Ortho-hydroxyalkylation of aminopyridines: A novel approach to heterocycles

Article abstract of DOI:10.1055/s-1999-3608

Reaction of 6-substituted N-alkyl-3-aminopyridines with aldehydes in the presence of dichlorophenylborane gives selectively 2-hydroxyalkyl-3- aminopyridines. Dehydration of the latter under pyrolytic or Lewis acid conditions generates a quinone methide imine intermediate which can undergo electrocyclic or [4+2] cycloaddition reactions to give naphthyridines, dihydronaphthyridines or tetrahydronaphthyridines. Palladium-catalyzed cyclization of the 2-(1-hydroxyallyl)-3-aminopyridines gives the corresponding 4-azaindoles.

Full text of DOI:10.1055/s-1999-3608

PAPER
1893
ortho-Hydroxyalkylation of Aminopyridines: A Novel Approach to
Heterocycles
Peter Zakrzewski, Mathew Gowan, Laird A. Trimble, Cheuk K. Lau*
Merck Frosst Centre For Therapeutic Research, P. O. Box 1005, Pointe Claire-Dorval, Quebec, Canada, H9R 4P8
Fax +1(514)4284900; E-mail: lau@merck.com
Received 7 June 1999; revised 23 June 1999
Abstract: Reaction of 6-substituted N-alkyl-3-aminopyridines with
aldehydes in the presence of dichlorophenylborane gives selectively
2-hydroxyalkyl-3-aminopyridines. Dehydration of the latter under
pyrolytic or Lewis acid conditions generates a quinone methide
imine intermediate which can undergo electrocyclic or [4+2] cy-
cloaddition reactions to give naphthyridines, dihydronaphthyridines
or tetrahydronaphthyridines. Palladium-catalyzed cyclization of the
2-(1-hydroxyallyl)-3-aminopyridines gives the corresponding 4-
azaindoles.
Key words: o-hydroxyalkylaminopyridines, naphthyridines, dihy-
dronaphthyridines, tetrahydronaphthyridines, 4-azaindoles, hetero-
cycles, boron, Lewis acids
o-Hydroxyalkylaminopyridines are useful synthetic inter-
mediates for preparing nitrogen containing heterocycles.
Pyrolysis of these compounds generates a quinone me-
thide imine intermediate that can be trapped by an olefin
in a [4+2] cycloaddition to give dihydronaphthyridines.1
Recently, we reported a facile method to prepare various
substituted o-N-alkylaminobenzyl alcohols as o-quinone
methide imine precursors.2 Dehydration of these o-N-
Scheme 1
alkylaminobenzyl alcohols under pyrolytic or Lewis acid
conditions, followed by trapping the corresponding o-
quinone methide imine intermediates with an olefin via
N-methylaniline,2 3-(methylamino)pyridine (1a) was
treated with dichlorophenylborane at 80 °C for 2 hours.
Benzaldehyde and diisopropyethylamine were then added
to the aminoborane complex at 0 °C. The mixture was al-
lowed to react at 0 °C for 4 hours and then at room tem-
prature for 20 hours. No alkylation product formation was
observed. The lack of reactivity of 1a may be attributed to
the competing complexation of the basic nitrogen on the
pyridine ring with the borane reagent. Substitution ortho
to the pyridine nitrogen is known to reduce the interaction
of that nitrogen with Lewis acids.5,6 Thus, 2-methoxy-5-
(methylamino)pyridine (1b) was prepared and the effect
of the 2-substitution on the ortho-hydroxyalkylation reac-
tion was studied. Treatment of 1b with dichlorophenylbo-
rane followed by the addition of benzaldehyde and
diisopropylethylamine gave the corresponding 2-(1-hy-
droxybenzyl)-3-(methylamino)pyridine (2a) in 65% yield
(see experimental). In contrast to the N-alkylanilines, the
formation of the aminoborane complex in this case could
be achieved at 0 °C instead of 85 °C. Similarly, 2-chloro-
5-(methylamino)pyridine (1c) gave a 72% yield of the ex-
pected product 2b. Although the 2-position of 3-aminopy-
ridine is the preferred site of electrophilic substitution,6 it
is still of interest to note that none of the 4-substituted
electrocyclic or [4+2] cycloaddition reactions has led to
the synthesis of dihydro- and tetrahydroquinoline deriva-
tives respectively.2 We also reported that the analogous 2-
(1-hydroxyallyl)anilines can be cyclized in the presence
of a palladium catalyst to give indoxyls.3 Herein we report
the extension of this methodology to prepare a variety of
2-hydroxyalkyl-3-N-alkylaminopyridines and its applica-
tion to the synthesis of naphthyridines, dihydronaphthy-
ridines, tetrahydronaphthyridines and 4-azaindoles
(Scheme 1).
o-Hydroxyalkylation of N-Alkylaminopyridines
Dichlorophenylborane is a versatile reagent that has been
used in the ortho-specific alkylation of phenols and
anilines.2,4 We were interested to see if this methodology
can be applied to aminopyridines and other heterocycles
in spite of the possible coordination of the pyridine nitro-
gen with the boron reagent and the deactivation of the
ring. Also of interest is the regiochemistry of the proposed
reaction if it does proceed. 3-Aminopyridine was chosen
initially for this study, derivatives of which were available
commercially. Using the methodology we developed for
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P. Zakrzewski et al.
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product was observed. Placing a chloro substituent at the
2-position ortho to the amino group (1d) also failed to
force alkylation at the 4-position. The results are summa-
rized in Table 1.
Table 2 Synthesis of 3-Amino-2-(1-hydroxyalkyl)pyridines 2c-l
Table 1 Synthesis of 3-Amino-2-(1-hydroxybenzyl)pyridines 2a,b
The successful reaction of 1b and 1c with benzaldehyde
established the feasibility of the ortho-hydroxyalkylation
reaction of 3-N-alkylaminopyridines. The extension of
this methodology using other aldehydes was examined
next. 2-Methoxy-5-(methylamino)pyridine (1b) reacted
readily with cinnamaldehyde, an α,β-unsaturated alde-
hyde, to give the corresponding 2-(1-hydroxy-3-phenyl-
allyl)-3-(methylamino)pyridine (2c) in 58% yield. Yields
of the reactions of 1b with acrolein and crotonaldehyde
were slightly lower. They gave yields of only 40 and 46%
of 2d and 2e, respectively. Significant amounts of starting
material was recovered in both cases. The reaction did not
perform as well with enolizable aldehydes. Compound 1b
gave only 9% of the desired product 2f (not fully charac-
terized) as a mixture (1:1) of diastereomers when reacted
with citronellal and did not react with propionaldehyde at
all. 2-Chloro-5-(methylamino)pyridine (1c) reacted with
cinnamaldehyde to give 2g in 62% yield but gave only
traces of desired product when reacted with acrolein. It
appeared that the chloro-substituted pyridine is less reac-
tive. These results are summarized in Table 2.
hydroquinolines.2b Thermolysis of the analogous 2-(1-
hydroxyallyl)-3-N-(methylamino)pyridines 2 is expected
to behave similarly to give the dihydronaphthyridines 3.
Thus, when 2c was pyrolysed at 180 °C (refluxing dichlo-
robenzene) for 2.75 hours, the dihydro-1,5-naphthyridine
3a was isolated in 31% yield. Compound 3a was very un-
stable, turning green immediately when in contact with
air, and it decomposed rapidly at ambient temperature
even under nitrogen. Thermolysis of the crotyl alcohol de-
rivative 2e gave no isolable product even though there is
some evidence that the desired product may have formed.
It appeared that the dihydronaphthyridine product that
was formed was very unstable and decomposed readily
under the reaction conditions. In contrast, the chloropyri-
dine derivative 2g cyclized readily at lower temperature
(150 °C) and shorter time (0.25 h) to give the correspond-
ing dihydronaphthyridine derivative 3b in 68% yield.
Thermolysis of the 5-allylamino-2-methoxy analog 2h at
180°C for 0.25 hour also gave a better yield of the dihy-
dronaphthyridine product 3c (65%) than did the N-methyl
compound 2c. It is interesting to find that during this reac-
tion the corresponding aromatized naphthyridine 4a was
also isolated in 28% yield. When 2h was heated to 180 °C
for 20 hours, none of the dihydro compound 3c was ob-
tained, instead, the aromatized naphthyridine 4a was iso-
lated in 43% yield. Apparently, the intermediate dihydro
compound was sensitive to the trace amount of air present
in the reaction and aromatized readily with concomitant
elimination of the allyl group. Whereas pyrolysis of the
crotyl alcohol derivative 2e gave no isolable product, the
5-allylamino crotyl alcohol derivative 2j gave 16% yield
of the corresponding dihydro product 3d. The N-allyl sub-
stituent seems to impart some stability to the dihydro
The 5-allylamino-2-methoxy derivative 1e behaved simi-
larly. Reaction of 1e with benzaldehyde and cinnamalde-
hyde gave 2h and 2i in 55 and 40% respectively. With
crotonaldehyde, 1e gave only 32% yield of 2j. In contrast,
reaction of the 5-allylamino-2-chloropyridine (1f) with
benzaldehyde and cinnamaldehyde gave significantly bet-
ter yields of the corresponding products 2k (80%) and 2l
(79%), respectively. Even though 1f gave a better yield of
the alkylation product with cinnamaldehyde than 1e, com-
pound 1f did not react with acrolein.
