Substituted 3,4-pyridynes: Clean cycloadditions

Article abstract of DOI:10.1039/a909772d

The stabilisation of 3,4-pyridyne (1) by an alkoxy group adjacent to the ring nitrogen is reported. The regioselective lithiation of 2-ethoxy- (14), 2-methoxy- (18), 2-isopropoxy- (19) and 6-isopropoxy- (26) -3-chloropyridines with tertbutyllithium at low temperatures, followed by elimination of lithium chloride affords 2- and 6-alkoxy-3,4-pyridynes. These species are trapped m situ with furan in a Diels-Alder reaction to give 5-8 in 66-89% yield, and do not give products typical of polymerisation or nucleophilic addition to the 3,4-pyridyne intermediates. As a comparison treatment of 3-chloropyridine with furan and LDA gives only 19% of adduct (4). We also report the novel use of the isopropoxy (rather than methoxy) group in these systems, which can act as a heteroatomic electron donating group which inhibits a-lithiation by tert-butyllithium because of its increased steric bulk. The Royal Society of Chemistry 2000.

Full text of DOI:10.1039/a909772d

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Substituted 3,4-pyridynes: clean cycloadditions
Stephen J. Connon and Anthony F. Hegarty*
Department of Chemistry, University College Dublin, Dublin 4, Ireland
1
Received (in Cambridge, UK) 13th December 1999, Accepted 28th February 2000
Published on the Web 31st March 2000
The stabilisation of 3,4-pyridyne (1) by an alkoxy group adjacent to the ring nitrogen is reported. The regioselective
lithiation of 2-ethoxy- (14), 2-methoxy- (18), 2-isopropoxy- (19) and 6-isopropoxy- (26) -3-chloropyridines with tert-
butyllithium at low temperatures, followed by elimination of lithium chloride affords 2- and 6-alkoxy-3,4-pyridynes.
These species are trapped in situ with furan in a Diels–Alder reaction to give 5–8 in 66–89% yield, and do not give
products typical of polymerisation or nucleophilic addition to the 3,4-pyridyne intermediates. As a comparison
treatment of 3-chloropyridine with furan and LDA gives only 19% of adduct (4). We also report the novel use of the
isopropoxy (rather than methoxy) group in these systems, which can act as a heteroatomic electron donating group
which inhibits α-lithiation by tert-butyllithium because of its increased steric bulk.
priate precursors with butyllithium, and used as a comparison
the trapping of unsubstituted 3,4-pyridyne (1) generated using
LDA.
Introduction
Pyridynes (didehydropyridines)1 are reactive intermediates
formally derived by the removal of two adjacent hydrogens
from a pyridine ring. Of the two possible regioisomers, 3,4-
pyridyne (1) has received the most synthetic attention.2a–d Many
Results and discussion
Treatment of 3-chloropyridine (9) and 3-bromopyridine (10)
with LDA at Ϫ78 ЊC results in regioselective lithiation at the
C-4 position to give the corresponding 3-halo-4-lithiopyridines
(11, 12).6 Furan is then added and the temperature allowed to
rise slowly to ambient, during which time elimination of
lithium halide occurs resulting in 1, which is intercepted in a
Diels–Alder reaction (Scheme 1) to give the required 5,8-epoxy-
5,8-dihydroisoquinoline (4).
methods of preparing this species in solution have emerged,
including dehydrohalogenation of 3- and 4-halopyridines,
dehalogenation of 3,4-dihalopyridines, lead tetraacetate oxid-
ation of 1-aminotriazolo[4.5]pyridine, loss of CO2 and N2 from
pyridine-3-diazonium carboxylate, and fluoride induced desilyl-
ation of trialkylsilylpyridyl triflates.3–5 3,4-Pyridyne can be
trapped in a Diels–Alder reaction with reactive dienophiles
(for example, furans). However compared to its carbocyclic
analogue, benzyne (2), generated by similar methods, the yields
of trapped product remain low,1 limiting their use as synthetic
intermediates. This indicates that the relative instability of 1
compared to 2 is related to the nature of the pyridyne bond
rather than how it is generated.
