Intramolecular Diels-Alder reactions of α,β-unsaturated oxime ethers as 1-azadienes: synthesis of [c]-fused pyridines

Article abstract of DOI:10.1016/j.tet.2007.09.090

The intramolecular hetero-Diels-Alder reaction of α,β-unsaturated oxime ethers as the diene with acetylenic dienophiles, readily prepared from salicylaldehyde derivatives, is described as a rapid and versatile route to [c]-annelated pyridines in modest to

Full text of DOI:10.1016/j.tet.2007.09.090

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Tetrahedron 64 (2008) 874e882
www.elsevier.com/locate/tet
Intramolecular DielseAlder reactions of a,b-unsaturated oxime
ethers as 1-azadienes: synthesis of [c]-fused pyridines
Timothy E. Hurst a, Timothy J. Miles b, Christopher J. Moody a,
*
a School of Chemistry, University of Nottingham, University Park, Nottingham NG7 2RD, UK
b GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, UK
Received 24 July 2007; accepted 7 September 2007
Available online 25 October 2007
Abstract
The intramolecular hetero-DielseAlder reaction of a,b-unsaturated oxime ethers as the diene with acetylenic dienophiles, readily prepared
from salicylaldehyde derivatives, is described as a rapid and versatile route to [c]-annelated pyridines in modest to good yields.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
with electron-deficient acetylenes,19 subsequently extended
by others,20 we now report an intramolecular variant using
a,b-unsaturated oxime ethers as 1-azadienes in a route to
[c]-annelated pyridines.
The hetero-DielseAlder reaction is a useful route to a range
of six-membered heterocyclic compounds,1,2 and the use of
both 1-aza and 2-aza-dienes as 4p-components in such reac-
tions is well known.3e6 Since the discovery by Ghosez and
co-workers that a,b-unsaturated N,N-dimethylhydrazones par-
ticipate readily in [4þ2]-cycloadditions,7 their high reactivity
towards electron-deficient dienophiles, presumably being due
to the strong electron-donating effect of the dimethylamino
substituent, the hetero-DielseAlder reaction of 1-azabuta-
dienes has proved to be a versatile method for the preparation
of a range of pyridines and dihydropyridines. Intramolecular
DielseAlder (IMDA) reactions of a,b-unsaturated N,N-dime-
thylhydrazones with alkynes have also been reported,8,9 and
this is an attractive route to annelated pyridines since the ini-
tial DielseAlder adducts readily aromatise by loss of dimethy-
lamine.10e12 In contrast, analogous a,b-unsaturated oxime
ethers are often thought of as poorer 1-azadienes, and conse-
quently there are fewer examples of both intermolecular and
intramolecular hetero-DielseAlder routes to pyridines involv-
ing vinyl oximes as dienes.13e18 In continuation of our recent
work on the synthesis of highly functionalised pyridines via
hetero-DielseAlder reaction of 3-siloxy-1-aza-1,3-butadienes
2. Results and discussion
2.1. Preparation of hetero-DielseAlder substrates
The required substrates for hetero-DielseAlder reaction
were prepared in three steps from commercially available
starting materials. First, alkylation of salicylaldehyde 1a and
3-methylsalicylaldehyde 1b with propargyl chloride pro-
ceeded in excellent yield to provide the aryl propargyl ethers
(Scheme 1). Next, the WadswortheEmmons reaction was ex-
amined. Treatment of the required b-ketophosphonate, either
obtained from commercial sources or prepared by acylation
of phosphonate-derived carbanions by known or modified
methods,21 with sodium hydride or potassium tert-butoxide
in dimethoxyethane (DME) or toluene, followed by slow addi-
tion of the aldehyde gave the desired a,b-unsaturated ketones
2aed as single (E )-geometric isomers in good to excellent
yields. Further functionalisation to the 1-aza-1,3-butadiene
moiety was readily achieved by conversion of 2aed into the
O-methyl oximes 3aed on heating with methoxylamine hy-
drochloride and sodium acetate trihydrate in aqueous ethanol
in almost quantitative yield, without the need for further puri-
fication by column chromatography.
* Corresponding author. Tel.: þ44 115 846 8500.
E-mail address: c.j.moody@nottingham.ac.uk (C.J. Moody).
0040-4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.09.090

T.E. Hurst et al. / Tetrahedron 64 (2008) 874e882
875
OMe
N
yield (Table 1, entry 2). Variations in the diene component
were also tolerated. Indeed, IMDA reaction of substrates 3c
and d (Table 1, entries 3 and 4) proceeded smoothly, albeit
in modest yield, to provide the tetra-substituted pyridines 6c
and d.
R3
R2
O
R3
R2
CHO
c
a, b
HO
R1
O
O
R1
R1
OMe
N
OMe
N
1a-b
2a-d
3a-d
Me
Me
[3,3]
d
e
O
O
OMe
N
Me
O
Me
3a
7
c
Ph
R4
Scheme 2. Chromene byproduct resulting from competing [3,3]-sigmatropic
rearrangement of 3a.
O
O
Me
Me
Introduction of an electron-withdrawing group at the termi-
nus of the acetylene would be expected to facilitate the IMDA
reaction on the basis of lowering the relevant LUMO of the di-
enophile, assuming that the a,b-unsaturated oximes participate
in a ‘normal’ electron-demand hetero-DielseAlder reaction
(HOMOdiene/LUMOdienophile). This indeed proved to be the
case; heating oxime 5a in xylene in a sealed tube at 180 ꢀC
gave the desired tetra-substituted pyridine 8a in 50% yield
(Table 1, entry 5). The reaction still proceeds at 140 ꢀC, unlike
the terminal acetylenes, although a slight drop in yield is no-
ticed (Table 1, entry 6). IMDA reaction of oxime 5b also pro-
ceeded smoothly, with the expected product 8b isolated in
62% and 42% yields after 16 h at 180 ꢀC and 140 ꢀC, respec-
tively (Table 1, entries 7 and 8). However, IMDA reaction of
oxime 5c gave only small amounts of the expected 2-chloro-
pyridine 8c (Table 1, entry 9), with the main isolated product
being pyridine 6b that arises through formal loss of the chlo-
rine atom, although it is not yet clear at which stage this loss
occurs. As may be expected, introduction of a bulky TMS
group into the dienophile greatly retarded the IMDA reaction
(Table 1, entry 10), such that even after prolonged heating
69% of the unreacted starting material was recovered, with
12% of the desilylated pyridine 6b as the only other isolable
product.