Synthesis of Dihydro-1,5-naphthyridines
Thermolysis of 2-(1-hydroxyallyl)-N-alkylanilines are
known to generate o-quinone methide imine intermedi-
ates which can undergo electrocyclic reactions to give di-
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ortho-Hydroxyalkylation of Aminopyridines: A Novel Approach to Heterocycles
1895
have been shown to react with olefins in a [4+2] cycload-
dition reaction.2 Extension of this methodology to 3-alkyl-
aminopyridines 2 was successful. Treatment of 2a with
BF3◊OEt2 (2 equiv) and allyltrimethylsilane (2 equiv) at
60°C in dichloroethane gave a 50% yield of the corre-
sponding tetrahydronaphthyridine derivative 5a (Table
5). The reaction is stereoselective, the two substituents at
positions 2 and 4 are cis as expected from an endo [4+2]
cycloaddition reaction. Strong NOE was observed be-
tween H-2 and H-4 indicating that the two protons are di-
axial. This was further supported by the large trans diaxial
coupling between H-2 and H-3ax(J = 9.6 Hz) and H-4 and
H-3ax(J = 10.1 Hz). Reaction of 2a with cyclopentene re-
quires THF as cosolvent and gave 5b in 65% yield with a
cis ring junction in which all three hydrogens are cis to
each other. The regio- and relative stereochemistry were
determined by 2D-COSY and NOSEY experiments.
Table 3 Synthesis of Dihydro-1,5-naphthyridines 3
compounds. Thermolysis of the chloro-N-allyl derivative Strong NOE was observed between the ring junction pro-
2l gave a 57% yield of the corresponding dihydronaphthy- tons as well as the benzylic proton. Reaction of allyltri-
ridine 3e. The results are summarized in Table 3.
methylsilane with the 2-chloro-N-allyl analog 2k gave the
corresponding tetrahydronaphthyridine 5c in 42% yield.
The stereochemistry of 5c is similar to that of 5a.
Synthesis of 1,5-Naphthyridines
The ease in removal of the N-allyl substituent has led to
the preparation of the N-allyl-1,2-dihydronaphthyridines
described above as precursors to 1,5-naphthyridines.
There are few other references in the literature to methods
for the synthesis of 1,5-naphthyridines.7 As mentioned
earlier, thermolysis of the 5-allylamino-2-methoxycin-
namyl alcohol (2h) gave initially the dihydronaphthyri-
dine 3c, which upon heating for an extended period of
time gave the fully aromatized 1,5-naphthyridine 4a in
43% yield. The dihydronaphthyridine 3c could also be
converted to 4a in 54% yield when treated with tet-
rakis(triphenylphosphine)rhodium hydride in the pres-
ence of trifluoroacetic acid at 85 °C.2b Similarly, 3d and
3e were converted to the corresponding 1,5-naphthyridine
derivatives 4b and 4c in yields of 51 and 52%, respective-
ly. The results are summarized in Table 4.
Table 5 Synthesis of Tetrahydronaphthyridines 5
Synthesis of a Octahydrobenzo[b][1,5]naphthyridine
Derivative
Table 4 Synthesis of 1,5-Naphthyridines 4
As mentioned earlier, ortho-hydroxyalkylation of 2-meth-
oxy-5-(methylamino)pyridine (1b) with citronellal gave
very poor yield of 2f. This compound was intended as a
substrate for an intramolecular [4+2] cycloaddition reac-
tion. However, in a misguided experiment where diiso-
propylamine was absent, 1b reacted with citronellal in the
presence of dichlorophenylborane to give the octahy-
drobenzo[b][1,5]naphthyridine 6 {[α]D +23 (c = 0.9,
CHCl3)} in 40% yield. The formation of 6 was stereose-
lective as only one single isomer was obtained. The rela-
tive stereochemistry was determined by 2D-COSY and
NOSEY, HMQC and HMBC experiments. The vicinal
coupling constant of the protons across the ring junction,
J(5a, 9a), was measured to be 10.8 Hz which is consistent
with a trans ring junction. The 7-methyl substituent was
determined to be equatorial based on the analysis of the
coupling constant of H-7 and H-6ax (δ 0.85). This proton
appeared as an apparent quartet, due to approximate equal
Lewis Acid-Catalyzed [4+2] Cycloaddition Reactions
ortho-Quinone methide imines generated from treatment
of N-alkyl-2-(1-hydroxyalkyl)anilines with a Lewis acid
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1896
P. Zakrzewski et al.
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geminal and two trans diaxial vicinal coupling (11.0 Hz). by an inseparable impurity. Without further characteriza-
H-7 and is therefore axial and the methyl substituent is tion, compound 9c was treated with tetrabutylammonium
equatorial. The formation of 6 is most likely a cationic fluoride in the presence of methyl bromoacetate to give
process. The proposed mechanism is shown in Scheme 2. the O-alkylated product 10 in 55% yield (Scheme 3). No
A small amount (4%) of the precursor 7 was also isolated. C-2 alkylated product was observed. The 2-chloro-5-(me-
thylamino)cinnamyl alcohol derivative 8d behaved simi-
larly, but it required one equiv. of PdCl2(MeCN)2 for the
cyclization and gave the corresponding 4-azaindoxyl de-
rivative 9d in 54% yield.
Scheme 3
Scheme 2
In summary, we have shown that ortho-hydroxyalkylation
of 3-N-alkylaminopyridine can be achieved readily, in a
regioselective manner, using dichlorophenylborane as the
chelating agent. The resulting 3-N-alkylamino-2-(1-hy-
Synthesis of 4-Azaindoles
Palladium-catalyzed intramolecular cyclization of 2-allyl-
aniline derivatives to indoles is well documented.8 Re-
cently, we have reported the palladium-assisted
cyclization of 2-(1-hydroxyallyl)anilines to indoxyls.3
Herein, we have successfully applied this methodology to
the synthesis of 4-azaindoxyls 9 in good yields. Protection
of the allylic alcohols 2 with a t-butyldimethylsilyl sub-
stituent followed by the treatment of the resulting siloxy-
allyl intermediates 8 with 20 mol% of PdCl2(MeCN)2, 1.5
equivalent of benzoquinone as reoxidant, three equiva-
lents of K2CO3, and ten equivalents of LiCl in THF gave
the corresponding 4-azaindoxyls 9 in very good yields.
The results are summarized in Table 6.
droxyallyl)pyridines serve as key intermediates in the
syntheses of naphthyridines, dihydronaphthyridines, tet-
rahydronaphthyridines and 4-azaindoles.
1H NMR and 13C NMR spectra were measured with a Bruker
AMX300, Bruker ARX400, or Bruker ARX 500 Spectrometer.
Melting points were measured on a Büchi 510 melting point appa-
ratus and are uncorrected. Low-resolution mass spectral analyses
were performed on a PE/SCIEX LC-MS. Exact masses were ob-
tained by high resolution mass spectroscopy performed by Dr. O.
Maimer of McGill University, Montreal, Quebec. Elemental analy-
ses were performed at the University of Montreal, Montreal, Que-
bec. IR spectra were obtained on a Perkin-Elmer Infrared
Spectrophotometer, Model 681. Flash chromatography was per-
formed using Merck silica gel 60, 230–400 mesh and tlc using
Merck silica gel 60F 254 sheets.
Table 6 Synthesis of 4-Azaindoles
N-Alkylation of Aminopyridines; General Procedure A
N-Alkylation of aminopyridines was performed by treating the ami-
nopyridine with LDA followed by the addition of an alkyl halide.
The LDA was prepared freshly from diisopropylamine (100 mmol)
and BuLi (2.5 M) in anhyd THF (100 mL). The LDA was added
dropwise to an anhyd THF (100 mL) solution of aminopyridine at –
78°C. The mixture was warmed to 0 °C and allowed to react for 1 h
before MeI (7.78 mL, 125 mmol) was added dropwise. The reaction
was kept at –78 °C for 2 h and then allowed to warm to r.t. over-
night. Aq NH4Cl (200 mL) and EtOAc (400 mL) were added. The
organic extracts were washed with brine (200 mL) and dried
(MgSO4). The mixture was filtered and concentrated under vacuum.
The crude product was purified by flash chromatography on silica
gel.
Silylation of the 2-methoxy-5-(methylamino)pyridine de-
rivative 2d gave a 77% yield of 8a, which was then cy-
clized to give the azaindole 9a in essentially quantitative
yield. Cyclization of the crotyl alcohol derivative 8b gave
only 51% yield of 9b. In the case of the N-allyl analog 8c,
the cyclization gave 63% of 9c which was contaminated
3-Amino-N-methylpyridine (1a)
Yield: 17%.
1H NMR (400 MHz, CD3COCD3): δ = 2.79 (d, 3 H, J = 4.6 Hz,
CH3N), 5.20 (br s, 1 H, NH), 6.88 (m, 1 H), 7.05 (m, 1 H), 7.81 (dd,
1 H, J = 4.6, 1.3 Hz), 8.00 (d, 1 H, J = 3.5 Hz).
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ortho-Hydroxyalkylation of Aminopyridines: A Novel Approach to Heterocycles
1897
13C NMR (100.6 MHz, CD3COCD3): δ = 121.9, 128.6, 140.5,
HRMS: m/z
calcd. for C8H10N2Cl
(M+1):169.0533;
142.3, 151.1.
found:169.0533.