One possibility is that the pyridine ring nitrogen partially
polarises the strained aryne bond. If 3,4-pyridyne has some
dipole character (1a), then attack by nucleophiles may compete
effectively with cyclisation. We postulated that if this effect was
responsible for the lower yields of cyclised products associated
with pyridynes, it could be circumvented by generation of a
3,4-pyridyne with an electron donating substituent ‘ortho’ to
the ring nitrogen (3). We chose to investigate the furan trapping
of such species, generated by dehydrohalogenation of appro-
Scheme 1
The dependence of this process on the reaction temperature,
amounts of furan and base present and the order of addition
(base to substrate/substrate to base) was determined. From the
results of these experiments it emerged that 9 was a more robust
pyridyne precursor than 10, which is expected since α-lithio-
bromopyridines have a higher propensity for ring opening and
competing “Base Catalysed Halogen Dance” (BCHD) reac-
tions, making 11 more stable than 12 at Ϫ78 ЊC.3,6,7
Optimum conditions for pyridyne generation using this
method involved treating 9 with 1.1 and 10 equivalents of LDA
and furan, respectively. The order of addition of the base
proved to be unimportant. Under these conditions, 4 was
isolated in 19% yield. The other products in the crude reaction
DOI: 10.1039/a909772d
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This journal is © The Royal Society of Chemistry 2000
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Table 1 Yields of adduct formed from 2-substituted 3,4-pyridynes
mixture arose from addition of diisopropylamine to the aryne
(ca. 20%) and polymeric products (ca. 60%) derived from
addition of 11 to 1.
Precursor
Base
Adduct
Yield (%)a
In seeking to avoid these two wasteful processes, the depro-
tonation route to the lithiated precursor was initially aban-
doned in favour of a halogen–metal exchange methodology
at C-4 using the excellent protocol of Gribble and Saulnier,6
who obtained no base derived products when 1 was generated
from 3-chloro-4-iodopyridine and tBuLi, although the yield of
furan trapped product remained modest (<40%). To counter
the dipolar nature of these unsubstituted 3,4-pyridynes and
thus discourage polymerisation, an electron donating substitu-
ent was introduced at C-2. 2-Ethoxy-3-chloro-4-iodopyridine
(15) and 2-piperidino-3-chloro-4-iodopyridine (17) were pre-
pared from 2,3-dichloropyridine (13) by the routes outlined in
Scheme 2.
13
14
16
13
14
16
18
19
nBuLi
nBuLi
nBuLi
tBuLi
tBuLi
tBuLi
tBuLi
tBuLi
20
6
21
20
6
21
5
7
0
29
36
0
71
0
74
66
a Refers to isolated yields after chromatography.
Scheme 4
that stabilisation of the 3-anion by coordination of nitrogen to
the lithium counterion (23) is responsible for this effect.
The small decrease in trapped product yield which was
observed with increasing steric bulk at C-2 encouraged us to
generate a 6-substituted 3,4-pyridyne. In this case the substitu-
ent is not in close proximity to the aryne bond but still adjacent
to the ring nitrogen. With this in mind we prepared 25 and 26
from 2,5-dichloropyridine (24) and the appropriate alkoxides
(Scheme 5).
Scheme 2
t
Lithiation of these precursors with BuLi and subsequent
trapping with furan gave the desired adducts (6, 21) in 63 and
74% yields respectively, with no polymeric products detected in
the crude mixture.
Although this was a pleasing result, these precursors proved
difficult to prepare in good yield owing to the inefficiency of
the iodination reaction. In order to overcome this difficulty a
more practical 2-substituted pyridyne precursor was required.
With this in mind it was decided to generate pyridynes from
3-chloropyridines with various electron donating substituents
at the 2 position using n- or tert-butyllithium as the lithiating
reagent with 10 equivalents of furan trap (Scheme 3).