4
5a-d
R1 R2
R3
R4
2a, 3a
H
H
H
Me
5a CO2Me
2b, 3b Me
Me
Me
5b
5c
Ph
Cl
2c, 3c Me Me
2d, 3d Me Me CH2OMe 5d SiMe3
Scheme 1. Reagents and conditions: (a) HC^CCH2Cl, K2CO3, EtOH, reflux,
16 h, 86e100%; (b) (RO)2P(O)CHR2COR3, NaH or KOtBu, DME or toluene,
rt, 16 h, 75e96%; (c) MeONH2$HCl, NaOAc$3H2O, EtOH, H2O, 60 ꢀC, 16 h,
94e98%; (d) PhI, Pd(PPh3)2Cl2 (7 mol %), CuI (30 mol %), Et3N, THF, 60 ꢀC,
16 h, 66%; (e) LiHMDS, electrophile, THF, ꢁ78 ꢀC to rt, 16 h, 41e53%.
A range of substrates bearing a substituent at the terminus
of the acetylenic dienophile were also prepared in order to ex-
amine their effect on the intramolecular hetero-DielseAlder
reaction. The IMDA substrates 5a, c, or d bearing a methyl
ester, chloro or trimethylsilyl group at the alkyne terminus
were prepared directly from oxime 3b via deprotonation of
the alkyne with lithium hexamethyldisilazide (LiHMDS)
and trapping with the appropriate electrophile. IMDA sub-
strate 5b was obtained by Sonogashira reaction between acet-
ylene 2b and iodobenzene under standard conditions to give
4, followed by formation of the corresponding oxime as de-
tailed above.
We also envisaged that direct conversion of the a,b-unsat-
urated ketones to the aromatic products should be possible
through a one-pot oxime formation/hetero-DielseAlder reac-
tion. Pleasingly, treatment of ketones 2b and 4 with methoxyl-
amine hydrochloride and triethylamine in xylene in a sealed
tube and heating to 180 ꢀC for 16 h gave the desired pyridines
in 29% and 37% yields, respectively (Table 1, entries 11 and
12).
2.2. Intramolecular hetero-DielseAlder reactions
The key IMDA reactions were investigated under simple
thermal conditions. Heating oxime 3a to 180 ꢀC in xylene in
a sealed tube gave the desired [c]-annelated pyridine 6a in
30% yield after 16 h (Table 1, entry 1). On one occasion a mi-
nor byproduct (8%) was isolated, which was identified as
(3E )-4-(2H-chromen-8-yl)but-3-en-2-one O-methyl oxime 7
(Scheme 2) that presumably arises through a [3,3]-sigmatropic
rearrangement and [1,5]-hydrogen shift in analogous fashion
to that previously reported for vinyl hydrazone dienes.12
blocking substituent in the form of a methyl group ortho to
the propargylic ether moiety eliminates this competing rear-
rangement, and the desired pyridine 6b was isolated in 37%
3. Conclusions
We have successfully demonstrated that the intramolecular
hetero-DielseAlder reaction of vinyl oxime ethers with acety-
lenes represents a rapid and versatile route to a range of
[c]-annelated pyridines, best results being obtained with elec-
tron-deficient acetylenes in accordance with the likely frontier
orbital interactions (HOMOdiene/LUMOdienophile). The results
A

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T.E. Hurst et al. / Tetrahedron 64 (2008) 874e882
Table 1
Intramolecular hetero-DielseAlder reactions
Entry
IMDA substrate
Product
Temp/ꢀC
Time/h
Yield/%
1
180
180
180
180
16
30
2
3
4
16
16
16
37
26
27
5
6
7
8
180
140
180
140
16
16
16
16
50
41
62
42
5a
8a
5b
8b

T.E. Hurst et al. / Tetrahedron 64 (2008) 874e882
877
Table 1 (continued)
Entry
IMDA substrate
Product
Temp/ꢀC
Time/h
Yield/%
16 (8c)
30 (6b)
9
180
16
10
6b
180e200
120
12a
11b
6b
180
16
29
12b
8b
180
16
37
a
Unreacted 5d recovered: 69%.
The hetero-DielseAlder substrates (3b and 5a) were formed in situ by heating the a,b-unsaturated ketone with methoxylamine hydrochloride and triethylamine
b
in xylene.
exemplify further the utility of a,b-unsaturated oximes as
1-azadienes in the hetero-DielseAlder route to pyridines, as
they exhibit comparable reactivity to that previously described
for analogous a,b-unsaturated hydrazone systems.
corresponding 13C frequency is 100 MHz). In the 13C NMR
spectra, signals corresponding to CH, CH2, or CH3 groups
are assigned from DEPT. High- and low-resolution mass spec-
tra were recorded on a Bruker MicroTOF spectrometer using
electrospray ionisation (ESI).
4. Experimental
4.1. General
4.1.1. General procedure 1dalkylation of salicylaldehydes
To a solution of the salicylaldehyde 1 (10.0 mmol) in etha-
nol (60 mL) were added potassium carbonate (15.0 mmol,
1.5 equiv) and propargyl chloride (50.0 mmol, 5.0 equiv).
The reaction mixture was heated under reflux for 16 h, cooled
to room temperature and the solvent removed in vacuo. The
residue was partitioned between sodium hydroxide solution
(2 M; 150 mL) and ether (3ꢂ150 mL). The combined organic
extracts were washed with water (150 mL), dried over MgSO4
and concentrated in vacuo. The crude product was purified by
flash chromatography on silica gel, eluting with ethyl acetatee
light petroleum (1:19) to afford the title compound.
Commercially available reagents were used throughout
without further purification unless otherwise stated; solvents
were dried by standard procedures. Light petroleum refers to
the fraction with bp 40e60 ꢀC and ether refers to diethyl ether.
Reactions were routinely carried out under a nitrogen atmo-
sphere. Fully characterised compounds were chromatographi-
cally homogeneous. IR spectra were recorded in the range
4000e600 cmꢁ1 using a Bruker Tensor 27 spectrometer. H
and 13C NMR spectra were recorded using a Bruker AV400
spectrometer operating at 400 MHz (1H frequency,
1

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T.E. Hurst et al. / Tetrahedron 64 (2008) 874e882
4.1.2. General procedure 2dWadswortheEmmons
reaction
4.2. Preparation of IMDA substrates
To a solution of sodium hydride (9.00 mmol, 1.5 equiv) or
potassium tert-butoxide (9.00 mmol, 1.5 equiv) in 1,2-dime-
thoxyethane (10 mL) was added the phosphonate
(9.00 mmol, 1.5 equiv) in 1,2-dimethoxyethane (5 mL) drop-
wise over 30 min. The reaction mixture was stirred for
30 min, followed by dropwise addition of the aldehyde
(6.00 mmol) in 1,2-dimethoxyethane (5 mL) over 30 min.
The resulting mixture was stirred at room temperature for
16 h and partitioned between saturated ammonium chloride
(75 mL) and ethyl acetate (3ꢂ75 mL). The combined organic
extracts were washed with water (75 mL) and saturated brine
(75 mL), dried over MgSO4 and concentrated in vacuo. The
crude product was purified by flash chromatography on silica
gel, eluting with ethyl acetateelight petroleum (1:9), to afford
the title compound.