HRMS: m/z calcd. for C6H9N2 (M + 1):109.0765; found:109. 0765.
o-Hydroxyalkylation of N-Alkylaminopyridines; General Pro-
cedure B
5-Amino-2-methoxy-N-methylpyridine (1b)
Yield: 51%.
IR (film) ν = 3320 (NH), 1570, 1500, 1410, 1360, 1250 cm–1.
1H NMR (400 MHz, CD3COCD3): δ = 2.77 (d, 3 H, J = 5.4 Hz,
CH3N), 3.76 (s, 3 H, CH3O), 4.59 (br s, 1 H, NH), 6.55 (d, 1 H,
J = 8.8 Hz, C3-H), 7.04 (dd, 1 H, J = 8.8, 2.9 Hz, C4-H), 7.55 (d, 1
H, J = 3.0 Hz, C6-H).
13C NMR (100.6 MHz, CD3COCD3): δ = 35.3, 57.3, 115.3, 129.8,
133.9, 146.2, 161.6.
Dichlorophenylborane (3.6 mmol) was added to a cold (0 °C) solu-
tion of N-alkyl-aminopyridine (3 mmol) in dichloroethane (5 mL).
The mixture was stirred at 0 °C for 1 h. Diisopropylethylamine (7.2
mmol) was added to the mixture followed by the addition of the cor-
responding aldehyde (1 to 2 equiv) in dichloroethane (2.5 mL). The
temperature was kept constant at 0 °C for the duration of the reac-
tion. The reaction was quenched with aq NH4OH (3 mL) and mixed
vigourosly for 1 min. The mixture was diluted with Et2O (100 mL),
filtered through a Florisil column, and eluted with 25–40% EtOAc/
hexane. The eluate was concentrated in vacuo, the crude product
was chromatographed on silica gel and eluted with varying ratios of
EtOAc/hexane allowing for optimum separation.
HRMS: m/z calcd. for C7H11N2O (M
+
1):139.0871;
found:139.0871.
5-Amino-2-chloro-N-methylpyridine (1c)
Yield: 55%.
IR (KBr) ν = 3300 (NH), 1580, 1520, 1465, 1320, 1250 cm–1.
1H NMR (400 MHz, CD3COCD3): δ = 2.80 (d, 3 H, J = 5.2 Hz,
CH3N), 5.37 (s, 1 H, NH), 7.00 (dd, 1 H, J = 8.6 Hz, 3.1 Hz, C3-H),
7.11 (d, 1 H, J = 8.6 Hz, C4-H), 7.74 (d, 1 H, J = 2.9 Hz, C6-H).
13C NMR (100.6 MHz, CD3COCD3): δ = 126.2, 128.7, 138.7,
142.2, 150.4.
[6-(Methoxy)-3-(methylamino)-2-pyridyl]phenylmethanol (2a)
Yield: 65%; mp 124 °C.
IR (KBr) ν = 3370, 3330 (NH, OH), 1500, 1425, 1270 cm–1.
1H NMR (400 MHz, CD3COCD3); δ = 2.70 (d, 3 H, J = 5.2 Hz,
CH3N), 3.84 (s, 3 H, CH3O), 4.63 (br s, 1 H, NH), 5.36 (d, 1 H,
J = 5.7 Hz, OH), 5.77 (d, 1 H, J = 5.4 Hz, CHOH), 6.61 (d, 1 H,
J = 8.7 Hz), 7.07 (d, 1 H, J = 8.7 Hz), 7.23 (m, 3 H), 7.42 (d, 2 H,
J = 8.8 Hz).
Anal. calcd. for C6H7ClN2: C, 50.54; H, 4.95; N, 19.65. Found: C,
50.80; H, 4.97; N, 19.65.
13C NMR (100.6 MHz, CD3COCD3): δ = 35.15, 57.48, 78.72,
114.0, 128.0, 131.6, 132.0, 132.9, 142.8, 147.1, 148.0, 160.0.
3-Amino-2-chloro-N-methylpyridine (1d)
Yield: 88%.
IR (film) ν = 3420, 3330 (NH), 1580, 1490, 1370, 1320, 1005 cm–1.
1H NMR (300 MHz, CD3COCD3): δ = 2.88 (d, 3 H, J = 5.0 Hz,
CH3N), 5.21 (br s, 1 H, NH), 6.98 (dd, 1 H, J = 8.0, 1.6 Hz), 7.17
(dd, 1 H, J = 8.0, 4.6 Hz), 7.60 (dd, 1 H, J = 4.6, 1.6 Hz).
13C NMR (100.6 MHz, CD3COCD3): δ = 47.4, 121.6, 128.6, 140.2,
141.4, 147.2.
HRMS: m/z calcd. for C14H17N2O2 (M + 1): 245.1290; found:
245.1289
[6-Chloro-3-(methylamino)-2-pyridyl]phenylmethanol (2b)
Yield: 72%; mp 128 °C.
IR (KBr) ν = 3380 (NH), 3250 (OH), 1575, 1495, 1415 cm–1.
1H NMR (400 MHz, CD3COCD3): δ = 2.73 (d, 3 H, J = 5.2 Hz,
CH3N), 5.52 (br s, 2 H, NH, OH), 5.85 (s, 1 H, CHOH), 6.98 (d, 1
H, J = 8.5 Hz), 7.15 (d, 1 H, J = 8.5 Hz), 7.23 (m, 1 H), 7.29 (m, 2
H), 7.42 (m, 2 H).
HRMS: m/z calcd. for C6H8ClN2 (M
+
1):143.0376;
found:143.0376.
13C NMR (100.6 MHz, CD3COCD3): δ = 80.46, 125.1, 128.1,
N-Allyl-5-amino-2-methoxypyridine (1e)
131.2, 132.2, 133.0, 140.1, 146.9, 147.8, 151.2.
Yield: 77%.
Anal. calcd. for C13H13N2ClO: C, 62.78; H, 5.27; N, 11.26. Found:
C, 63.29; H,5.33; N, 11.01.
IR (KBr) ν = 3350 (NH), 1480, 1370, 1255 cm–1.
1H NMR (400 MHz, CD3COCD3): δ = 3.74 (t, 2 H, J = 5.7 Hz,
CH2N), 3.76 (s, 3 H, CH3O), 4.77 (br s, 1 H, NH), 5.08 (m, 1 H,
CH2= ), 5.26 (m, 1 H, CH2= ), 5.93 (m, 1 H, CH= ), 6.55 (d, 1 H,
J = 8.7 Hz, C3-H), 7.07 (dd, 1 H, J = 8.8, 2.9 Hz, C4-H), 7.55 (d, 1
H, J = 3 Hz, C6-H).
13C NMR (100.6 MHz, CD3COCD3): δ = 51.6, 57.4, 115.2, 120.2,
130.3, 135.0, 141.0, 144.9, 161.8.
HRMS: m/z calcd for C13H14N2ClO (M + 1): 249.0795; found:
249.0794.
(E)-1-[6-Methoxy-3-(methylamino)-2-pyridyl]-3-phenylprop-2-
en-1-ol (2c)
Yield: 58%.
IR (film) ν = 3350 (NH, OH), 1600, 1470, 1260 cm–1.
1H NMR (400 MHz, CD3COCD3): δ = 2.80 (d, 3 H, J = 5.0 Hz,
CH3N), 3.83 (s, 3 H, CH3O), 4.77 (br s, 1 H, NH), 4.95 (d, 1 H,
J = 5.6 Hz, OH), 5.35 (t, 1 H, J = 5.4 Hz, CHOH), 6.50 (dd, 1 H,
J = 15.9, 6.6 Hz, CH=CHCHOH), 6.62 (d, 1 H, J = 8.7 Hz), 6.75 (d,
1 H, J = 15.9 Hz, CH=CH-CHOH), 7.10 (d, 1 H, J = 8.7 Hz), 7.20
(t, 1 H, J = 7.4 Hz), 7.30 (t, 2 H, J = 7.3 Hz), 7.42 (d, 2 H, J = 8.9
Hz).
Anal. calcd.for C9H12N2O: C, 65.83; H, 7.37; N, 17.06. Found: C,
66.31; H, 7.38; N, 16.94.
HRMS: m/z calcd. for C9H12N2O:164.0950; found:164.0949.
N-Allyl-5-amino-2-chloropyridine (1f)
Yield: 81%.
IR (KBr) ν = 3400, 3300 (NH), 1580, 1480, 1450, 1300, 1140 cm–1.
1H NMR (300 MHz, CD3COCD3): δ = 3.79 (m, 2 H, CH2N), 5.12
(ddd, 1 H, J = 10.4, 3.3, 1.5 Hz, CH2= ), 5.26 (ddd, 1 H, J = 10.4,
3.3, 1.5 Hz, CH2= ), 5.54 (s, 1 H, NH), 5.91 (m, 1 H, CH= ), 7.03
(dd, 1 H, J = 8.7, 3.0 Hz), 7.10 (dd, 1 H, J = 8.7, 0.6 Hz), 7.78 (d, 1
H, J = 3.0 Hz).
13C NMR (100.6 MHz, CD3COCD3): δ = 50.4, 120.3, 126.9, 128.6,
140.0, 140.1, 142.5, 149.2.
13C NMR (100.6 MHz, CD3COCD3): δ = 35.3, 57.5, 77.8, 114.0,
127.8, 131.4, 132.4, 133.5, 134.8, 135.0, 142.2, 143.1, 146.2, 160.2.
HRMS: m/z calcd for C16H19N2O2 (M + 1): 271.1446; found:
271.1445.