Scheme 5
t
When 25 was treated with BuLi and furan as before, the
usual colourless to yellow colour change associated with lithi-
ation was observed but only starting material was isolated on
workup. Using similar reaction conditions, 26 gave only 43%
yield of trapped material (8). The regioselectivity of lithiation
in these compounds therefore seemed to be in question. In
order to test this, 25 and 26 were treated with tBuLi, holding the
anion at Ϫ78 ЊC for various times (t) followed by quenching
with 4.0 equivalents of trimethylsilyl chloride (TMSCl) as
1
shown in Scheme 6. H NMR analysis of the crude reaction
mixtures after workup gave the results summarised in Table 2.
Scheme 3
The 2-alkoxypyridines all gave good yields of trapped
product with in each case a complete absence of polymer; the
only other product detected was starting material (Table 1). In
contrast 2,3-dichloropyridine (13) gave only polymer, irre-
spective of the base used. The failure of 16 to generate the
corresponding aryne with tBuLi was surprising; instead
2-piperidinopyridine (22) was formed in quantitative yield. A
sample of 22 was also obtained independently by treating
2-chloropyridine with piperidine in refluxing toluene overnight.
This arises presumably from halogen–metal exchange at C-3
(Scheme 4).
Examples of halogen–metal exchange reactions involving
chlorine with butyllithium in pyridine systems are rare, and
then usually at C-4 in poly-chloro substrates.8,9 It is possible
Scheme 6
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ethanol (20 cm3) and the resulting suspension was stirred for 30
Table 2 Lithiation of 2-alkoxy-5-chloropyridines
min, or until the sodium had disappeared and hydrogen liber-
ation ceased. 2,3-Dichloropyridine (0.88 g, 5.95 mmol) was
added and the resulting mixture refluxed overnight. The reac-
tion vessel was allowed to cool to room temperature and
quenched with saturated aqueous NH4Cl (10 cm3) and
extracted with CHCl3 (4 × 25 cm3). The organic extracts were
combined, dried (Na2SO4), and the solvent removed in vacuo to
give a yellow liquid (0.92 g). Purification by flash chromato-
graphy (90:10 light petroleum–EtOAc, Rf 0.55) gave 2-ethoxy-
3-chloropyridine12 (782 mg, 83%) as a colourless liquid (Found:
C, 53.2; H, 5.0; Cl, 22.6; N, 8.7. C7H8ClNO requires: C, 53.35;
H, 5.1; Cl, 22.5; N, 8.9%); δH (CDCl3) 1.44 (t, 3H, J = 7.2), 4.43
(q, 2H, J = 7.2), 6.81 (dd, 1H J1 = 7.7, J2 = 5.0), 7.61 (dd, 1H,
J1 = 7.7, J2 = 1.7), 8.04 (dd, 1H, J1 = 5.0, J2 = 1.7); δC (CDCl3)
14.1, 61.4, 116.9, 116.9, 138.1, 144.6, 159.0; m/z 157 (Mϩ), 142,
129, 113, 94, 78.
25a, 26a
25b, 26b
25c, 26c
Compound
t/min
(%)
(%)
(%)
25
25
25
26
26
26
10
20
60
10
20
60
82
96
100
0
0
0
10
4
0
56
68
100
8
0
0
44
32
0
It is clear that in the case of 25, that the strong directing
ability of the methoxy group towards ‘ortho’ lithiation7 governs
the regioselectivity. Deprotonation at position C-3 is predomin-
ant initially and then becomes total to form 25a, even if one
might expect the proton at C-4 to be more acidic than its
counterpart at C-3.10 In the isopropyl analogue 26, however,
the bulky isopropoxy group prevents α lithiation by the large
tBuLi molecule. Here the kinetic 26c and thermodynamic 26b
products are present in almost equal amounts if the reaction is
quenched after 10 min, indicating initial lithiation at C-6 and
C-4. This converts over time to the more stable C-4 anion,
giving only 26b after quenching. With this isopropoxypyridine
(26), no deprotonation at C-3 is observed. With a method of
generating a 6-substituted 3,4-pyridyne now in hand, 26 was
lithiated and trapped with furan to give adduct 8 as the sole
product in 89% yield.
