310, 1135, 957, 759, 557, 535 cm–1. 1H NMR (250 MHz,
CDCl3, 25 °C): δ = 9.33 (s, 1 H), 3.48 (s, 3 H), 2.76 (s, 3 H) ppm.
13C NMR (62.9 MHz, CDCl3, 25 °C): δ = 166.4 (C), 163.1 (C), (CH2), 43.8 (CH), 30.8 (CH2), 24.0 (CH3) ppm. MS: m/z = 298.5
152.3 (CH), 39.7 (CH3), 22.3 (CH3) ppm. MS: m/z = 174.0 [M +
H]+. HRMS: calcd. for C5H7N3O2S 196.0157, found 196.0152 [M
+ Na]+.
[M + H]+. HRMS: calcd. for C17H18N2O3 299.1396, found
299.1400.
General Procedure for the Preparation of Triazines 15a and 15b: To
General Procedure for the Preparation of Triazines 13a and 13b:
Compounds 13a and 13b were obtained following the same experi-
mental protocol employed for the synthesis of 8a–c using the ap-
propriate amino alcohol 4/7 and the triazine 12.
a solution of the corresponding cycloadduct 14a or 14b
(0.35 mmol) in methanol (2 mL) was added sodium hydrogen car-
bonate (1.06 mmol) and a solution of bromine in methanol (2 ,
0.77 mmol). The reaction mixture was refluxed for 2 h and
quenched by the addition of satd. NaHCO3 (15 mL). The aqueous
phase was extracted with DCM (3ϫ30 mL), then the organic layer
dried with MgSO4 and evaporated in vacuo. The resulting crude
product was purified by flash chromatography (petroleum ether/
ethyl acetate, 5:5) to give the desired halogenated compounds 15a
and 15b.
Benzyl [1-(5-Methyl-1,2,4-triazin-3-yloxy)but-3-yn-2-yl]carbamate
(13a): Yield 1.60 g (87%); colorless oil. IR (NaCl): ν = 3315, 3226,
˜
2119, 1688, 1531, 1339, 1265, 1243, 1084, 1046 cm–1. 1H NMR
(400 MHz, CDCl3, 25 °C): δ = 8.85 (s, 1 H), 7.28–7.35 (m, 5 H),
5.12 (d, J = 6.0 Hz, 1 H), 5.11 (s, 2 H), 4.99–5.04 (m, 1 H), 4.68
(d, J = 4.7 Hz, 2 H), 2.51 (s, 2 H), 2.36 (d, J = 2.3 Hz, 1 H) ppm.
13C NMR (100.7 MHz, CDCl3, 25 °C): δ = 164.6 (C), 162.7 (C), Benzyl {5-Bromo-6-methyl-2,3-dihydrofuro[2,3-b]pyridin-3-yl}car-
155.5 (C), 145.9 (CH), 136.1 (C), 128.6 (2 CH), 128.2 (CH), 128.1 bamate (15a): Yield 0.10 g (79%); white solid; m.p. 117–119 °C. IR
(2 CH), 79.7 (C), 73.0 (CH), 69.3 (CH2), 67.2 (CH2), 42.8 (CH), (KBr): ν = 3279, 1677, 1533, 1417, 1260, 1229, 1053, 750 cm–1. H
1
˜
21.6 (CH3) ppm. MS: m/z = 335.5 [M + H]+. HRMS: calcd. for
NMR (400 MHz, CDCl3, 25 °C): δ = 7.69 (s, 1 H), 7.30–7.37 (m,
5 H), 5.62 (d, J = 7.6 Hz, 1 H), 5.40–5.44 (m, 1 H), 5.11 (s, 2 H),
4.72 (t, J = 9.8 Hz, 1 H), 4.35 (dd, J = 4.3, 9.8 Hz, 1 H), 2.49 (s, 3
H) ppm. 13C NMR (100.7 MHz, CDCl3, 25 °C): δ = 166.5 (C),
157.2 (C), 155.8 (C), 138.3 (CH), 136.0 (C), 128.7 (2 CH), 128.5
(CH), 128.3 (2 CH), 118.5 (C), 112.3 (C), 76.5 (CH2), 67.4 (CH2),
51.3 (CH), 24.9 (CH3) ppm. MS: m/z = 363.0 [M + H]+ for 79Br,
365.0 [M + H]+ for 81Br. HRMS: calcd. for C16H15BrN2O3
363.0344, found 363.0344 for 79Br.
C16H16N4O3 335.1120, found 335.1137.