1-[6-Methoxy-3-(methylamino)-2-pyridyl]prop-2-en-1-ol (2d)
Following the general procedure B, 1b (415 mg, 3 mmol) was react-
ed with acrolein (336 mg, 6 mmol) at –20 °C for 0.25 h, then at 0 °C
Synthesis 1999, No. 11, 1893–1902 ISSN 0039-7881 © Thieme Stuttgart · New York

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P. Zakrzewski et al.
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for 2.5 h to afford, after chromatography, 240 mg (40%) of 2d and
153 mg (36%) of the starting material.
IR (KBr) ν = 3380 (OH, NH), 1580, 1490, 1420, 1260 cm–1.
1H NMR (400 MHz, CD3COCD3): δ = 2.79 (d, 3 H, J = 5.4 Hz,
CH3N), 3.80 (s, 3 H, CH3O), 4.66 (br s, 1 H, NH), 4.81 (d, 1 H,
J = 5.8 Hz, OH), 5.08 (dt, 1 H, CH2=CH, J = 10.3, 1.8 Hz), 5.15 (t,
1 H, J = 5.8 Hz, CHOH), 5.34 (dt, 1 H, CH2=CH, J = 17.2, 1.7 Hz),
6.05 (m, 1 H, CH=CH2), 6.60 (d, 1 H, J = 8.7 Hz), 7.09 (d, 1 H,
J = 8.7 Hz).
1H NMR (400 MHz, CD3COCD3): δ = 3.67 (t, 2 H, J = 5.5 Hz,
CH2C=), 3.84 (s, 3 H, CH3O), 4.78 (br s, 1 H, NH), 5.00 (dd, 1 H,
J = 10.3, 1.4 Hz, CH2=), 5.07 (dd, 1 H, J = 17, 1.2 Hz, CH2=), 5.43
(d, 1 H, J = 5.3 Hz, OH), 5.80 (m, 1 H, CH=), 5.82 (d, 1 H, J = 5.2
Hz, CHO), 6.58 (d, 1 H, J = 8.7 Hz), 7.06 (d, 1 H, J = 8.7 Hz), 7.22
(m, 1 H), 7.29 (t, 2 H, J = 7.4 Hz), 7.44 (d, 2 H, J = 7.5 Hz).
13C NMR (400 MHz, CD3COCD3): δ = 51.0, 57.5, 79.3, 113.9,
119.7, 129.3, 131.5, 132.1, 133.0, 140.8, 141.5, 147.4, 147.9, 160.1.
HRMS: m/z calcd for C16H19N2O2 (M + 1): 271.1447; found:
271.1446.
13C NMR (100.6 MHz, CD3COCD3): δ = 35.1, 57.4, 78.0, 113.9,
118.8, 127.7, 143.0, 143.6, 146.0, 160.1.
(E)-1-[3-(Allylamino)-6-methoxy-2-pyridyl]-3-phenylprop-2-
en-1-ol (2i)
Yield: 40%.
IR (film) ν = 3380 (NH, OH), 1580, 1490, 1420, 1255 cm–1.
1H NMR (400 MHz, CD3COCD3): δ = 3.79 (m, 2 H, CH2N), 3.82
(s, 3 H, CH3O), 5.00 (s, 1 H, NH), 5.06 (d, 1 H, J = 1.7 Hz, OH),
5.07 (dd, 1 H, J = 10.4, 1.7 Hz, CH2=CH), 5.23 (dd, 1 H, J = 17.2,
1.8 Hz, CH2=CH), 5.38 (m, 1H, CHOH), 5.92 (m, 1 H, CH2=CH),
6.49 (dd, 1 H, J = 15.9, 6.3 Hz, CH=CHPh), 6.55 (d, 1 H, J = 7.2
Hz), 6.76 (d, 1 H, J = 16.6 Hz, CH=CHPh), 7.10 (d, 1 H, J = 8.7
Hz), 7.24 (m, 3 H), 7.40 (m, 2 H).
13C NMR (100.6 MHz, CD3COCD3): δ = 51.1, 57.6, 78.4, 114.0,
120.0, 129.1, 131.4, 132.4, 133.6, 134.9, 135.0, 141.0, 141.8, 142.1,
146.3, 160.4.
HRMS: m/z calcd for C10H15N2O2 (M + 1): 195.1134; found:
195.1134.
(E)-1-[6-Methoxy-3-(methylamino)-2-pyridyl]but-2-en-1-ol
(2e)
Yield: 46%.
IR (KBr) ν = 3360 (NH, OH), 1490, 1470, 1260, 1030 cm–1.
1H NMR (300 MHz, CD3COCD3): δ = 1.65 (d, 3H, J = 6.3 Hz,
CH3C), 2.78 (d, 3H, J = 3.7 Hz, CH3N), 3.80 (s, 3H, CH3O), 4.57 (s,
1H, NH), 4.70 (d, 1H, J = 5.6 Hz, OH), 5.06 (t, 1H, J = 5.5 Hz,
CHO), 5.70 (m, 2H, CH2 = ), 6.59 (d, 1H, J = 8.6 Hz), 7.06 (d, 1H,
J = 8.6 Hz).
13C NMR (100.6 MHz, CD3COCD3): δ = 21.9, 35.2, 57.4, 77.6,
113.6, 127.6, 131.0, 136.8, 142.8, 146.7, 160.1.
HRMS: m/z calcd for C18H21N2O2 (M + 1): 297.1603; found:
296.1604.
HRMS: m/z calcd. for C11H17N2O2 (M+1): 209.1290; found:
209.1290.
[3-(Allylamino)-6-methoxy-2-pyridyl]but-2-en-1-ol (2j)
Yield: 32%.
(3R)-1-[6-Methoxy-3-(methylamino)-2-pyridyl]-3,7-dimethyl-
oct-6-en-1-ol (2f)
Following the general procedure B, 1b (423 mg, 3.06 mmol) was re-
acted with citronellal (565 mg, 3.67 mmol) at 0 °C for 4.5 h and then
at r.t. for 70 h to give, after chromatography, 76 mg (9%) of the ma-
terial tentatively assigned as the title compound 2f as a mixture (1:1)
of diastereomers and 208 mg (50%) of the starting material.
1H NMR (400 MHz, CD3COCD3): δ = 0.96 (d, 3 H, J = 6.5 Hz,
CH3CHCH2), 1.18 (m, 1 H), 1.40 (m, 1 H, CHCH3), 1.55 (m, 1 H),
1.57 (s, 3 H, CH3C=), 1.60 (m, 1 H), 1.63 (s, 3 H, CH3C=), 1.75 (m,
1 H), 1.89 (m, 1 H), 1.95 (m, 1 H), 2.77 (d, 3 H, J = 4.1 Hz, CH3N),
3.79 (s, 3 H, CH3O), 4.45 (m, 1 H, CHOH), 4.82 (m, 1 H, OH), 4.92
(br s, 1 H, NH), 5.08 (m, 1 H, CH=CMe2), 6.57 (d, 1 H, J = 8.6 Hz),
7.04 (d, 1 H, J = 8.6 Hz).
13C NMR (100.6 MHz, CD3COCD3): δ = 21.8, 21.8, 23.7, 24.7,
30.0, 30.2, 30.3, 35.2, 35.3, 41.7, 42.6, 47.1, 47.2, 57.3, 57.3, 75.3,
76.2, 113.3, 133.3, 127.3, 127.4, 129.9, 129.9, 135.4, 143.1, 143.3,
148.8, 149.1, 160.0, 160.1.
1H NMR (300 MHz, CD3COCD3): δ = 1.66 (m, 3 H, CH3C=), 3.76
(m, 2 H, CH2N), 3.80 (s, 3 H, CH3O), 4.82 (d, 1 H, J = 5.1 Hz, OH),
4.82 (br s, 1 H, NH), 5.09 (m, 2 H, CHO, CH2=), 5.23 (m, 1 H,
CH2=), 5.73 (m, 2 H, CH=CH), 5.93 (m, 1 H, =CHCN), 6.55 (d, 1
H, J = 8.7 Hz), 7.07 (d, 1 H, J = 8.7 Hz).
13C NMR (100.6 MHz, CD3COCD3): δ = 21.8, 51.1, 57.4, 78.2,
113.6, 119.8, 128.8, 131.1, 136.7, 141.1, 141.5, 146.8, 160.2.
HRMS: m/z calcd for C13H19N2O2 (M + 1): 235.1447; found:
235.1446.
[3-(Allylamino)-6-chloro-2-pyridyl]phenylmethanol (2k)
Yield: 80%.
IR (KBr) ν = 3420 (NH), 3250 (OH), 1570, 1490, 1420, 1315,
1165, 1145, 1035 cm–1.
1H NMR (300 MHz, CD3COCD3): δ = 3.74 (m, 2 H, CH2N), 5.03
(m, 2H, CH2=), 5.57 (d, 1 H, J = 4.7 Hz, OH), 5.66 (s, 1 H, NH),
5.79 (m, 1 H, CH=), 5.89 (d, 1 H, J = 4.5 Hz, CHO), 6.96 (d, 1 H,
J = 8.6 Hz), 7.11 (d, 1 H, J = 8.5 Hz), 7.25 (m, 3 H), 7.42 (m, 2 H).
13C NMR (100.6 MHz, CD3COCD3): δ = 49.9, 80.9, 119.9, 126.2,
127.9, 131.1, 132.2, 133.0, 139.7, 140.0, 146.5, 146.8, 151.3.