In summary, 2-alkoxy (14, 18, 19) and 6-isopropoxypyridines
(26), have been shown to serve as excellent precursors for substi-
tuted 3,4-pyridynes under direct lithiation conditions at low
temperatures. The high sensitivity of 1 to substituents at both
C-2 and C-6 appears to support the proposal of aryne ‘triple’
bond polarisation by the ring nitrogen, as none of the ubiqui-
tous polymeric material was formed in cases where the precur-
sor contained an electron donating group at these positions.
Since the only other product detected in the cases reported here
was starting material, this also shows that the 3,4-pyridynes
derived from these species are resistant to nucleophilic attack by
their lithiated precursors. The ease of preparation of these
compounds by direct lithiation, in addition to superior yields
of cycloadduct with furan, may make them of more synthetic
value than present literature methods.
2-Ethoxy-3-chloro-4-iodopyridine (15)
Procedure B. An oven dried, 25 cm3 three-neck round-
bottomed flask fitted with an internal thermometer, addition
funnel, nitrogen adapter, rubber septum and magnetic stirring
bar was charged with dry THF (5 cm3) and dry diiso-
propylamine (0.49 cm3, 3.49 mmol) at Ϫ78 ЊC under N2 with
stirring. To this was added n-butyllithium (1.7 cm3 of 2.5 M
solution in hexane; 4.19 mmol) via a syringe. This was stirred
at Ϫ78 ЊC for 20 min, and then over 15 min 2-ethoxy-3-
chloropyridine (0.55 g, 3.49 mmol) in THF (2 cm3) was added,
keeping the internal temperature at Ϫ78 ЊC to give a bright
yellow solution. This mixture was stirred for 20 min at Ϫ78 ЊC
and a solution of iodine (1.06 g, 4.19 mmol) in THF (6 cm3) was
added via syringe. The mixture was allowed to warm to room
temperature overnight and poured into 8% aqueous (10 cm3)
sodium bisulfite and extracted with Et2O (3 × 15 cm3). The
combined organic extracts were washed with 10% NaHCO3 (20
cm3), water (20 cm3) and brine (50 cm3), dried (Na2CO3), and
concentrated in vacuo to give crude material (0.62 g) consisting
of mostly 14 and 15. These were carefully separated by flash
chromatography (90:10 light petroleum–EtOAc, Rf 0.64) to
give 2-ethoxy-3-chloro-4-iodopyridine (0.24 g, 24%) as a
colourless oil (Found: C, 29.5; H, 2.6; N, 5.2. C7H7ClINO
requires: C, 29.7; H, 2.5; N, 4.9%); δH (CDCl3) 1.44 (t, 3H,
J = 7.2), 4.43 (q, 2H, J = 7.2), 7.23 (d, 1H, J = 5.3), 7.56 (d, 1H,
J = 5.3); δC (CDCl3) 14.2, 63.5, 110.8, 123.4, 127.5, 144.3, 158.9;
m/z 283 (Mϩ), 268, 255, 239.
Experimental
General
2-Piperidino-3-chloropyridine (16)
1H NMR spectra were recorded at 270 MHz on a JEOL JMN-
GX270 FT spectrometer using tetramethylsilane as a reference.
Chemical shifts quoted in ppm and coupling constants in Hz.
13C decoupled spectra were recorded at 67.8 MHz on this
instrument. A VG analytical 7070 mass spectrometer, with
attached INCOS 2400 data system, in the EI mode, was used
for recording mass spectra. Thin layer chromatography (TLC)
was performed on Merck precoated Kieselgel 60F254 slides, and
Merck silica 9385, particle size 0.04–0.063 mm, was used for
flash chromatography. Reaction solvents were dried according
to standard literature procedures.11 Microanalyses were carried
out by the Microanalytical Laboratory, University College
Dublin.