Benzyl [1-(5-Methyl-1,2,4-triazin-3-yloxy)pent-4-yn-2-yl]carbamate
(13b): Yield 1.25 g (65%); white solid; m.p. 136–138 °C. IR (KBr):
1
ν = 3305, 3010, 2129, 1708, 1556, 1551, 1220, 1086, 764 cm–1. H
˜
NMR (250 MHz, CDCl3, 25 °C): δ = 8.85 (s, 1 H), 7.29–7.35 (m,
5 H), 5.43 (d, J = 8.4 Hz, 1 H), 5.10 (s, 2 H), 4.73 (dd, J = 5.0,
10.8 Hz, 1 H), 4.6 (dd, J = 5.0, 10.8 Hz, 1 H), 4.27–4.35 (m, 1 H),
2.65–2.69 (m, 2 H), 2.51 (s, 3 H), 2.04 (t, J = 2.6 Hz, 1 H) ppm.
13C NMR (62.9 MHz, CDCl3, 25 °C): δ = 164.7 (C), 162.5 (C), Benzyl {6-Bromo-7-methyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-3-
155.7 (C), 145.8 (CH), 136.3 (C), 128.6 (2 CH), 128.2 (CH), 128.1
yl}carbamate (15b): Yield 0.11 g (81%); white solid; m.p. 144–
(2 CH), 79.4 (C), 71.5 (CH), 68.0 (CH2), 67.0 (CH2), 48.7 (CH), 146 °C. IR (KBr): ν = 3216, 3027, 1710, 1530, 1448, 1431, 1242,
˜
21.6 (CH3), 21.5 (CH2) ppm. MS: m/z = 349.0 [M + Na]+. HRMS:
1168, 1060 cm–1. H NMR (250 MHz, CDCl3, 25 °C): δ = 7.48 (s,
1 H), 7.30–7.35 (m, 5 H), 5.24 (d, J = 7.3 Hz, 1 H), 5.07 (s, 2 H),
4.22–4.29 (m, 3 H), 3.05 (dd, J = 4.6, 16.7 Hz, 1 H), 2.76–2.82 (m,
1 H), 2.50 (s, 3 H) ppm. 13C NMR (62.9 MHz, CDCl3, 25 °C): δ =
158.4 (C), 155.8 (C), 154.7 (C), 142.9 (CH), 136.1 (C), 128.7 (2
CH), 128.4 (CH), 128.2 (2 CH), 113.4 (C), 113.1 (C), 69.1 (CH2),
67.1 (CH2), 43.3 (CH), 30.5 (CH2), 24.3 (CH3) ppm. MS: m/z =
377.0 [M + H]+ for 79Br, 379 [M + H]+ for 81Br [M + H]+. HRMS:
calcd. for C17H17BrN2O3 377.0501, found 377.0489 for 79Br.
1
calcd. for C17H18N4O3 349.1277, found 349.1274.
Benzyl
{6-Methyl-2,3-dihydrofuro[2,3-b]pyridin-3-yl}carbamate
(14a): A solution of compound 13a (0.5 g, 1.60 mmol) in chloro-
benzene (5 mL) was heated at 180 °C under microwave irradiation
for 1 h. The solvent was removed in vacuo and the residue was
purified by flash chromatography (DCM/MeOH, 95:5) to afford
the corresponding cycloaddition compound 14a; yield 0.32 g
(71%); white solid; m.p. 132–134 °C. IR (KBr): ν = 3294, 2949,
˜
1679, 1596, 1531, 1258, 1069, 753 cm–1. 1H NMR (250 MHz, General Procedure for the Suzuki Palladium Coupling Reaction: To
CDCl3, 25 °C): δ = 7.48 (d, J = 7.4 Hz, 1 H), 7.29–7.33 (m, 5 H), a solution of the corresponding bromide (0.53 mmol) in toluene
6.65 (d, J = 7.4 Hz, 1 H), 5.69 (d, J = 7.6 Hz, 1 H), 5.33–5.41 (m, (12 mL) were added successively 1,3-dimethylphenylboronic acid
1 H), 5.09 (s, 2 H), 4.65 (t, J = 10.2 Hz, 1 H), 4.31 (dd, J = 4.2,
(0.1 g, 0.64 mmol), ethanol (6 mL) and satd. NaHCO3 (4 mL). The
10.2 Hz, 1 H), 2.83 (s, 3 H) ppm. 13C NMR (100.7 MHz, CDCl3, mixture was degassed and flushed with nitrogen several times be-
25 °C): δ = 167.8 (C), 159.1 (C), 155.9 (C), 136.2 (C), 134.9 (CH), fore adding tetrakis(triphenylphosphane)palladium (0.061 g,
128.7 (2 CH), 128.4 (CH), 128.2 (2 CH), 116.4 (CH), 115.6 (C),
0.05 mmol) in one portion. The mixture was degassed one more
76.0 (CH2), 67.2 (CH2), 51.6 (CH), 24.2 (CH3) ppm. MS: m/z = time and then refluxed under nitrogen for 20 h. The organic solvent
285.5 [M + Na]+. HRMS: calcd. for C16H16N2O3 285.1239, found
285.1258.