(E)-[6-Chloro-3-(methylamino)-2-pyridyl]-3-phenylprop-2-en-
1-ol (2g)
Yield: 62%.
HRMS: m/z calcd for C15H16N2ClO (M + 1): 275.0951; found:
275.0952.
1H NMR (300 MHz, CD3COCD3): δ = 2.83 (d, 3 H, J = 4.7 Hz,
CH3N), 5.04 (d, 1 H, J = 5.0 Hz, OH), 5.39 (m, 1 H, CHO), 5.59 (br
s, 1 H, NH), 6.51 (dd, 1 H, J = 16, 6.1 Hz, CH=), 6.76 (d, 1 H, J = 17
Hz, PhCH=), 7.02 (d, 1 H, J = 8.5 Hz), 7.15 (d, 1 H, J = 8.5 Hz),
7.25 (m, 3 H), 7.42 (m, 2 H).
[3-(Allylamino)-6-chloro-2-pyridyl]-3-phenylprop-2-en-1-ol
(2l)
Yield: 79%.
13C NMR (100.6 MHz, CD3COCD3): δ = 79.4, 124.9, 128.1, 131.5,
132.5, 133.5, 133.9, 135.4, 140.3, 142.0, 148.0, 150.3.
1H NMR (300 MHz, CD3COCD3): δ = 3.85 (m, 2 H, CH2N), 5.10
(dq, 1 H, J = 10.4, 1.7 Hz, CH2=), 5.15 (d, 1 H, J = 4.8 Hz, OH),
5.24 (dq, 1 H, J = 17.3, 1.7 Hz), 5.43 (m, 1 H, CHO), 5.81 (br s, 1
H, NH), 5.90 (m, 1 H, =CHCN), 6.55 (dd, 1 H, J = 16.0, 6.0 Hz,
CH=CPh), 6.75 (dd, 1 H, J = 16.0, 1.1 Hz, =CHPh), 7.02 (d, 1 H,
J = 8.6 Hz), 7.11 (d, 1 H, J = 8.6 Hz), 7.27 (m, 3 H), 7.43 (m, 2 H).
13C NMR (100.6 MHz, CD3COCD3): δ = 50.0, 79.9, 120.1, 126.0,
127.9, 131.4, 132.5, 133.5, 133.8, 135.4, 140.0, 140.6, 141.9, 146.8,
150.3.
HRMS: m/z calcd. for C15H16N2ClO (M + 1): 275.0952; found:
275.0951.
[3-(Allylamino)-6-methoxy-2-pyridyl]phenylmethanol (2h)
Yield: 55%; mp 59–60 °C.
IR (KBr) ν = 3370 (NH), 3150 (OH), 1490, 1275, 1260, 1030 cm–1.
Synthesis 1999, No. 11, 1893–1902 ISSN 0039-7881 © Thieme Stuttgart · New York

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ortho-Hydroxyalkylation of Aminopyridines: A Novel Approach to Heterocycles
1899
HRMS: m/z calcd. for C17H18N2ClO (M + 1): 301.1109; found:
301.1108.
HRMS: m/z calcd for C15H13N2O (M + 1): 237.1028; found:
237.1028.
1-Allyl-6-methoxy-2-methyl-1,2-dihydro[1,5]naphthyridine
(3d)
Yield: 16%.
Synthesis of 1,2-Dihydro[1,5]naphthyridine; General Proce-
dure C
2-Hydroxyallyl-3-alkylaminopyridine (1 mmol) is dissolved in di-
chlorobenzene (10 mL) and heated to reflux at 180 °C for 4 h. After
the completion of the reaction, the mixture was chromatographed
on silica gel column packed with hexane. The sample was eluted
first with hexane and then with 10% EtOAc/Hexane.
1H NMR (300 MHz, CD3COCD3): δ = 1.10 (d, 3 H, J = 6.4 Hz,
CH3C), 3.76 (s, 3 H, CH3O), 3.84 (m, 2 H, CH2N), 4.19 (m, 1 H),
5.15 (m, 1 H, CH2=), 5.29 (m, 1 H, CH2=), 5.89 (m, 1 H), 5.92 (dd,
1 H, J = 9.9, 5.4 Hz), 6.32 (d, 1 H, J = 9.9 Hz), 6.41 (d, 1 H, J = 8.7
Hz), 6.88 (d, 1 H, J = 8.7 Hz).
13C NMR (100.6 MHz, CD3COCD3): δ = 24.0, 56.2, 57.2, 59.2,
113.9, 120.8, 127.6, 130.8, 136.0, 140.1, 140.3, 142.8, 160.7.
6-Methoxy-1-methyl-2-phenyl-1,2-dihydro[1,5]naphthyridine
(3a)
Yield: 31%.
MS: m/z for C13H17N2O (M+1):217.
IR (KBr) ν = 3150, 1560, 1470, 1450, 1410, 1295, 1280, 1135 cm–1.
1-Allyl-6-chloro-2-phenyl-1,2-dihydro[1,5]naphthyridine (3e)
Yield: 57%.
1H NMR (400 MHz, CD3COCD3): δ = 2.67 (s, 3 H, CH3N), 3.79 (s,
3 H, CH3O), 5.18 (d, 1 H, J = 5.0 Hz, CHPh), 5.94 (dd, 1 H,
J = 10.0, 5.2 Hz, CH=CHCH), 6.44 (d, 1 H, J = 10.1 Hz,
CH=CHCH), 6.47 (d, 1 H, J = 8.7 Hz, C3-H), 6.84 (d, 1 H, J = 8.6
Hz, C4-H), 7.30 (m, 5 H).
13C NMR (100.6 MHz, CD3COCD3): δ = 35.5, 52.7, 65.2, 109.8,
121.2, 126.2, 126.9, 128.3, 129.1, 130.4, 137.2, 137.6, 142.1, 156.2.
1H NMR (300 MHz, CD3COCD3): δ = 3.62 (m, 1 H, CH2N), 3.90
(m, 1 H, CH2N), 5.10 (dq, 1 H, J = 10.3, 1.6 Hz, CH2=), 5.18 (dq, 1
H, J = 17.3, 1.7 Hz, CH2=), 5.45 (dd, 1 H, J = 4.7, 1.6 Hz), 5.65 (m,
1 H, =CHCN), 5.99 (dd, 1 H, J = 10.1, 4.7 Hz), 6.39 (dd, 1 H,
J = 10.1, 0.8 Hz), 6.85 (d, 1 H, J = 8.5 Hz), 6.96 (d, 1 H, J = 8.5 Hz),
7.37 (m, 5 H).
13C NMR (100.6 MHz, CD3COCD3): δ = 55.3, 68.7, 121.5, 124.4,
128.0, 129.5, 131.7, 133.1, 133.8, 136.3, 137.5, 141.5, 145.0, 145.4,
147.8.
The product is very unstable. MS showed no parent ion; only the
aromatized [1,5]-naphthyridine was observed, m/z = 237 (M + 1).
6-Chloro-1-methyl-2-phenyl-1,2-dihydro[1,5]naphthyridine
(3b)
Yield: 68%.
Synthesis of [1,5]Naphthyridines; General Procedure D
To a solution of 3 (0.25 mmol) in anhyds EtOH was added
CF3CO2H (0.58 mmol) and (PPh3)4RhH (0.10–0.25 mmol). The
mixture was refluxed for 2–20 h, then cooled to r.t. Aq 1 N NaOH
was added and the mixture was extracted twice with EtOAc. The
combined organic layers were washed once with brine and dried
(MgSO4). The solvents were removed under vacuum and the pro-
duct was isolated by column chromatography.
1H NMR (300 MHz, CD3COCD3): δ = 2.70 (s, 3 H, CH3N), 5.32 (d,
1 H, J = 5.1 Hz, CHPh), 6.03 (dd, 1 H, J = 10, 4.9 Hz, =CHCPh),
6.41 (d, 1 H, J = 10 Hz, CH=CCPh), 6.80 (d, 1 H, J = 8.5 Hz), 7.00
(d, 1 H, J = 8.5 Hz), 7.32 (m, 5 H).
13C NMR (100.6 MHz, CD3COCD3): δ = 40.0, 69.9, 123.6, 128.2,
129.7, 131.4, 133.1, 133.8, 136.6, 141.6, 145.7, 145.9, 146.6.
HRMS: m/z calcd for C15H14ClN2 (M + 1): 257.0846; found:
257.0847.
2-Methoxy-6-phenyl[1,5]naphthyridine (4a)
Following the General Procedure D, 3c (69 mg, 0.25 mmol) was
converted to 4a (32 mg, 54%) after 4 h at 85 °C. Spectral data for
4a are listed above.
1-Allyl-6-methoxy-2-phenyl-1,2-dihydro[1,5]naphthyridine
(3c) and 2-Methoxy-6-phenyl[1,5]naphthyridine (4a)
Following the general procedure C, 2h (114 mg, 0.38 mmol) was
pyrolysed at 180 °C for 0.25 h to give, after chromatography, 69 mg
(65%) of 3c and 25 mg (28%) of 4a.
2-Methoxy-6-methyl[1,5]naphthyridine (4b)
Yield: 51%; mp 50–51 °C (Lit. 52 °C).
IR (KBr) ν = 1600, 1590, 1470, 1250 cm–1.