4.2.1. 2-(Prop-2-ynyloxy)benzaldehyde
Prepared as previously described.12
4.2.2. 3-Methyl-2-(prop-2-ynyloxy)benzaldehyde
Following general procedure 1, the title compound was ob-
tained from 3-methylsalicylaldehyde 1b (0.340 g, 2.50 mmol),
potassium carbonate (0.518 g, 3.75 mmol) and propargyl chlo-
ride (0.90 mL, 12.5 mmol) as a pale oil (0.375 g, 86%) (found:
MHþ, 175.0758; C11H10O2þH requires 175.0754); nmax
(CHCl3)/cmꢁ1 3306 (alkyne CeH), 2126 (C^C), 1693
(C]O), 1588 (C]C), 1469 (C]C), 1249 (CeO), 1086
(CeO); dH (400 MHz; CDCl3) 10.42 (1H, s, CHO), 7.71 (1H,
d, J¼7.6 Hz, H-6), 7.45 (1H, d, J¼7.6 Hz, H-4), 7.17 (1H, t,
J¼7.6 Hz, H-5), 4.68 (2H, d, J¼2.0 Hz, CH2), 2.54 (1H, t,
J¼2.0 Hz, C^CH), 2.36 (3H, s, Me); dC (100 MHz; CDCl3)
190.6 (CH), 158.9 (C), 137.5 (CH), 132.4 (C), 130.2 (C),
126.5 (CH), 125.0 (CH), 77.9 (C), 76.8 (CH), 62.1 (CH2),
15.9 (Me); m/z (ESI) 197 (MNaþ, 100%), 175 (MHþ, 37),
147 (66).
4.1.3. General procedure 3dpreparation of O-methyl
oximes
A solution of the ketone 2 (4.00 mmol), methoxylamine hy-
drochloride (5.00 mmol, 1.25 equiv) and sodium acetate trihy-
drate (4.20 mmol, 1.05 equiv) in ethanol (28 mL) and water
(3.5 mL) was heated to 60 ꢀC for 16 h. The reaction mixture
was cooled to room temperature and the solvent removed in va-
cuo. The resulting residue was partitioned between water
(65 mL) and ethyl acetate (3ꢂ65 mL). The combined organic
extracts were washed with water (2ꢂ65 mL) and saturated brine
(65 mL), dried over MgSO4 and concentrated in vacuo to afford
the title compound that was used without further purification.
4.2.3. (E )-4-(2-(Prop-2-ynyloxy)phenyl)but-3-en-2-one 2a
Following general procedure 2, the title compound was
obtained from 2-(prop-2-ynyloxy)benzaldehyde (0.288 g,
1.80 mmol), sodium hydride (0.108 g, 2.70 mmol) and di-
methyl-2-oxopropylphosphonate (0.448 g, 2.70 mmol) as
a pale oil (0.329 g, 91%) (lit.,12 oil); dH (400 MHz; CDCl3)
7.88 (1H, d, J¼16.4 Hz, C]CH), 7.56 (1H, d, J¼7.6 Hz, H-
6), 7.37 (1H, t, J¼7.6 Hz, H-5), 7.05 (1H, d, J¼7.6 Hz, H-
3), 7.02 (1H, t, J¼7.6 Hz, H-4), 6.73 (1H, d, J¼16.4 Hz,
C]CH), 4.78 (2H, d, J¼1.2 Hz, CH2), 2.55 (1H, t,
J¼1.2 Hz, C^CH), 2.38 (3H, s, Me); dC (100 MHz; CDCl3)
199.0 (C), 156.1 (C), 138.4 (CH), 131.6 (CH), 128.3 (CH),
128.1 (CH), 124.0 (C), 121.8 (CH), 112.8 (CH), 78.1 (C),
76.1 (CH), 56.2 (CH2), 27.2 (Me).
4.1.4. General procedure 4dfunctionalisation of terminal
alkynes
To a solution of O-methyl oxime 3b (0.973 g, 4.00 mmol) in
THF (10 mL) at ꢁ78 ꢀC was added lithium hexamethyldisila-
zide (1 M in THF; 4.20 mL, 4.20 mmol) dropwise over 20 min.
The reaction mixture was stirred at ꢁ78 ꢀC for 1 h, then the
electrophile (6.00 mmol) added dropwise over 15 min. The re-
sulting mixture was then stirred for a further 1 h at ꢁ78 ꢀC, al-
lowed to warm to room temperature and stirred for 16 h. The
reaction was quenched by addition of saturated ammonium
chloride (75 mL), and the aqueous phase extracted with ethyl
acetate (3ꢂ75 mL). The combined organic extracts were
washed with water (75 mL), dried over MgSO4 and concen-
trated in vacuo. The crude product was purified by flash chro-
matography on silica gel to afford the title compound.
4.2.4. (E )-4-(3-Methyl-2-(prop-2-ynyloxy)phenyl)but-3-en-
2-one 2b
Following general procedure 2, the title compound was ob-
tained
from
3-methyl-2-(prop-2-ynyloxy)benzaldehyde
(0.314 g, 1.80 mmol), sodium hydride (0.108 g, 2.70 mmol)
and dimethyl-2-oxopropylphosphonate (0.448 g, 2.70 mmol)
as a pale oil (0.340 g, 88%) (found: MHþ, 215.1077;
C14H14O2þH requires 215.1066); nmax (CHCl3)/cmꢁ1 3307
(alkyne CeH), 2127 (C^C), 1669 (C]O), 1644 (C]C),
1623 (C]C), 1607 (C]C), 1462 (C]C), 1259 (CeO), 1090
(CeO); dH (400 MHz; CDCl3) 7.94 (1H, d, J¼16.4 Hz,
C]CH), 7.44 (1H, d, J¼7.6 Hz, H-6), 7.24 (1H, d, J¼
7.6 Hz, H-4), 7.08 (1H, t, J¼7.6 Hz, H-5), 6.69 (1H, d,
J¼16.4 Hz, C]CH), 4.55 (2H, d, J¼1.2 Hz, CH2), 2.55
(1H, t, J¼1.2 Hz, C^CH), 2.41 (3H, s, Me), 2.34 (3H, s, Me);
dC (100 MHz; CDCl3) 198.9 (C), 156.0 (C), 139.0 (CH), 133.6
(CH), 132.1 (C), 128.5 (CH), 128.4 (C), 125.2 (CH), 125.0
(CH), 78.6 (C), 76.1 (CH), 61.4 (CH2), 27.0 (Me), 16.4
(Me); m/z (ESI) 237 (MNaþ, 61%), 215 (MHþ, 100).
4.1.5. General procedure 5dintramolecular hetero-Dielse
Alder reaction
A solution of the a,b-unsaturated oxime 3/5 (0.50 mmol) in
dry xylene (10 mL) was placed in a sealed tube and heated to
the required temperature for the time shown in Table 1. The
reaction mixture was then cooled to room temperature, con-
centrated in vacuo and the crude product purified by flash
chromatography on silica gel to afford the title compound.