was removed, the residue was hydrolyzed with water (15 mL), and
the aqueous phase was extracted with DCM (3ϫ25 mL). The com-
bined organic layers were dried with MgSO4, the solvent was evap-
orated, and the crude product was purified by flash chromatog-
raphy (petroleum ether/ethyl acetate, 7:3) to give the desired cou-
pling derivatives 16a and 16b.
Benzyl
{7-Methyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-3-yl}car-
bamate (14b): A solution of compound 13b (0.5 g, 1.54 mmol) in
chlorobenzene (5 mL) was heated at 240 °C under microwave irra-
diation for 1 h. The solvent was removed in vacuo and the residue
was purified by flash chromatography (DCM/MeOH, 95:5) to af-
ford the corresponding cycloaddition compound 14b; yield 0.31 g
Benzyl {5-(2,6-Dimethylphenyl)-6-methyl-2,3-dihydrofuro[2,3-b]pyr-
idin-3-yl}carbamate (16a): Yield 0.13 g (65%); yellowish oil. IR
(67%); beige solid; m.p. 133–135 °C. IR (KBr): ν = 3025, 1708,
(NaCl): ν = 3304, 2956, 1695, 1524, 1416, 1227, 1087, 1008, 909,
˜
˜
1
1558, 1551, 1258, 1106, 1067, 694 cm–1. 1H NMR (250 MHz, 729 cm–1. H NMR (400 MHz, CDCl3, 25 °C): δ = 7.30–7.36 (m,
CDCl3, 25 °C): δ = 7.31–7.35 (m, 5 H), 7.28 (d, J = 8.0 Hz, 1 H), 6 H), 7.18 (t, J = 7.6 Hz, 1 H), 7.11 (d, J = 7.6 Hz, 2 H), 5.50–5.51
6.76 (d, J = 8.0 Hz, 1 H), 5.13–5.15 (m, 1 H), 5.09 (s, 2 H), 4.25– (m, 1 H), 5.20 (m, 1 H), 5.12 (s, 2 H), 4.81 (t, J = 9.7 Hz, 1 H),
4.29 (m, 3 H), 3.07 (dd, J = 4.4, 16.6 Hz, 1 H), 2.75–2.81 (m, 1 H),
4.39 (dd, J = 4.4, 9.7 Hz, 1 H), 2.11 (s, 3 H), 1.95 (s, 3 H), 1.53 (s,
3626
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© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 3619–3627

Synthesis of Chroman Isosteres
3 H) ppm. 13C NMR (100.7 MHz, CDCl3, 25 °C): δ = 166.9 (C),
156.7 (C), 155.8 (C), 138.5 (C), 136.5 (C), 136.3 (C), 136.1 (C),
135.8 (CH), 129.0 (C), 128.7 (2 CH), 128.5 (CH), 128.3 (2 CH),
127.7 (2 CH), 127.7 (CH), 116.4 (C), 76.1 (CH2), 67.4 (CH2), 51.8
(CH), 22.2 (CH3), 20.6 (2 CH3) ppm. MS: m/z = 389.5 [M + H]+.
HRMS: calcd. for C24H24N2O3 389.1865, found 389.1881.