1H NMR (300 MHz, CD3COCD3): δ = 2.64 (s, 3 H, CH3C), 4.01 (s,
3 H, CH3O), 7.13 (d, 1 H, J = 9.0 Hz), 7.51 (d, 1 H, J = 8.7 Hz), 8.01
(d, 1 H, J = 8.7 Hz), 8.11 (d, 1 H, J = 9.0 Hz).
13C NMR (100.6 MHz, CD3COCD3): δ = 28.8, 57.9, 120.9, 129.9,
139.7, 144.6, 145.3, 146.2, 161.5, 166.9.
In another experiment, pyrolysis of compound 2h (192 mg, 0.71
mmol) at 180 °C for 20 h gave only compound 4a (73 mg, 43%).
3c
1H NMR (400 MHz, CD3COCD3): δ = 3.59 (m, 1 H, CH2N), 3.78
(s, 3 H, CH3O), 3.88 (m, 1 H, CH2N), 5.09 (m, 1 H, CH2=), 5.18 (m,
1 H, CH2=), 5.34 (dd, 1 H, J = 5.0, 1.5 Hz, CHPh), 5.70 (m, 1 H,
CH=CH2), 5.92 (dd, 1 H, J = 10.0, 5.0 Hz, =CHCPh), 6.39 (m, 1 H,
CH=CCPh), 6.44 (d, 1 H, J = 8.7 Hz), 6.92 (d, 1 H, J = 8.7 Hz), 7.31
(m, 5 H).
HRMS: m/z calcd for C10H11N2O (M + 1): 175.0871; found:
175.0872.
2-Chloro-6-phenyl[1,5]naphthyridine (4c)
Yield: 52%; mp 131–132 °C.
IR (KBr) ν = 1570, 1475, 1100 cm–1.
1H NMR (300 MHz, CD3COCD3): δ = 7.56 (m, 3 H), 7.79 (d, 1 H,
J = 8.8 Hz), 8.32 (m, 2 H), 8.40 (m, 2 H), 8.47 (dd, 1 H, J = 8.8, 0.6
Hz).
13C NMR (100.6 MHz, CD3COCD3): δ = 127.9, 131.1, 132.5,
133.9, 135.0, 141.9, 143.3, 145.5, 147.6, 147.8, 155.3, 162.8.
13C NMR (100.6 MHz, CD3COCD3): δ = 55.7, 57.3, 68.3, 114.3,
121.2, 126.6, 130.5, 131.7, 132.7, 133.6, 134.5, 138.8, 140.8, 141.7,
148.3, 160.8.
HRMS: m/z calcd for C18H19N2O (M + 1): 279.1497; found:
279.1498.
4a
Mp 114–115 °C.
IR (KBr) ν = 1608, 1470, 1382, 1250 cm–1.
1H NMR (400 MHz, CD3COCD3): δ = 4.06 (s, 3 H, CH3O), 7.21 (d,
1 H, J = 9.0 Hz), 7.50 (m, 3 H), 8.25 (m, 5 H).
HRMS: m/z calcd for C14H10ClN2 (M + 1): 241.0532; found:
241.0532.
13C NMR (100.6 MHz, CD3COCD3): δ = 58.2, 121.7, 126.6, 132.0,
133.7, 134.1, 140.5, 143.9, 145.2, 146.1, 146.6, 159.4, 167.4.
1,2,3,4-Tetrahydro[1,5]naphthyridines; General Procedure E
To a solution of 2 (1.0 mmol) in dichloroethane (5.5 mL) was added
an olefin (2–20 mmol) and BF3•OEt2 (2 mmol). The mixture was
Synthesis 1999, No. 11, 1893–1902 ISSN 0039-7881 © Thieme Stuttgart · New York

1900
P. Zakrzewski et al.
PAPER
stirred at 60–80°C for 1–4.5 h and cooled to r.t. Aqueous sat. K2CO3
solution was added and the mixture was extracted twice with
EtOAc. The combined organic layers were washed once with distil-
led water, once with brine, and dried (MgSO4). The solvents were
removed under vacuum and the product was isolated by column
chromatography.
(5aR,7R,9aS)-2-Methoxy-5,7,10,10-tetramethyl-
5,5a,6,7,8,9,9a,10-octahydrobenzo[b][1,5]naphthyridine (6)
To a solution of 1b (429 mg, 3.1 mmol) in dichloroethane (8 mL) at
0°C was added dichlorophenylborane (588 mg, 3.7 mmol). The
mixture was stirred at 0 °C for 1 h. A solution of (R)-(+)-citronellal
(574 mg, 3.7 mmol) in dichloroethane (2 mL) was added dropwise
and the mixture was stirred at 0 °C for 2.5 h. Aq NH4OH (3 mL) was
added at 0°C and the mixture stirred vigorously for 1 min. It was di-
luted with Et2O (ca 100 mL), transferred to a Florisil packed co-
lumn, and eluted with 60% EtOAc/hexane. The solvents were
removed under vacuum. The residue was chromatographed to give
340 mg (40%) of 6 and 38 mg (4%) of 7.
6-Methoxy-1-methyl-4-phenyl-2-[(1,1,1-trimethylsilyl)methyl]-
1,2,3,4-tetrahydro[1,5]naphthyridine (5a)
Following the General Procedure E, 2a (253 mg, 1.0 mmol) was re-
acted with allyltrimethylsilane (237 mg, 2.1 mmol) to give 176 mg
(50%) of 5a.
IR (film) ν = 2920, 1470, 1425, 1382, 1255, 1240 cm–1.
6
[α]D +23.3 (c = 0.9, CHCl3),
IR (film) ν = 2920, 1470, 1410, 1250 cm–1
1H NMR (500 MHz, CD3COCD3). δ = 0.01 [s, 9 H, (CH3)3Si], 0.81
(dd, 1 H, J = 14.7, 10.1 Hz, CH2Si), 1.12 (dd, 1 H, J = 14.6, 3.1 Hz,
CH2Si), 2.09 (m, 1 H, CH2CPh), 2.35 (ddd, 1 H, J = 13.4, 5.9, 3.9
Hz, CH2CPh), 2.82 (s, 3 H, CH3N), 3.39 (m, 1 H, CHN), 3.45 (s, 3
H, CH3O), 4.16 (dd, 1 H, J = 10.1, 5.9 Hz, CHPh), 6.48 (dd, 1 H,
J = 8.7, 0.9 Hz), 7.15 (m, 4 H), 7.28 (m, 2 H).
13C NMR (100.6 MHz, CD3COCD3): δ = 3.7, 26.4, 41.7, 44.4, 50.6,
56.9, 61.1, 113.1, 130.6, 131.1, 132.7, 133.8, 144.1, 148.0, 150.1,
160.5.
1H NMR (500 MHz, CD3COCD3): δ = 0.85 (q, 1 H, J = 11 Hz, H-
6ax ), 0.94 (ddd, 1 H, J = 12.9, 12.9, 3.7 Hz, H-8ax), 0.96 (d, 3 H,
J = 6.6 Hz), 1.02 (s, 3 H), 1.23 (ddd, 1 H, J = 12.5, 12.5, 3.4 Hz, H-
9ax), 1.34 (dd, 1 H, J = 10.8, 3.2 Hz, H-9a), 1.37 (s, 3 H), 1.53 (m,
1 H, H-7), 1.77 (br d, 1 H, J = 12.9 Hz, H-8eq), 1.95 (ddd, 1 H,
J = 12.9, 3.2, 3.2 Hz, H-9eq), 2.32 (ddd, 1 H, J = 12.5, 1.9, 1.9 Hz,
H-6eq), 2.73 (dt, 1 H, J = 10.6, 3.7 Hz, H-5a), 2.85 (s, 3 H, NH),
3.79 (s, 3 H, CH3), 6.43 (d, 1 H, J = 8.7 Hz), 7.04 (d, 1 H, J = 8.7
Hz).
HRMS: m/z calcd for C20H29N2OSi (M + 1): 341.2049; found:
341.2048.
13C NMR (100.6 MHz, CD3COCD3): δ = 26.9, 28.9, 29.2, 30.5,
36.1, 39.6, 41.7, 42.1, 46.6, 52.7, 57.0, 63.1, 112.7, 130.2, 141.9,
152.2, 159.9.
2-Methoxy-5-methyl-9-phenyl-5a,6,7,8,8a,9-hexahydro-5H-cy-
clopenta[b][1,5]naphthyridine (5b)
Following the General Procedure E, 2a (245 mg, 1.0 mmol) was re-
acted with cyclopentene (1.35 g, 20 mmol) in a mixture of dichlo-
roethane (7 mL) and THF (3 mL) at 60 °C for 1 h to give 191 mg
(65%) of 5b.
HRMS: m/z calcd. for C17H27N2O (M + 1): 275.2123; found:
275.2124.
7
1H NMR (500 MHz, benzene-d6): δ = 0.74 (ddd, 1 H, J = 12.3, 12.3,
3.4 Hz), 0.80 (d, 3 H, J = 6.4 Hz, CH3C), 0.85 (dd, 1 H, J = 12.0,
12.0 Hz), 1.16 (m, 1 H), 1.27 (ddd, 1 H, J = 12.5, 12.5, 3.4 Hz), 1.4–
1.8 (m, 6 H), 2.05 (dt, 1 H, J = 11.4, 3.7 Hz), 2.40 (s, 3 H, CH3N),
3.32 (dt, 1 H, J = 11.4, 3.7 Hz), 3.95 (s, 3 H, CH3O), 4.75 (s, 2 H),
6.72 (d, 1 H, J = 9.0 Hz), 6.88 (dd, 1 H, J = 9.0, 3.2 Hz), 7.90 (d, 1
H, J = 3.2 Hz).