T.E. Hurst et al. / Tetrahedron 64 (2008) 874e882
879
4.2.5. (E )-3-Methyl-4-(3-methyl-2-(prop-2-ynyloxy)phenyl)-
but-3-en-2-one 2c
added triethylamine (0.84 mL, 6.00 mmol) followed by alkyne
2b (0.857 g, 4.00 mmol) in THF (5 mL). The reaction mixture
was heated to 60 ꢀC for 16 h, cooled to room temperature and
partitioned between saturated ammonium chloride solution
(150 mL) and ethyl acetate (3ꢂ150 mL). The combined or-
ganic extracts were washed with saturated ammonium chloride
solution (150 mL) and saturated brine (150 mL), dried over
MgSO4 and concentrated in vacuo. The crude product was pu-
rified by flash chromatography on silica gel, eluting with ethyl
acetateelight petroleum (1:9) to afford the title compound as
a colourless oil (0.768 g, 66%) (found: MHþ, 291.1382;
C20H18O2þH requires 291.1380); nmax (CHCl3)/cmꢁ1 2233
(C^C), 1669 (C]C), 1644 (C]C), 1622 (C]C), 1606 (C]
C), 1588 (C]C), 1491 (C]C), 1461 (C]C), 1443 (C]C),
1260 (CeO), 1090 (CeO); dH (400 MHz; CDCl3) 8.05 (1H,
d, J¼16.5 Hz, C]CH), 7.49 (1H, d, J¼7.6 Hz, H-6), 7.40e
7.38 (2H, m, ArH), 7.35e7.32 (3H, m, ArH), 7.28 (1H, d,
J¼7.2 Hz, H-4), 7.12 (1H, t, J¼7.6 Hz, H-5), 6.72 (1H, d,
J¼16.5 Hz, C]CH), 4.81 (2H, s, CH2), 2.41 (3H, s, Me),
2.34 (3H, s, Me); dC (100 MHz; CDCl3) 199.0 (C), 156.0
(C), 139.2 (CH), 133.6 (CH), 132.3 (C), 131.6 (CH), 128.8
(CH), 128.7 (C), 128.4 (CH), 128.1 (CH), 125.1 (CH), 125.0
(CH), 122.1 (C), 87.9 (C), 84.0 (C), 62.3 (CH2), 26.9 (Me),
16.5 (Me); m/z (ESI) 313 (MNaþ, 51%), 291 (MHþ, 100).
Following general procedure 2, the title compound was
obtained from 3-methyl-2-(prop-2-ynyloxy)benzaldehyde
(0.401 g, 2.30 mmol), potassium tert-butoxide (0.387 g,
3.45 mmol) and diethyl 1-methyl-2-oxopropylphosphonate21
(0.718 g, 3.45 mmol) as a pale oil (0.420 g, 82%) (found:
MHþ, 229.1227; C15H16O2þH requires 229.1223); nmax
(CHCl3)/cmꢁ1 3307 (alkyne CeH), 2128 (C^C), 1665
(C]O), 1623 (C]C), 1586 (C]C), 1461 (C]C), 1263
(CeO), 1089 (CeO); dH (400 MHz; CDCl3) 7.78 (1H, s,
C]CH), 7.23e7.20 (2H, m, ArH), 7.10 (1H, t, J¼7.6 Hz,
H-5), 4.50 (2H, d, J¼1.3 Hz, CH2), 2.52 (1H, t, J¼1.3 Hz,
C^CH), 2.51 (3H, s, Me), 2.37 (3H, s, Me), 2.01 (3H, s,
Me); dC (100 MHz; CDCl3) 200.5 (C), 155.2 (C), 138.6 (C),
136.0 (CH), 131.8 (CH), 131.7 (C), 129.5 (C), 128.2 (CH),
124.3 (CH), 78.9 (C), 75.6 (CH), 61.0 (CH2*), 26.0 (Me), 16.4
(Me), 13.0 (Me); m/z (ESI) 251 (MNaþ, 75%), 229 (MHþ,
100).
4.2.6. (E )-1-Methoxy-3-methyl-4-(3-methyl-2-(prop-2-
ynyloxy)phenyl)but-3-en-2-one 2d
To
a solution of potassium tert-butoxide (0.421 g,
3.75 mmol) in toluene (4 mL) was added diethyl 4-methoxy-
3-oxobutan-2-ylphosphonate (prepared from diethyl ethyl-
phosphonate and methyl-2-methoxyacetate using the method
described in Ref. 21) (0.893 g, 3.75 mmol) in toluene (3 mL)
dropwise over 15 min. The reaction mixture was stirred for
30 min, followed by dropwise addition of 3-methyl-2-(prop-
2-ynyloxy)benzaldehyde (0.436 g, 2.50 mmol) in toluene
(3 mL) over 15 min. The resulting mixture was stirred at
room temperature for 16 h and partitioned between saturated
ammonium chloride (45 mL) and ethyl acetate (3ꢂ45 mL).
The combined organic extracts were washed with water
(45 mL) and saturated brine (45 mL), dried over MgSO4 and
concentrated in vacuo. The crude product was purified by flash
chromatography on silica gel, eluting with ethyl acetateelight
petroleum (1:9), to afford the title compound as a pale oil
(0.487 g, 75%) (found: MHþ, 259.1336; C16H18O3þH re-
quires 259.1329); nmax (CHCl3)/cmꢁ1 3307 (alkyne CeH),
2127 (C^C), 1683 (C]O), 1627 (C]C), 1586 (C]C),
1461 (C]C), 1261 (CeO), 1090 (CeO), 1056 (CeO); dH
(400 MHz; CDCl3) 7.70 (1H, s, C]CH), 7.23e7.20 (2H, m,
ArH), 7.09 (1H, t, J¼7.6 Hz, H-5), 4.61 (2H, s, CH2), 4.49
(2H, d, J¼1.2 Hz, CH2), 3.49 (3H, s, OMe), 2.53 (1H, t,
J¼1.2 Hz, C^CH), 2.35 (3H, s, Me), 2.03 (3H, s, Me); dC
(100 MHz; CDCl3) 197.9 (C), 155.2 (C), 136.1 (C), 135.2
(CH), 132.1 (CH), 131.8 (C), 129.1 (C), 128.1 (CH), 124.4
(CH), 78.9 (C), 75.7 (CH), 74.8 (CH2), 61.1 (CH2), 59.4
(Me), 16.4 (Me), 13.1 (Me); m/z (ESI) 281 (MNaþ, 100%),
259 (MHþ, 42), 241 (72).