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Benzyl
{6-(2,6-Dimethylphenyl)-7-methyl-3,4-dihydro-2H-pyrano-
[2,3-b]pyridin-3-yl}carbamate (16b): Yield 0.17 g (80%); colorless
oil. IR (NaCl): ν = 1709, 1534, 1448, 1425, 1236, 1147, 1099,
˜
909 cm–1. H NMR (250 MHz, CDCl3, 25 °C): δ = 7.32–7.36 (m,
1
5 H), 7.07–7.20 (m, 4 H), 5.26 (d, J = 7.2 Hz, 1 H), 5.11 (s, 2 H),
4.28–4.33 (m, 3 H), 3.12 (dd, J = 4.4, 16.6 Hz, 1 H), 2.77–2.83 (m,
1 H), 2.09 (s, 3 H), 1.96 (s, 3 H), 1.95 (s, 3 H) ppm. 13C NMR
(62.9 MHz, CDCl3, 25 °C): δ = 158.6 (C), 155.8 (C), 153.9 (C),
140.6 (CH), 138.2 (C), 136.4 (C), 136.3 (C), 136.2 (Cq), 130.0 (C),
128.7 (2 CH), 128.4 (CH), 128.2 (2 CH), 127.6 (CH), 127.6 (2 CH),
111.3 (C), 69.0 (CH2), 67.1 (CH2), 43.8 (CH), 30.7 (CH2), 21.8
(CH3), 20.7 (CH3), 20.6 (CH3) ppm. MS: m/z = 403.5 [M + H]+.
HRMS: calcd. for C25H26N2O3 403.2022, found 403.2023.
General Procedure for the Preparation of the Final Derivatives 17a
and 17b: The compounds 17a and 17b were obtained following the
same experimental procedure used for the synthesis of compounds
10a–f starting from the corresponding Cbz-protected amines 16a
and 16b (0.4 mmol).
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1469.
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4567.
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2006, 128, 87–89.
3-(Dimethylamino)-5-(2,6-dimethylphenyl)-6-methyl-2,3-dihydro-
furo[2,3-b]pyridine (17a): Yield 0.08 g (68 %); colorless oil. IR
(NaCl): ν = 2924, 2360, 1584, 1143, 1414, 1229, 771 cm–1. 1H NMR
˜
(400 MHz, CDCl3, 25 °C): δ = 7.18 (dd, J = 7.4, 1.2 Hz, 1 H), 7.12
(d, J = 7.4 Hz, 2 H), 4.55–4.61 (m, 2 H), 4.46–4.52 (m, 1 H), 2.24
(s, 6 H), 2.12 (s, 3 H), 1.99 (s; 3 H), 1.98 (s, 3 H) ppm. 13C NMR
(100.7 MHz, CDCl3, 25 °C): δ = 167.6 (C), 155.8 (C), 139.0 (C),
136.6 (CH), 136.5 (C), 136.5 (C), 128.0 (C), 127.7 (2 CH), 127.6
(CH), 115.0 (C), 71.6 (CH2), 64.6 (CH), 40.7 (2 CH3), 22.2 (CH3),
20.7 (CH3), 20.6 (CH3) ppm. MS: m/z = 283.5 [M + H]+. HRMS:
calcd. for C18H22N2O 283.1810, found 283.1822.
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521–522.
3-(Dimethylamino)-6-(2,6-dimethylphenyl)-7-methyl-3,4-dihydro-
2H-pyrano[2,3-b]pyridine (17b): Yield 0.10 g (86%); white solid;
m.p. 112–114 °C. IR (KBr): for the fumaric salt ν = 3401, 2921,
˜
1
2452, 1706, 1568, 1450, 1292, 1248, 1153, 980, 765 cm–1. H NMR
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(400 MHz, CDCl3, 25 °C): δ = 7.16 (dd, J = 6.3, 8.5 Hz, 1 H), 7.07–
7.11 (m, 3 H), 4.94–4.53 (m, 1 H), 4.07–4.12 (m, 1 H), 2.77–2.94
(m, 3 H), 2.40 (s, 6 H), 2.08 (s, 3 H), 1.97 (s, 3 H), 1.96 (s, 3 H)
ppm. 13C NMR (100.7 MHz, CDCl3, 25 °C): δ = 159.3 (C), 153.2
(C), 140.2 (CH), 138.6 (C), 136.6 (C), 136.5 (C), 129.2 (C), 127.5
(3CH), 112.8 (C), 68.5 (CH2), 57.2 (CH), 42.8 (2 CH3), 28.6 (CH2),
21.8 (CH3), 20.7 (CH3), 20.6 (CH3) ppm. MS: m/z = 297.0 [M +
H]+. HRMS: calcd. for C19H24N2O 297.1980, found 297.1967.
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Supporting Information (see also the footnote on the first page of
this article): 13C NMR spectra of compounds 1–17.
Acknowledgments
Authors acknowledge Prof. Andrzej Bojarski (Polish Academy of
Sciences, Cracow, Poland) for fruitful discussions and for the bio-
logical evaluation of the final compounds.
Received: February 24, 2009
Published Online: June 5, 2009
Eur. J. Org. Chem. 2009, 3619–3627
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3627