IR (KBr) ν = 2950, 1470, 1415, 1250, 1015 cm–1.
1H NMR (500 MHz, CD3COCD3): δ = 1.16–1.95 (m, 6 H,
CH2CH2CH2), 2.78 (m, 1 H, CHCPh), 2.81 (s, 3 H, CH3N), 3.60 (s,
3 H, CH3O), 3.75 (m, 1 H, CHN), 4.20 (d, 1 H, J = 5.2 Hz, CHPh),
6.52 (dd, 1 H, J = 8.6, 0.6 Hz), 7.05 (d, 1 H, J = 8.6 Hz), 7.24 (m, 3
H), 7.43 (m, 2 H).
13C NMR (100.6 MHz, CD3COCD3); δ = 27.8, 33.0, 35.9, 40.4,
52.7, 53.3, 57.2, 69.0, 112.3, 127.9, 130.8, 132.3, 135.4, 142.6,
146.2, 149.3, 160.6.
13C NMR (100.6 MHz, CD3COCD3): δ = 23.1, 26.7, 30.0, 35.3,
37.0, 39.5, 40.9, 54.3, 57.2, 65.0, 115.0, 115.6, 130.5, 136.0, 146.8,
153.2, 161.3.
MS: m/z calcd for C17H27N2O (M + 1): 275; found: 275.
HRMS: m/z calcd for C19H23N2O (M + 1): 295.1810; found:
295.1811.
3-Alkylamino-2 -(1-tert-butyldimethylsilyloxyallyl)pyridines;
General Procedure F
1-Allyl-6-chloro-4-phenyl-2-[(1,1,1-trimethylsilyl)methyl]-
1,2,3,4-tetrahydro[1,5]naphthyridine (5c)
Following the General Procedure E, 2k (279 mg, 1.0 mmol) was re-
acted with allyltrimethylsilane (2.3 g, 20 mmol) in a mixture of di-
chloroethane (7 mL) and THF (3 mL) at 80 °C for 1.25 h to give 159
mg (42%) of 5c.
To a solution of 2 (1.5 mmol) in dichloroethane (10 mL) were added
dimethylaminopyridine (1.7 mmol), tert-butyldimethylsilyl chlor-
ide (2.3 mmol), and Et3N (1.7 mmol). The mixture was stirred at r.t.
for 20 h. Sat. aq NH4Cl solution was added and the mixture extrac-
ted twice with EtOAc. The combined organic extracts were washed
once with brine and dried (MgSO4). The solvents were removed un-
der vacuum and the residue was purified by column chromatogra-
phy.
IR (film) ν = 2940, 1565, 1435, 1240 cm–1.
1H NMR (300 MHz, CD3COCD3): δ = 0.03 [s, 9 H, (CH3)3Si], 0.77
(dd, 1 H, J = 14.6, 11.4 Hz, CH2Si), 1.11 (dd, 1 H, J = 14.6, 2.6 Hz,
CH2Si), 2.17 (m, 1 H, CH2CPh), 2.42 (m, 1 H, CH2CPh), 3.69 (m,
1 H, CHCSi), 3.85 (m, 1 H, CH2N), 4.08 (m, 1 H, CH2N), 4.25 (dd,
1 H, J = 9.2, 5.5 Hz, CHPh), 5.22 (m, 2 H, CH2=), 5.91 (m, 1 H,
CH=), 7.01 (s, 2 H), 7.16 (m, 3 H), 7.28 (m, 2 H).
13C NMR (100.6 MHz, CD3COCD3): δ = 3.5, 27.0, 43.6, 50.2, 55.9,
59.5, 120.7, 127.1, 127.4, 131.0, 133.1, 133.7, 139.4, 141.0, 147.0,
149.5, 150.7.
N-{2-[(E)-1-{[1-(tert-Butyl)-1,1-dimethylsilyl]oxy}prop-2-enyl]-
6-methoxy-3-pyridyl}-N-methylamine (8a)
Yield: 77%.
IR (KBr) ν = 3400 (NH), 2940, 2920, 2840, 1495, 1455, 1410,
1265, 1245 cm–1.
1H NMR (300 MHz, CD3COCD3): δ = 0.04 (s, 3 H, CH3Si), 0.09 (s,
3 H, CH3Si), 0.89 (s, 9 H, C4H9Si), 2.79 (d, 3 H, J = 4.3 Hz, CH3N),
3.77 (s, 3 H, CH3O), 4.90 (br s, 1 H, NH), 5.11 (dt, 1 H, J = 10.4,
1.8 Hz, CHO), 5.33 (m, 2 H, CH2=), 6.09 (m, 1 H, CH=), 6.58 (d, 1
H, J = 8.7 Hz), 7.05 (d, 1 H, J = 8.7 Hz).
HRMS: m/z calcd. for C21H28ClN2Si (M + 1): 371.1710; found:
371.1709.
13C NMR (100.6 MHz, CD3COCD3): δ = –0.7, 22.9, 30.2, 35.1,
57.3, 84.6, 114.1, 118.4, 127.8, 142.7, 144.2, 145.4, 159.9.
Synthesis 1999, No. 11, 1893–1902 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
ortho-Hydroxyalkylation of Aminopyridines: A Novel Approach to Heterocycles
1901
HRMS: m/z calcd for C16H29N2O2Si (M + 1): 309.1998; found:
309.1999.
13C NMR (100.6 MHz, CD3COCD3): δ = 0.3, 5.8, 13.1, 23.0, 30.5,
57.5, 108.1, 124.3, 127.9, 131.0, 134.8, 138.6, 163.8.
N-[2-((E)-1-{[1-(tert-Butyl)-1,1-dimethylsilyl]oxy}but-2-enyl)-
6-methoxy-3-pyridyl]-N-methylamine (8b)
Yield: 71%.
HRMS: m/z calcd. for C16H26N2O2Si (M + 1): 307.1842; found:
307.1843.
IR (KBr) ν = 3400, 2940, 2920, 2840, 1465, 1250 cm–1.
3-{[1-(tert-Butyl)-1,1-dimethylsilyl]oxy}-2-ethyl-5-methoxy-1-
methyl-1H-pyrrolo[3,2-b]pyridine (9b)
1H NMR (300 MHz, CD3COCD3): δ = 0.05 (s, 3 H, CH3Si), 0.08 (s,
3 H, CH3Si), 0.88 (s, 9 H, C4H9Si), 1.66 (dd, 3 H, J = 4.9, 1.2 Hz,
CH3C=), 2.77 (d, 3 H, J = 4.6 Hz, CH3N), 3.76 (s, 3 H, CH3O), 4.97
(br s, 1 H, NH), 5.22 (m, 1 H, CHO), 5.77 (m, 2 H, CH=CH), 6.56
(d, 1 H, J = 8.7 Hz), 7.04 (d, 1 H, J = 8.7 Hz).
13C NMR (100.6 MHz, CD3COCD3); δ = –0.09, –0.08, 21.8, 22.8,
30.2, 35.1, 57.2, 84.6, 113.8, 127.7, 130.5, 135.7, 144.0, 146.4,
159.9.
A mixture of 8b (125 mg, 0.39 mmol), LiCl (166 mg, 3.9 mmol),
benzoquinone (63 mg, 0.58 mmol), K2CO3 (160 mg, 1.2 mmol), and
PdCl2(MeCN)2 (20 mg, 0.077 mmol) in anhyd THF (5 mL) was
heated to reflux for 3.5 h. The resulting mixture was diluted with
Et2O, transferred to a silica gel packed column, and eluted with
Et2O. The solvents were removed under vacuum and the residue
was purified by column chromatography to give 63 mg (51%) of 9b.
IR (KBr) ν = 2940, 2920, 2840, 1550, 1460, 1395, 1255 cm–1.
HRMS: m/z calcd. C17H31N2O2Si (M + 1): 323.2155; found:
323.2156.
1H NMR (300 MHz, CD3COCD3): δ = 0.31 [s, 6 H, (CH3)2Si], 1.06
(s, 9 H, C4H9Si), 1.21 (t, 3 H, J = 7.5 Hz, CH3C), 2.82 (q, 2 H,
J = 7.5 Hz, CH2C=), 3.68 (s, 3 H, CH3N), 3.90 (s, 3 H, CH3O), 6.45
(d, 1 H, J = 8.7 Hz), 7.60 (d, 1 H, 8.7 Hz).
N-{2-[(E)-1-{[1-(tert-Butyl)-1,1-dimethylsilyl]oxy}prop-2-enyl]-
6-methoxy-3-pyridyl}-N-allylamine (8c)
Yield: 49%.
13C NMR (100.6 MHz, CD3COCD3): δ = 0.31, 18.4, 21.2, 23.0,
1H NMR (300 MHz, CD3COCD3): δ = 0.03 (s, 3 H, CH3Si), 0.09 (s,
3 H, CH3Si), 0.88 (s, 9 H, C4H9Si). 1.67 (dd, 3 H, J = 4.8, 1.2 Hz,
CH3C=), 3.72 (m, 2 H, CH2N), 3.76 (s, 3 H, CH3O), 5.11 (m, 2 H,
CH2=, NH), 5.26 (m, 2 H, CH2=, CHO), 5.76 (m, 2 H, CH=CH),
5.96 (m, 1 H, =CHCN), 6.53 (d, 1 H, J = 8.7 Hz), 7.05 (d, 1 H, 8.7
Hz).