In a 50 cm3 round-bottomed flask 2,3-dichloropyridine (1.43 g,
9.66 mmol) was dissolved in dry toluene (10 cm3), and distilled
piperidine (3 cm3, 30.38 mmol) was added. A condenser was
fitted and the resulting solution was heated under reflux over-
night. Work-up and purification by flash chromatography
(CHCl3, Rf 0.88) gave 2-piperidino-3-chloropyridine (1.46 g,
77%) as a colourless liquid (Found: C, 61.25; H, 6.7; Cl, 17.8; N,
14.45. C10H13ClN2 requires: C, 61.1; H, 6.7; Cl, 18.0; N, 14.2%);
δH 1.59 (m, 6H), 3.14 (m, 4H), 6.63 (dd, 1H, J1 = 7.7, J2 = 4.8),
7.42 (dd, 1H, J1 = 7.7, J2 = 1.7), 8.04 (dd, 1H, J1 = 4.8, J2 = 1.7);
m/z 196 (Mϩ), 161, 113, 84.
Note: unless otherwise specified ‘work-up’ refers to concen-
tration of the reaction mixture in vacuo, taking up the residue
in chloroform, washing with 10% NaHCO3, water, and brine
followed by drying (Na2SO4) of the organic layer and removal
of the solvent in vacuo.
2-Piperidino-3-chloro-4-iodopyridine (17)
Procedure B was followed using dry THF (5 cm3), diisopro-
pylamine (0.28 cm3, 2.05 mmol), n-butyllithium (1.28 cm3 of
1.6 M solution in hexane, 2.05 mmol), 2-piperidino-3-chloro-
pyridine (402 mg, 2.05 mmol). Work-up gave crude material
(451 mg) consisting of mostly 16 and 17. These were carefully
separated by flash chromatography (90:10 light petroleum–
EtOAc, Rf 0.75) to give 2-piperidino-3-chloro-4-iodopyridine
(101 mg, 15%) as a viscous colourless liquid (Found: C, 37.2; H,
Precursors: 2-ethoxy-3-chloropyridine (14)
Procedure A. In a 100 cm3 round-bottomed flask fitted with a
stirring bar at 0 ЊC, sodium metal (ca. 0.5 g) was added to dry
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3.6; N, 8.8. C10H12ClIN2 requires: C, 37.2; H, 3.75; N, 8.7%); δH
(CDCl3) 1.63 (m, 6H), 3.24 (m, 4H), 7.32 (d, 1H, J = 5.1), 7.74
(d, 1H, J = 5.1); δC (CDCl3) 25.4, 25.8, 25.9, 50.7, 51.0, 111.9,
127.3, 128.0, 145.3, 159.8; m/z 322 (Mϩ), 287, 239, 159.
syringe. The mixture was allowed to warm to room temperature
overnight. The insoluble polymeric material was removed by
filtration and washed well with ether. The washings were com-
bined and after work-up the crude product (3.74 g) was purified
by flash chromatography (EtOAc, Rf 0.22) to give 5,8-epoxy-
5,8-dihydroisoquinoline (0.743 g, 19%) as a light amber oil
(Found: C, 74.2; H, 4.8; N, 9.5. C9H7NO requires: C, 74.5; H,
4.9; N, 9.65%); δH (CDCl3) 5.72 (s, 1H), 5.82 (s, 1H), 6.97 (dd,
1H, J1 = 5.5, J2 = 1.8), 7.04 (dd, 1H, J1 = 5.5, J2 = 1.8), 7.23 (d,
1H, J = 4.6), 8.28 (d, 1H, 4.6), 8.44 (s, 1H).
2-Methoxy-3-chloropyridine (18)
Procedure A was followed using 2,3-dichloropyridine (0.71 g,
4.8 mmol) and dry methanol (20 cm3). Purification by flash
chromatography (90:10 light petroleum–EtOAc, Rf 0.59) gave
2-methoxy-3-chloropyridine13 (572 mg, 83%) as a colourless
liquid (Found: C, 50.1; H, 4.15; Cl, 24.95; N, 10.0. C6H6ClNO
requires: C, 50.2; H, 4.2; Cl, 24.7; N, 9.8%); δH (CDCl3) 3.94
(s, 3H), 6.76 (dd, 1H, J1 = 7.7, J2 = 4.9), 7.61 (dd, 1H, J1 = 7.7,
J2 = 1.7), 8.04 (dd, 1H, J1 = 4.9, J2 = 1.7); m/z 143 (Mϩ), 129,
113, 101, 78.