4.2.8. (E )-4-(2-(Prop-2-ynyloxy)phenyl)but-3-en-2-one
O-methyl oxime 3a
Following general procedure 3, the title compound was ob-
tained from ketone 2a (0.280 g, 1.40 mmol), methoxylamine
hydrochloride (0.146 g, 1.75 mmol) and sodium acetate trihy-
drate (0.200 g, 1.47 mmol) as a pale oil (0.314 g, 98%) (found:
MHþ, 230.1192; C14H15NO2þH requires 230.1181); nmax
(CHCl3)/cmꢁ1 3308 (alkyne CeH), 2125 (C^C), 1600
(C]C), 1487 (C]C), 1457 (C]C), 1240 (CeO), 1055
(CeO); dH (400 MHz; CDCl3) 7.57 (1H, d, J¼7.6 Hz, H-6),
7.35e7.24 (2H, m, ArHþC]CH), 7.04e6.86 (2H, m, ArH),
6.85 (1H, d, J¼16.4 Hz, C]CH), 4.77 (2H, d, J¼1.2 Hz,
CH2), 3.96 (3H, s, OMe), 2.54 (1H, t, J¼1.2 Hz, C^CH),
2.10 (3H, s, Me); dC (100 MHz; CDCl3) 156.3 (C), 154.9
(C), 145.8 (C), 129.2 (CH), 127.3 (CH), 126.6 (CH), 126.4
(CH), 121.8 (CH), 112.8 (CH), 78.5 (C), 75.8 (CH), 61.8
(Me), 56.3 (CH2), 10.2 (Me); m/z (ESI) 252 (MNaþ, 11%),
230 (MHþ, 100).
4.2.9. (E )-4-(3-Methyl-2-(prop-2-ynyloxy)phenyl)but-3-en-
2-one O-methyl oxime 3b
Following general procedure 3, the title compound was ob-
tained from ketone 2b (0.300 g, 1.40 mmol), methoxylamine
hydrochloride (0.146 g, 1.75 mmol) and sodium acetate trihy-
drate (0.200 g, 1.47 mmol) as a pale oil (0.333 g, 98%) (found:
MHþ, 244.1346; C15H17NO2þH requires 244.1332); nmax
(CHCl3)/cmꢁ1 3307 (alkyne CeH), 2127 (C^C), 1619
(C]C), 1586 (C]C), 1462 (C]C), 1240 (CeO), 1056
(CeO); dH (400 MHz; CDCl3) 7.43 (1H, d, J¼6.8 Hz, H-6),
7.29 (1H, d, J¼16.8 Hz, C]CH), 7.13 (1H, d, J¼7.2 Hz, H-
4), 7.05 (1H, t, J¼7.2 Hz, H-5), 6.81 (1H, d, J¼16.8 Hz,
C]CH), 4.51 (2H, d, J¼1.2 Hz, CH2), 3.96 (3H, s, OMe),
4.2.7. (E )-4-(2-(3-Phenylprop-2-ynyloxy)-3-methylphenyl)-
but-3-en-2-one 4
To a solution of iodobenzene (0.67 mL, 6.00 mmol), bis(tri-
phenylphosphine)palladium(II) chloride (0.201 g, 0.286 mmol)
and copper(I) iodide (0.229 g, 1.20 mmol) in THF (15 mL) was

880
T.E. Hurst et al. / Tetrahedron 64 (2008) 874e882
2.54 (1H, t, J¼1.2 Hz, C^CH), 2.34 (3H, s, Me), 2.12 (3H, s,
Me); dC (100 MHz; CDCl3) 156.1 (C), 154.8 (C), 131.9 (C),
131.2 (CH), 130.2 (C), 127.9 (CH), 126.9 (CH), 124.9 (CH),
124.0 (CH), 79.0 (C), 75.6 (CH), 61.9 (Me), 61.1 (CH2),
16.4 (Me), 10.2 (Me); m/z (ESI) 266 (MNaþ, 22%), 244
(MHþ, 100).
3.77 (3H, s, OMe), 2.34 (3H, s, Me), 2.11 (3H, s, Me); dC
(100 MHz; CDCl3) 156.1 (C), 154.5 (C), 153.3 (C), 131.6
(C), 131.3 (CH), 130.2 (C), 127.5 (CH), 127.4 (CH), 125.2
(CH), 124.3 (CH), 82.6 (C), 78.6 (C), 61.9 (Me), 60.6 (CH2),
52.8 (Me), 16.4 (Me), 10.2 (Me); m/z (ESI) 324 (MNaþ,
100%), 302 (MHþ, 17).
4.2.10. (E )-3-Methyl-4-(3-methyl-2-(prop-2-ynyloxy)-
phenyl)but-3-en-2-one O-methyl oxime 3c
4.2.13. (E )-4-(2-(3-Phenylprop-2-ynyloxy)-3-methylphenyl)-
but-3-en-2-one O-methyl oxime 5b
Following general procedure 3, the title compound was ob-
tained from ketone 2c (0.297 g, 1.30 mmol), methoxylamine
hydrochloride (0.136 g, 1.63 mmol) and sodium acetate trihy-
drate (0.186 g, 1.37 mmol) as a pale oil (0.242 g, 72%) (found:
MHþ, 258.1497; C16H19NO2þH requires 258.1489); nmax
(CHCl3)/cmꢁ1 3308 (alkyne CeH), 2128 (C^C), 1586
(C]C), 1461 (C]C), 1253 (CeO), 1055 (CeO); dH
(400 MHz; CDCl3) 7.14e7.13 (2H, m, ArH), 7.06 (1H, d,
J¼7.6 Hz, H-4), 7.01 (1H, s, C]CH), 4.47 (2H, d,
J¼1.2 Hz, CH2), 3.97 (3H, s, OMe), 2.48 (1H, t, J¼1.2 Hz,
C^CH), 2.36 (3H, s, Me), 2.15 (3H, s, Me), 2.06 (3H, s,
Me); dC (100 MHz; CDCl3) 156.9 (C), 155.0 (C), 135.7 (C),
131.5 (C), 130.7 (C), 130.3 (CH), 128.6 (CH), 126.5 (CH),
124.0 (CH), 79.3 (C), 75.0 (CH), 61.8 (Me), 60.5 (CH2),
16.5 (Me), 14.4 (Me), 10.8 (Me); m/z (ESI) 280 (MNaþ,
32%), 258 (MHþ, 100).
Following general procedure 3, the title compound was ob-
tained from ketone 4 (0.667 g, 2.30 mmol), methoxylamine hy-
drochloride (0.240 g, 2.88 mmol) and sodium acetate trihydrate
(0.329 g, 2.42 mmol) as a pale oil (0.690 g, 94%) (found:
MHþ, 320.1661; C21H21NO2þH requires 320.1645); nmax
(CHCl3)/cmꢁ1 2235 (C^C), 1599 (C]C), 1491 (C]C), 1462
(C]C), 1443 (C]C), 1244 (CeO), 1056 (CeO); dH
(400 MHz; CDCl3) 7.49e7.31 (7H, m, 6ꢂArHþC]CH), 7.17
(1H, d, J¼7.4 Hz, H-4), 7.08 (1H, t, J¼7.4 Hz, H-5), 6.86 (1H,
d, J¼16.6 Hz, C]CH), 4.77 (2H, s, CH2), 3.97 (3H, s, OMe),
2.41 (3H, s, Me), 2.08 (3H, s, Me); dC (100 MHz; CDCl3)
156.2 (C), 155.0 (C), 131.9 (CH), 131.8 (C), 131.2 (CH), 130.3
(C), 128.6 (CH), 128.3 (CH), 128.1 (CH), 126.7 (CH), 124.8
(CH), 124.0 (CH), 122.3 (C), 87.4 (C^CPh), 84.3 (C^CPh),
62.0 (CH2), 61.9 (Me), 16.5 (Me), 10.2 (Me); m/z (ESI) 342
(MNaþ, 42%), 320 (MHþ, 100), 288 (30).