13C NMR (100.6 MHz, CD3COCD3): δ = –0.09, –0.08, 21.8, 22.9,
30.3, 51.2, 57.2, 84.7, 113.8, 119.8, 128.7, 130.5, 135.6, 141.0,
142.6, 146.5, 160.1.
30.4, 33.8, 57.5, 108.2, 124.5, 128.0, 134.2, 136.6, 138.5, 163.9.
HRMS: m/z calcd. for C17H29N2O2Si (M + 1): 321.1998; found:
321.1999.
3-{[1-(tert-Butyl)-1,1-dimethylsilyl]oxy}-1-allyl-2-ethyl-5-meth-
oxy-1H-pyrrolo[3,2-b]pyridine (9c)
A mixture of 8c (142 mg, 0.41 mmol), LiCl (174 mg, 4.1 mmol),
benzoquinone (66 mg, 0.61 mmol), K2CO3 (168 mg, 1.2 mmol), and
PdCl2(MeCN)2 (21mg, 0.081 mmol) in anhyd THF (6 mL) was hea-
ted to reflux for 4 h. It was diluted with Et2O, transferred to a silica
gel packed column, and eluted with Et2O. The solvents were remo-
ved under vacuum and the residue was purified by column chroma-
tography to afford 89 mg (63%) of 9c. The compound was
contaminated by an unseparable unknown impurity and was not
characterized. It was used without further purification in the next
step (formation of compound 10).
HRMS: m/z calcd for C19H33N2O2Si (M + 1): 349.2311; found:
349.2310.
N-{2-[(E)-1-{[1-(tert-Butyl)-1,1-dimethylsilyl]oxy}-3-phenyl-
pro-2-enyl]-6-chloro-3-pyridyl}-N-methylamine (8d)
Yield: 70%.
IR (KBr) ν = 3380 (NH), 2940, 2920, 2840, 1552, 1485, 1425,
1410, 1250 cm–1.
2-Benzyl-3-{[1-(tert-butyl)-1,1-dimethylsilyl]oxy}-5-chloro-1-
methyl-1H-pyrrolo[3,2-b]pyridine (9d)
1H NMR (300 MHz, CD3COCD3); δ = 0.03 (s, 3 H, CH3Si), 0.15 (s,
3 H, CH3Si), 0.93 (s, 9 H, C4H9), 1.83 (d, 3 H, J = 4.3 Hz, CH3N),
5.49 (dd, 1 H, J = 5.7, 2.4 Hz, CHO), 5.62 (br s, 1 H, NH), 6.54 (dd,
1 H, J = 16, 5.7 Hz, CH=), 6.77 (d, 1 H, J = 16 Hz, PhCH=), 7.03
(d, 1 H, J = 8.5 Hz), 7.14 (d, 1 H, J = 8.5 Hz), 7.27 (m, 3 H), 7.43
(m, 2 H).
13C NMR (100.6 MHz, CD3COCD3): δ = –0.09, –0.08, 22.87,
30.24, 30.31, 84.39, 125.1, 128.2, 131.5, 132.6, 133.1, 133.5, 135.3,
140.4, 141.7, 148.4, 149.6.
A mixture of 8d (254 mg, 0.65 mmol), LiCl (280 mg, 6.5 mmol),
benzoquinone (106 mg, 0.98 mmol), K2CO3 (271 mg, 2.0 mmol),
and PdCl2(MeCN)2 (169 mg, 0.65 mmol) in anhyd THF (7 mL) was
stirred at r.t. for 48 hours. It was diluted with Et2O, transferred to a
silica gel packed column, and eluted with Et2O. The solvents were
removed under vacuum and the title compound 9d (136 mg, 54%)
was isolated by column chromatography.
IR (film) ν = 2930, 2920, 2840, 1565, 1445, 1190 cm–1.
HRMS: m/z calcd for C21H30ClN2OSi (M + 1): 389.1816; found:
389.1815.
1H NMR (300 MHz, CD3COCD3): δ = 0.30 [s, 6 H, (CH3)2Si], 1.02
(s, 9 H, C4H9Si), 3.57 (s, 3 H, CH3N), 4.26 (s, 2 H, CH2Ph), 7.04 (d,
1 H, J = 8.5 Hz), 7.25 (m, 5 H), 7.73 (d, 1 H, J = 8.5 Hz).
13C NMR (100.6 MHz, CD3COCD3): δ = 0.45, 22.9, 30.3, 30.4,
120.2, 124.0, 130.9, 131.3, 133.1, 133.6, 135.8, 135.9, 141.7, 143.6,
147.1.
4-Azaindoles 9a–d
3-{[1-(tert-Butyl)-1,1-dimethylsilyl]oxy}-5-methoxy-1,2-dime-
thyl-1H-pyrrolo[3,2-b]pyridine (9a)
To a mixture of LiCl (225 mg, 5.2 mmol), benzoquinone (85 mg,
0.79 mmol), K2CO3 (217 mg, 1.6 mmol), and PdCl2(MeCN)2 (28
mg, 0.11 mmol) in anhyd THF (4 mL) was added a solution of 8a
(162 mg, 0.52 mmol) in THF (2 mL). The mixture was stirred at r.t.
for 1.75 h. The mixture was diluted with Et2O, transferred to a silica
gel packed column, and eluted with Et2O. The solvents were remo-
ved under vacuum and the residue was purified by column chroma-
tography to give 163 mg (100%) of 9a; mp 70 °C.
HRMS: m/z calcd for C21H28ClN2OSi (M + 1): 387.1659; found:
387.1658.
Methyl 2-[(1-Allyl-2-ethyl-5-methoxy-1H-pyrrolo[3,2-b]pyri-
din-3-yl)oxy]acetate (10)
To a solution of 9c (89 mg) in THF (4 mL) were added methyl bro-
moacetate (97 mg, 0.63 mmol) and Bu4NF (1.0 M in THF, 0.515
mL, 0.515 mmol) successively and the mixture was stirred at r.t. for
3.5 h. Sat. aq NH4Cl was added and the mixture was extracted twice
with EtOAc. The combined organic layers were washed once with
distilled water, once with brine, and dried (MgSO4). The title com-
pound 10 (43 mg, 55%) was isolated by column chromatography.
IR (KBr) ν = 2950, 2920, 1560, 1490, 1455, 1400, 1260, 1175 cm–1.
1H NMR (400 MHz, CD3COCD3): δ = 0.27 [s, 6 H, (CH3)2Si], 1.05
(s, 9 H, C4H9Si), 2.33 (s, 3 H, CH3C–N), 3.64 (s, 3 H, CH3N), 3.89
(s, 3 H, CH3O), 6.43 (d, 1 H, J = 8.8 Hz), 7.59 (d, 1H, J = 8.7 Hz).
Synthesis 1999, No. 11, 1893–1902 ISSN 0039-7881 © Thieme Stuttgart · New York

1902
P. Zakrzewski et al.
PAPER
(4) Lau, C. K.; Mintz, M.; Bernstein, M. A.; Dufresne, C.
IR (film) ν = 2950, 2920, 1750, 1550, 1400 cm–1.
Tetrahedron Lett. 1993, 34, 5527.
1H NMR (300 MHz, CD3COCD3): δ = 1.23 (t, 3 H, J = 7.6 Hz,
CH3C), 2.84 (q, 2 H, J = 15.1, 9.1 Hz, CH2CN), 3.67 (s, 3 H,
CH3OCO), 3.87 (s, 3 H, CH3O), 4.74 (m, 2 H, CH2N), 4.77 (m, 1 H,
CH2=), 5.07 (m, 1 H, CH2=), 5.15 (s, 2 H, CH2O), 5.95 (m, 1
H, =CHCN), 6.45 (d, 1 H, J = 8.8 Hz), 7.58 (d, 1 H, J = 8.8 Hz).
13C NMR (100.6 MHz, CD3COCD3): δ = 18.5, 21.3, 50.0, 55.8,
57.2, 73.1, 108.6, 120.2, 125.5, 127.6, 136.8, 136.9, 138.1, 139.5,
163.8, 175.2.
(5) Comprehensive Heterocyclic Chemistry. Vol. 2. Edited by
Boulton, A. J. and McKillop, A. Pergamon Press, New York
1984. p 173.
(6) Abramovitch, R. A.; Saha, J. G. In Advances in Heterocyclic
Chemistry. Vol. 6. Edited by Katritzky, A. R. and Boulton, A.
J. Academic Press, New York 1966. p 229.
(a) Petrow, V.; Sturgeon, B. J. Chem. Soc. 1949, 1157.
(b) Baumgarten, H. E.; Su, H. C. F.; Barkley, R. P.
J. Heterocyclic Chem. 1966, 3, 357.
HRMS: m/z calcd for C16H21N2O4 (M + 1): 305.1501; found:
305.1500.
(c) El’tsov, A. V.; Nekrasov, S. V.; Smirnov, E. V. Zh. Org.
Khim. 1972, 8, 1309; Chem. Abstr. 1972, 77, 153892.
(d) Takeuchi, I.; Hamada, Y. Chem. Pharm. Bull. 1976, 24,
1813.
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Synthesis 1999, No. 11, 1893–1902 ISSN 0039-7881 © Thieme Stuttgart · New York