1-Methoxy-5,8-epoxy-5,8-dihydroisoquinoline (5)
Procedure C. An oven dried 25 cm3 round-bottomed flask
under N2 fitted with a stirring bar and a septum was charged
with a solution of 2-methoxy-3-chloropyridine (327 mg, 2.28
mmol) in dry THF (5 cm3) under N2 and cooled to Ϫ78 ЊC.
After 20 min at Ϫ78 ЊC, tert-butyllithium (1.5 cm3 of a 1.7 M
solution in hexane, 2.51 mmol) was added slowly with stirring
to give a cloudy bright yellow solution. After 60 min at Ϫ78 ЊC,
freshly distilled furan (1.66 cm3, 22.8 mmol) was added and
the mixture allowed to warm to room temperature overnight.
After work-up the crude product was purified by flash chrom-
atography (CHCl3, Rf 0.26) to give 1-methoxy-5,8-epoxy-5,8-
dihydroisoquinoline (294 mg, 74%) as a light amber oil (Found:
C, 68.85; H, 5.3; N, 7.8. C10H9NO2 requires: C, 68.6; H, 5.2; N,
8.0%); δH (CDCl3) 3.95 (s, 3H), 5.72 (s, 1H), 5.9 (s, 1H), 6.95 (d,
1H, J = 4.8), 7.02 (dd, 1H, J1 = 5.1, J2 = 2.0), 7.10 (dd, 1H,
J1 = 5.1, J2 = 2.0), 7.92 (d, 1H, J = 4.8); δC (CDCl3) 53.4, 79.7,
82.3, 111.1, 130.0, 142.3, 143.8, 145.4, 157.1, 163.4; m/z 175
(Mϩ), 146, 133, 117.
2-Isopropoxy-3-chloropyridine (19)
Procedure A was followed using 2,3-dichloropyridine (0.65 g,
4.39 mmol) and dry propan-2-ol (20 cm3). To generate the
alkoxide, heating to 50 ЊC was required. Purification by flash
chromatography (90:10 light petroleum–EtOAc, Rf 0.48) gave
2-isopropoxy-3-chloropyridine (535 mg, 71%) as a colourless
oil (Found: C, 56.4; H, 5.9; Cl, 20.5; N, 8.0. C8H10ClNO
requires: C, 56.0; H, 5.9; Cl, 20.7; N, 8.2%); δH (CDCl3) 1.38 (d,
6H, J = 6.2), 5.35 (septet, 1H, J = 6.2), 6.77 (dd, 1H, J1 = 7.7,
J2 = 5.0), 7.60 (dd, 1H, J1 = 7.7, J2 = 1.6), 8.02 (dd, 1H, J1 = 5.0,
J2 = 1.6); m/z 171 (Mϩ), 129, 101, 94, 78.
5-Chloro-2-methoxypyridine (25)
Procedure A was followed using 2,5-dichloropyridine (1.22 g,
8.24 mmol) and dry methanol (20 cm3). Purification by flash
chromatography (90:10 light petroleum–EtOAc, Rf 0.6) gave
5-chloro-2-methoxypyridine13 (1.02 g, 86%) as a colourless
liquid (Found: C, 50.3; H, 4.35; Cl, 24.55; N, 9.9. C6H6ClNO
requires: C, 50.1; H, 4.1; Cl, 24.7; N, 9.8%); δH (CDCl3) 3.88
(s, 3H), 6.67 (dd, 1H, J1 = 8.8, J2 = 0.7), 7.46 (dd, 1H, J1 = 8.8,
J2 = 2.6), 8.07 (dd, 1H, J1 = 2.6, J2 = 0.7); m/z 143 (Mϩ), 129,
113, 101, 78.