4.2.11. (E )-1-Methoxy-3-methyl-4-(3-methyl-2-(prop-2-ynyl-
oxy)phenyl)but-3-en-2-one O-methyl oxime 3d
4.2.14. (E )-4-(2-(3-Chloroprop-2-ynyloxy)-3-methyl-
phenyl)but-3-en-2-one O-methyl oxime 5c
Following general procedure 3, the title compound was ob-
tained from ketone 2d (0.387 g, 1.50 mmol), methoxylamine
hydrochloride (0.157 g, 1.88 mmol) and sodium acetate trihy-
drate (0.214 g, 1.58 mmol) as a pale oil (0.410 g, 95%) (found:
MHþ, 288.1603; C17H21NO3þH requires 288.1594); nmax
(CHCl3)/cmꢁ1 3308 (alkyne CeH), 2127 (C^C), 1596
(C]C), 1461 (C]C), 1254 (CeO), 1051 (CeO); dH
(400 MHz; CDCl3) 7.18e7.13 (3H, m, ArH), 7.06 (1H, d,
J¼7.4 Hz, H-4), 4.52 (2H, d, J¼1.2 Hz, CH2), 4.51 (2H, s,
CH2), 3.99 (3H, s, OMe), 3.43 (3H, s, OMe), 2.50 (1H, t,
J¼1.2 Hz, C^CH), 2.49 (3H, s, Me), 2.03 (3H, s, Me); dC
(100 MHz; CDCl3) 156.7 (C), 154.8 (C), 133.3 (C), 131.6
(C), 130.6 (C), 130.5 (CH), 128.6 (CH), 127.8 (CH), 123.9
(CH), 79.4 (C), 75.0 (CH), 62.3 (CH2), 62.0 (Me), 60.4
(CH2), 58.6 (Me), 16.6 (Me), 14.6 (Me); m/z (ESI) 310
(MNaþ, 67%), 288 (MHþ, 100).
Following general procedure 4, the title compound was ob-
tained from O-methyl oxime 3b (0.973 g, 4.00 mmol) and N-
chlorosuccinimide (0.801 g, 6.00 mmol) as a colourless oil
35
(0.546 g, 49%) (found: MHþ, 278.0947; C15H ClNO2þH re-
16
quires 278.0942); nmax (CHCl3)/cmꢁ1 2245 (C^C), 1627
(C]C), 1586 (C]C), 1463 (C]C), 1056 (CeO); dH
(400 MHz; CDCl3) 7.44 (1H, d, J¼7.6 Hz, H-4), 7.28 (1H,
d, J¼16.6 Hz, C]CH), 7.13 (1H, d, J¼7.6 Hz, H-6), 7.06
(1H, t, J¼7.6 Hz, H-5), 6.82 (1H, d, J¼16.6 Hz, C]CH),
4.52 (2H, s, CH2), 3.97 (3H, s, OMe), 2.33 (3H, s, Me),
2.13 (3H, s, Me); dC (100 MHz; CDCl3) 156.1 (C), 154.7
(C), 131.7 (C), 131.3 (CH), 130.3 (C), 127.8 (CH), 126.8
(CH), 125.0 (CH), 124.0 (CH), 66.0 (C), 64.9 (C), 61.9
(Me), 61.5 (CH2), 16.3 (Me), 10.2 (Me); m/z (ESI) m/z (ESI)
280/278 (MHþ, 36/100%), 246 (30).
4.2.15. (E )-4-(2-(3-Trimethylsilylprop-2-ynyloxy)-3-methyl-
phenyl)but-3-en-2-one O-methyl oxime 5d
4.2.12. (E )-4-(2-(3-Methoxycarbonylprop-2-ynyloxy)-
3-methylphenyl)but-3-en-2-one O-methyl oxime 5a
Following general procedure 4, the title compound was ob-
tained from O-methyl oxime 3b (0.973 g, 4.00 mmol) and
chlorotrimethylsilane (0.77 mL, 6.00 mmol) as a colourless
oil (0.664 g, 53%) (found: MHþ, 316.1724; C18H25NO2SiþH
requires 316.1727); nmax (CHCl3)/cmꢁ1 2181 (C^C), 1625
(C]C), 1586 (C]C), 1462 (C]C), 1056 (CeO), 848 (Ce
Si); dH (400 MHz; CDCl3) 7.44 (1H, d, J¼7.6 Hz, H-6),
7.30 (1H, d, J¼16.5 Hz, C]CH), 7.13 (1H, d, J¼7.6 Hz, H-
4), 7.05 (1H, t, J¼7.6 Hz, H-5), 6.82 (1H, d, J¼16.5 Hz,
C]CH), 4.53 (2H, s, CH2), 3.98 (3H, s, OMe), 2.35 (3H, s,
Me), 2.14 (3H, s, Me), 0.18 (9H, s, SiMe3); dC (100 MHz;
Following general procedure 4, the title compound was ob-
tained from O-methyl oxime 3b (0.973 g, 4.00 mmol) and
methyl chloroformate (0.46 mL, 6.00 mmol) as a colourless
oil (0.495 g, 41%) (found: MHþ, 302.1388; C17H19NO4þH
requires 302.1387); nmax (CHCl3)/cmꢁ1 2245 (C^C), 1717
(C]O), 1585 (C]C), 1462 (C]C), 1436 (C]C), 1266
(CeO), 1056 (CeO); dH (400 MHz; CDCl3) 7.43 (1H, d,
J¼7.6 Hz, H-6), 7.23 (1H, d, J¼16.5 Hz, C]CH), 7.14 (1H,
d, J¼7.6 Hz, H-4), 7.07 (1H, t, J¼7.6 Hz, H-5), 6.82 (1H, d,
J¼16.5 Hz, C]CH), 4.65 (2H, s, CH2), 3.86 (3H, s, OMe),

T.E. Hurst et al. / Tetrahedron 64 (2008) 874e882
881
CDCl3) 156.5 (C), 155.2 (C), 132.1 (C), 131.5 (CH), 130.5
(C), 128.4 (CH), 127.0 (CH), 125.1 (CH), 124.2 (CH), 100.8
(C), 93.0 (C), 62.2 (CH2), 61.9 (Me), 16.8 (Me), 10.6 (Me),
0.0 (SiMe3); m/z (ESI) 338 (MNaþ, 18%), 316 (MHþ, 100).
a sealed tube was heated at 180 ꢀC for 16 h. The reaction
mixture was cooled to room temperature and the solvent
removed in vacuo. The crude product was purified by flash
chromatography on silica gel, eluting with ethyl acetatee
light petroleum (1:9) to afford the title compound as a col-
ourless solid (0.031 g, 29%); data as above.