1-Ethoxy-5,8-epoxy-5,8-dihydroisoquinoline (6)
Procedure C was followed using 2-ethoxy-3-chloropyridine (403
mg, 2.56 mmol), tert-butyllithium (1.65 cm3 of a 1.7 M solution
in hexane, 2.81 mmol), furan (1.86 cm3, 25.6 mmol) and THF
(5 cm3). Work-up and flash chromatography (CHCl3, Rf 0.2)
gave 1-ethoxy-5,8-epoxy-5,8-dihydroisoquinoline (341 mg,
71%) as an amber oil (Found: C, 70.0; H, 5.9; N, 7.1. C11H11-
NO2 requires: C, 69.8; H, 5.9; N, 7.4%); δH (CDCl3) 1.37 (t, 3H,
J = 7.1), 4.40 (q, 2H, J = 7.1), 5.69 (s, 1H), 5.89 (s, 1H), 6.91 (d,
1H, J = 4.8), 6.97 (dd, 1H, J1 = 5.5, J2 = 2.1), 7.09 (dd, 1H,
J1 = 5.5, J2 = 2.1), 7.88 (d, 1H, J = 4.8); δC (CDCl3) 15.5, 62.5,
80.5, 83.2, 111.7, 130.7, 143.0, 144.6, 146.2, 157.8, 164.1; m/z
189 (Mϩ), 146, 133, 117.
5-Chloro-2-isopropoxypyridine (26)
Procedure A was followed using 2,5-dichloropyridine (0.98 g,
6.62 mmol) and dry propan-2-ol (20 cm3). To generate the
alkoxide, heating to 50 ЊC was required. Purification by flash
chromatography (90:10 light petroleum–EtOAc, Rf 0.46) gave
5-chloro-2-isopropoxypyridine (761 mg, 67%) as a colourless
oil (Found: C, 55.8; H, 5.75; Cl, 20.9; N, 8.4. C8H10ClNO
requires: C, 56.0; H, 5.9; Cl, 20.7; N, 8.2%); δH (CDCl3) 1.33 (d,
6H, J = 6.2), 5.23 (septet, 1H, J = 6.2), 6.62 (dd, 1H, J1 = 8.9,
J2 = 0.7), 7.48 (dd, 1H, J1 = 8.9, J2 = 2.8), 8.06 (dd, 1H, J1 = 2.8,
J2 = 0.7); m/z 171 (Mϩ), 129, 101, 94, 78.
1-Isopropoxy-5,8-epoxy-5,8 dihydroisoquinoline (7)
Procedure C was followed using 2-isopropoxy-3-chloropyridine
(288 mg, 1.68 mmol), tert-butyllithium (1.1 cm3 of a 1.7 M
solution in hexane, 1.85 mmol), furan (1.22 cm3, 16.8 mmol)
and THF (5 cm3). Work-up and flash chromatography (CHCl3,
Rf 0.2) gave 1-isopropoxy-5,8-epoxy-5,8-dihydroisoquinoline
(226 mg, 66%) as an amber oil (Found: C, 71.0; H, 6.5; N, 7.1.
C12H13NO2 requires: C, 70.9; H, 6.45; N, 6.9%); δH (CDCl3) 1.33
(d, 6H, J = 6.2), 5.30 (septet, 1H, J = 6.2), 5.67 (s, 1H), 5.87 (s,
1H), 6.89 (d, 1H, J = 4.8), 6.97 (dd, 1H, J1 = 5.5, J2 = 2.0), 7.11
(dd, 1H, J1 = 5.5, J2 = 2.0), 7.88 (d, 1H, J = 4.8); m/z 203 (Mϩ),
188, 146, 133, 117.
Trapped products: 5,8-epoxy-5,8-dihydroisoquinoline (4)
Note: as these compounds slowly aromatise over time,
immediate analysis is advised.