4.3. IMDA reactions
4.3.3. 1,2,7-Trimethyl-5H-chromeno[3,4-c]pyridine 6c
4.3.1. 2-Methyl-5H-chromeno[3,4-c]pyridine 6a
Following general procedure 5, the title compound was ob-
tained from O-methyl oxime 3c (0.129 g, 0.50 mmol) after
16 h at 180 ꢀC as a colourless solid (0.026 g, 26þ%); mp 74e
76 ꢀC (from ethyl acetateehexane) (found: MH , 226.1232;
C15H15NOþH requires 226.1226); nmax (CHCl3)/cmꢁ1 1590
(C]C), 1556 (C]C), 1464 (C]C), 1066 (CeO); dH
(400 MHz; CDCl3) 8.18 (1H, s, H-4), 7.59 (1H, d, J¼8.0 Hz,
H-10), 7.20 (1H, d, J¼7.2 H-8), 7.02 (1H, t, J¼7.2 Hz, H-9),
4.95 (2H, s, CH2), 2.60 (3H, s, Me), 2.53 (3H, s, Me), 2.31
(3H, s, Me); dC (100 MHz; CDCl3) 158.6 (C), 155.7 (C),
141.7 (CH), 137.2 (C), 131.8 (CH), 127.2 (C), 126.9 (C),
126.6 (C), 126.4 (CH), 122.1 (C), 120.8 (CH), 66.9 (CH2),
23.9 (Me), 17.7 (Me), 16.0 (Me); m/z (ESI) 226 (MHþ, 100%).
Following general procedure 5, the title compound was ob-
tained from O-methyl oxime 3a (0.115 g, 0.50 mmol) after
16 h at 180 ꢀC as a yellow oil (0.030 g, 30%) (lit.,12 oil); dH
(400 MHz; CDCl3) 8.30 (1H, s, H-4), 7.73 (1H, d,
J¼8.0 Hz, H-10), 7.41 (1H, s, H-1), 7.33 (1H, t, J¼8.0 Hz,
H-9), 7.08 (1H, t, J¼8.0 Hz, H-8), 7.01 (1H, d, J¼8.0 Hz,
H-7), 5.13 (2H, s, CH2), 2.61 (3H, s, Me); dC (100 MHz;
CDCl3) 158.7 (C), 155.8 (C), 145.0 (CH), 137.9 (C), 131.6
(CH), 123.9 (CH), 123.2 (C), 122.3 (CH), 120.6 (C), 117.8
(CH), 115.4 (CH), 65.8 (CH2), 24.5 (Me).
On one occasion, also isolated was (3E )-4-(2H-chromen-8-
yl)but-3-en-2-one O-methyl oxime 7 as a colourless oil (8%)
(found: MHþ, 230.1175; C14H15NO2þH requires 230.1176);
nmax (CHCl3)/cmꢁ1 1585 (C]C), 1488 (C]C), 1463
(C]C), 1239 (CeO), 1037 (CeO); dH (400 MHz; CDCl3)
7.37 (1H, dd, J¼1.8 and 7.6 Hz, H-5/H-7), 7.16 (1H, d,
J¼16.7 Hz, C]CH), 6.87 (1H, dd, J¼1.8 and 7.6 Hz, H-5/
H-7), 6.85 (1H, t, J¼7.6 Hz, H-6), 6.84 (1H, d, J¼16.7 Hz,
C]CH), 6.42 (1H, dt, J¼1.8 and 9.8 Hz, H-4), 5.81 (1H, dt,
J¼3.5 and 9.8 Hz, H-3), 4.89 (2H, dd, J¼1.8 and 3.5 Hz,
CH2), 3.96 (3H, s, OMe), 2.08 (3H, s, Me); dC (100 MHz;
CDCl3) 156.3 (C), 151.6 (C), 127.1 (CH), 126.6 (CH), 126.2
(CH), 126.1 (CH), 124.7 (CH), 124.1 (C), 122.7 (C), 122.0
(CH), 121.2 (CH), 65.7 (CH2), 61.8 (Me), 10.2 (Me); m/z
(ESI) 230 (MHþ, 100%).
4.3.4. 2-Methoxymethyl-1,7-dimethyl-5H-chromeno[3,4-c]-
pyridine 6d
Following general procedure 5, the title compound was ob-
tained from O-methyl oxime 3d (0.144 g, 0.50 mmol) after
16 h at 180 ꢀC as a colourless solid (0.035 g, 27þ%); mp 50e
52 ꢀC (from ethyl acetateehexane) (found: MH , 256.1346;
C16H17NO2þH requires 256.1332); nmax (CHCl3)/cmꢁ1 1588
(C]C), 1556 (C]C), 1464 (C]C), 1094 (CeO); dH
(400 MHz; CDCl3) 8.30 (1H, s, H-4), 7.65 (1H, d, J¼
7.9 Hz, H-10), 7.23 (1H, d, J¼7.6 Hz, H-8), 7.04 (1H, dd,
J¼7.6 and 7.9 Hz, H-9), 5.00 (2H, s, CH2), 4.72 (2H, s,
CH2), 3.48 (3H, s, OMe), 2.64 (3H, s, Me), 2.33 (3H, s, Me);
dC (100 MHz; CDCl3) 157.1 (C), 155.6 (C), 142.0 (CH), 138.1
(C), 132.1 (CH), 128.4 (C), 128.0 (C), 127.2 (C), 126.5 (CH),
121.9 (C), 120.9 (CH), 75.6 (CH2), 66.8 (CH2), 58.5 (Me), 16.8
(Me), 16.0 (Me); m/z (ESI) 270 (32%), 256 (MHþ, 100%).
4.3.2. 2,7-Dimethyl-5H-chromeno[3,4-c]pyridine 6b
(a) Following general procedure 5, the title compound was
obtained from O-methyl oxime 3b (0.122 g, 0.50 mmol)
after 16 h at 180 ꢀC as a colourless solid (0.039 g, 37%);
mp 107e109 ꢀC (from ethyl acetateehexane) (found:
MHþ, 212.1079; C14H13NOþH requires 212.1070); nmax
(CHCl3)/cmꢁ1 1610 (C]C), 1599 (C]C), 1561 (C]C),
1465 (C]C), 1021 (CeO); dH (400 MHz; CDCl3) 8.30
(1H, s, H-4), 7.57 (1H, d, J¼7.7 Hz, H-10), 7.38 (1H, s,
H-1), 7.21 (1H, d, J¼7.4 Hz, H-8), 6.97 (1H, dd, J¼7.7
and 7.4 Hz, H-9), 5.13 (2H, s, CH2), 2.60 (3H, s, Me), 2.27
(3H, s, Me); dC (100 MHz; CDCl3) 158.6 (C), 153.9 (C),
144.9 (CH), 138.3 (C), 132.8 (CH), 127.2 (C), 123.2
(C), 121.6 (CH), 121.5 (CH), 120.1 (C), 115.5 (CH), 65.8
(CH2), 24.6 (Me), 15.9 (Me); m/z (ESI) 212 (MHþ, 100%).