An oven dried, 100 cm3 three-neck round-bottomed flask
fitted with an internal thermometer, addition funnel, nitrogen
adapter, rubber septum and magnetic stirring bar was charged
with dry THF (20 cm3) and dry diisopropylamine (3.7 cm3, 26.4
mmol) at Ϫ78 ЊC under N2 with stirring. To this was added
n-butyllithium (16.5 cm3 of 1.6 M solution in hexane, 30 mmol)
dropwise, via syringe. This was stirred at Ϫ78 ЊC for 20 min and
then to this solution of LDA was added over 15 min 3-chloro-
pyridine (2.51 cm3, 26.4 mmol) in THF (5 cm3), keeping the
internal temperature at Ϫ78 ЊC. The resulting 3-chloro-4-
lithiopyridine partially precipitated as a white solid in a yellow
solution. This mixture was stirred for 20 min at Ϫ78 ЊC and
freshly distilled furan (19.2 cm3, 264 mmol) was added via a
3-Isopropoxy-5,8-epoxy-5,8-dihydroisoquinoline (8)
Procedure C was followed using 2-isopropoxy-5-chloropyridine
(479 mg, 2.79 mmol), tert-butyllithium (1.8 cm3 of a 1.7 M
solution in hexane, 3.07 mmol), furan (2 cm3, 27.9 mmol)
and THF (7 cm3). Work-up and flash chromatography (CHCl3,
Rf 0.18) gave 3-isopropoxy-5,8-epoxy-5,8-dihydroisoquinoline
(505 mg, 89%) as an amber oil (Found: C, 71.2; H, 6.3; N, 6.6.
C12H13NO2 requires: C, 70.9; H, 6.45; N, 6.9%); δH (CDCl3) 1.31
(d, 6H, J = 6.2), 5.24 (septet, 1H, J = 6.2), 5.63 (s, 1H), 5.73 (s,
1H), 6.63 (s, 1H), 6.89 (dd, 1H, J1 = 5.5, J2 = 2.1), 7.13 (dd, 1H,
1248
J. Chem. Soc., Perkin Trans. 1, 2000, 1245–1249

View Article Online
3 M. G. Reinecke, Tetrahedron, 1982, 38, 427.
J1 = 5.5, J2 = 2.1), 7.85 (s, 1H); δC (CDCl3) 22.0, 29.9, 68.2, 80.2,
81.5, 105.8, 111.5, 135.3, 139.4, 143.3, 161.1, 162.4; m/z 203
(Mϩ), 188, 146, 133, 117.
4 H. C. Van Der Plas and F. Roeterdink, The Chemistry of Functional-
Groups, Supplement C, Wiley, Chichester, 1983, p. 421.
5 M. Tsukazaki and V. Sniekus, Heterocycles, 1992, 32, 53.
6 M. Saulnier and G. Gribble, Heterocycles, 1993, 35, 151.
7 G. Queguiner, F. Marsais, V. Sniekus and J. Epsztajn, Adv.
Heterocycl. Chem., 1991, 52, 187.
Acknowledgements
8 J. D. Cook, B. J. Wakefield and C. J. Clayton, J. Chem. Soc., Chem.
Commun., 1967, 150.
9 J. D. Cook and B. J. Wakefield, J. Organomet. Chem., 1968, 13, 15.
10 (a) J. A. Zoltewicz, G. Grahe and C. L. Smith, J. Am. Chem. Soc.,
1969, 91, 5501; (b) In 3-chloropyridine H-4 is 53 times more
acidic than H-2 and H-5 (CH3ONa–CH3OD); J. A. Zoltewicz and
C. L. Smith, Tetrahedron, 1969, 25, 4331.
11 W. Amerego and E. Perrin, Purification of Laboratory Chemicals,
3rd edn., Pergamon, Oxford, 1988.
12 L. Lai, P. Lin, J. Wang, J. Hwu, M. Shiao and S. Tsay, J. Chem. Res.
(S), 1996, 4, 194.
S. C. is grateful to Bristol Myers-Squibb Corporation and to the
Irish-American Partnership for financial support.
References
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