(b) Following general procedure 5, the title compound was
obtained from O-methyl oxime 5d (0.158 g, 0.50 mmol)
after 120 h at 180e200 ꢀC as a colourless solid (0.013 g,
12%); data as above.
4.3.5. Methyl-2,7-dimethyl-5H-chromeno[3,4-c]pyridine-
4-carboxylate 8a
(a) Following general procedure 5, the title compound was
obtained from O-methyl oxime 5a (0.090 g, 0.30 mmol)
after 16 h at 180 ꢀC as a colourless solid (0.040 g, 50%);
mp 47e49 ꢀC (from ethyl acetateehexane) (found: MHþ,
270.1129; C16H15NO3þH requires 270.1125); nmax
(CHCl3)/cmꢁ1 1719 (C]O), 1597 (C]C), 1556 (C]C),
1472 (C]C), 1438 (C]C) 1087 (CeO); dH (400 MHz;
CDCl3) 7.56e7.55 (2H, m, ArH), 7.21 (1H, d,
J¼7.3 Hz, H-8), 6.97 (1H, dd, J¼7.3 and 8.1 Hz, H-9),
5.52 (2H, s, CH2), 4.01 (3H, s, OMe), 2.67 (3H, s, Me),
2.28 (3H, s, Me); dC (100 MHz; CDCl3) 165.0 (C), 156.7
(C), 152.9 (C), 142.4 (C), 139.1 (C), 132.1 (CH), 126.1
(C), 125.7 (C), 120.6 (CH), 120.5 (CH), 118.4 (C), 117.8
(CH), 63.9 (CH2), 51.9 (Me), 23.6 (Me), 14.6 (Me); m/z
(ESI) 292 (MNaþ, 28%), 284 (41), 270 (MHþ, 100).
(c) A solution of ketone 2b (0.107 g, 0.50 mmol), methoxyl-
amine hydrochloride (0.084 g, 1.00 mmol) and triethyl-
amine (0.101 g, 1.00 mmol) in xylene (10 mL) in

882
T.E. Hurst et al. / Tetrahedron 64 (2008) 874e882
(b) Following general procedure 5, the title compound was
obtained from O-methyl oxime 5a (0.151 g, 0.50 mmol)
after 16 h at 140 ꢀC as a colourless solid (0.055 g, 41%);
data as above.
H-10), 7.35 (1H, s, H-1), 7.23 (1H, d, J¼7.7 Hz, H-8), 6.99
(1H, t, J¼7.7 Hz, H-9), 5.26 (2H, s, CH2), 2.59 (3H, s, Me),
2.28 (3H, s, Me); dC (100 MHz; CDCl3) 158.6 (C), 153.7
(C), 146.5 (C), 141.4 (C), 133.4 (CH), 127.3 (C), 121.8
(CH), 121.7 (CH), 121.4 (C), 119.2 (C), 115.0 (CH), 64.7
(CH2), 24.3 (Me), 15.8 (Me); m/z (ESI) 248/246 (MHþ, 30/
100%). Also obtained was 2,7-dimethyl-5H-chromeno[3,4-c]-
pyridine 6b (30%).
4.3.6. 2,7-Dimethyl-4-phenyl-5H-chromeno[3,4-c]-
pyridine 8b
(a) Following general procedure 5, the title compound was
obtained from O-methyl oxime 5b (0.160 g, 0.50 mmol)
after 16 h at 180 ꢀC as a colourless solid (0.089 g, 62%);
mp 148e150 ꢀC (from ethyl acetateehexane) (found:
MHþ, 288.1396; C20H17NOþH requires 288.1383); nmax
(CHCl3)/cmꢁ1 1595 (C]C), 1579 (C]C), 1560 (C]C),
1498 (C]C), 1471 (C]C), 1450 (C]C), 1420 (C]C),
1021 (CeO); dH (400 MHz; CDCl3) 7.64 (1H, d,
J¼7.6 Hz, H-10), 7.51e7.44 (5H, m, ArH), 7.42 (1H, s,
H-1), 7.22 (1H, d, J¼7.5 Hz, H-8), 7.02 (1H, dd, J¼7.5
and 7.6 Hz, H-9), 5.18 (2H, s, CH2), 2.69 (3H, s, Me),
2.27 (3H, s, Me); dC (100 MHz; CDCl3) 157.7 (C),
155.2 (C), 153.9 (C), 139.2 (C), 139.0 (C), 132.6 (CH),
129.1 (CH), 128.9 (CH), 128.5 (CH), 127.0 (C), 121.8 (CH),
121.7(CH), 121.3 (C), 120.8 (C), 114.9 (CH), 65.5 (CH2),
24.8 (Me), 15.8 (Me); m/z (ESI) 288 (MHþ, 100%).
(b) Following general procedure 5, the title compound was
obtained from O-methyl oxime 5b (0.151 g, 0.50 mmol)
after 16 h at 140 ꢀC as a colourless solid (0.055 g, 41%);
data as above.
Acknowledgements
We thank the EPSRC for funding, and GlaxoSmithKline for
a CASE award (T.E.H.).
References and notes
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(c) A solution of ketone 4 (0.145 g, 0.50 mmol), methoxyl-
amine hydrochloride (0.084 g, 1.00 mmol) and triethyl-
amine (0.101 g, 1.00 mmol) in xylene (10 mL) in
a sealed tube was heated at 180 ꢀC for 16 h. The reaction
mixture was cooled to room temperature and the solvent
removed in vacuo. The crude product was purified by flash
chromatography on silica gel, eluting with ethyl acetatee
light petroleum (1:9) to afford the title compound as a col-
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4.3.7. 4-Chloro-2,7-dimethyl-5H-chromeno[3,4-c]pyridine 8c
Following general procedure 5, the title compound was ob-
tained from O-methyl oxime 5c (0.139 g, 0.50 mmol) after
16 h at 180 ꢀC as a colourless solid (0.020 g, 16%); mp
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35
246.0683; C14H ClNOþH requires 246.0680); nmax
12
(CHCl3)/cmꢁ1 1600 (C]C), 1548 (C]C), 1448 (C]C),
1056 (CeO); dH (400 MHz; CDCl3) 7.54 (1H, d, J¼7.7 Hz,