Vilsmeier-Haack reaction of tertiary alcohols: Formation of functionalised pyridines and naphthyridines

Article abstract of DOI:10.1039/b105634b

Vilsmeier-Haack reaction of 2-arylpropan-2-ols proceeds with multiple iminoalkylations leading to the formation of conjugated iminium salts which on ammonium acetate-induced cyclisation afford 4-arylnicotinaldehydes in good yields. Tertiary alcohols derived from aliphatic or alicyclic ketones by the addition of methyl Grignard are converted into substituted pyridines and naphthyridines by the action of Vilsmeier's reagent in N,N-dimethylformamide followed by nucleophile-assisted cyclisation in the presence of ammonium acetate.

Full text of DOI:10.1039/b105634b

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Vilsmeier–Haack reaction of tertiary alcohols: formation of
functionalised pyridines and naphthyridines
Ajith Dain Thomas and Chitoorthekkathil V. Asokan*
1
School of Chemical Sciences, Mahatma Gandhi University, Kottayam, Kerala, India-686 650.
E-mail: asokancv@yahoo.com; Tel: 91 481 598015
Received (in Cambridge, UK) 27th June 2001, Accepted 9th August 2001
First published as an Advance Article on the web 21st September 2001
Vilsmeier–Haack reaction of 2-arylpropan-2-ols proceeds with multiple iminoalkylations leading to the formation
of conjugated iminium salts which on ammonium acetate-induced cyclisation afford 4-arylnicotinaldehydes in good
yields. Tertiary alcohols derived from aliphatic or alicyclic ketones by the addition of methyl Grignard are converted
into substituted pyridines and naphthyridines by the action of Vilsmeier’s reagent in N,N-dimethylformamide
followed by nucleophile-assisted cyclisation in the presence of ammonium acetate.
Introduction
Results and discussion
Pyridines are important among heterocyclic compounds and
are present in several biological systems. They also find appli-
cations as agrochemicals and anticancer agents.1 Extensive
studies have been carried out on the synthesis of these valuable
compounds owing to their importance as drugs and biologic-
ally active natural products.2 The synthesis of pyridines with
aldehyde functionality is particularly significant, consider-
ing the lack of reactivity of pyridines towards electrophilic
substitution reactions.3 Moreover, the formyl group present
on these molecules makes them promising precursors for fur-
ther synthetic transformations. Surprisingly, the readily avail-
able tertiary alcohols have not been explored so far as starting
materials for the synthesis of pyridines.
2-Phenylpropan-2-ol 2a, prepared by the addition of methyl
Grignard to acetophenone 1a, was treated with the chloro-
methyleneiminium salt derived from POCl3 and DMF for
two hours at 80 ЊC, using DMF as solvent. Excess of solid
ammonium acetate (15 equiv.) was then added to the reaction
mixture, which was again heated at 80 ЊC for two more hours.
Subsequent treatment with saturated aq. potassium carbonate
afforded 4-phenylnicotinaldehyde 3a7,9 in 60% yield (Scheme 1).
The reaction was extended to several 2-arylpropan-2-ols
derived by the addition of methyl Grignard to substituted
acetophenones 1b–e. Thus the hitherto unreported 4-arylnico-
tinaldehydes 3b–e were obtained in 60–66% overall yield. All 4-
arylnicotinaldehydes 3 gave satisfactory spectral and analytical
data.
The Vilsmeier–Haack reaction is a convenient method for the
formylation of activated aromatic and heteroaromatic com-
pounds.4 Meth-Cohn and co-workers have extensively explored
the usefulness of chloromethyleneiminium salts in the synthesis
of heterocycles.5 Perumal and co-workers have reported some
interesting cyclisation reactions under Vilsmeier conditions.6
Reactions of aliphatic alkenes with chloromethyleneiminium
salts are often accompanied by multiple iminoalkylations
leading to the formation of conjugated polyenaldehydes as end
products. As early as 1966, Jutz et al. demonstrated that the
intermediate iminium salts formed from 2-phenylpropene and
isobutene can cyclise to substituted pyridine or naphthyr-
idine, respectively, in the presence of ammonium acetate.7 We
envisaged that the direct treatment of tertiary alcohols, readily
available by the addition of methyl Grignard to ketones, with
chloromethyleneiminium salts should lead to five-carbon units
with terminal electrophilic centres. Treatment of such inter-
mediates with ammonium acetate would provide an easy access
to valuable functionalised pyridines. We have subjected the ter-
tiary alcohols derived from alkyl aryl ketones such as substi-
tuted acetophenones to Vilsmeier conditions. The reactivity
of tertiary alcohols derived from α,β-unsaturated ketones
towards Vilsmeier reagents was also studied. In these cases, the
corresponding 4-aryl- or -styryl-pyridinecarbaldehydes were
obtained in good yields. Synthesis of functionalised 4-aryl-
pyridines is of significant importance due to the prevalence
of this moiety in alkaloids of biological importance such as
streptonigrin and β-carbolines.8 When the same reaction proto-
col was extended to tertiary alcohols derived from aliphatic
ketones and alicyclic ketones, napthyridine derivatives were
obtained, though in relatively lower yields.
Scheme 1 Reagents and conditions: i, CH3MgI, Et2O; ii, POCl3, DMF
(4 equiv.), 80 ЊC, 2 h; iii, NH4OAc, 80 ЊC, 2 h.
The mechanism for the formation of 4-arylpyridine-3-
carbaldehydes7 from 2-arylpropan-2-ols can be rationalised as
follows.7 Acid-catalysed dehydration of the alcohols 2 affords
the intermediate 2-arylprop-2-ene 4 which adds sequentially to
three moles of chloromethyleneiminium salt 5 to give the
multiply iminoalkylated bis(iminium) salt 6. This undergoes
cyclisation in the presence of ammonium acetate to form the
pyridyl iminium salt 7 which on subsequent hydrolysis affords
4-arylnicotinaldehyde 3 (Scheme 2).
DOI: 10.1039/b105634b
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This journal is © The Royal Society of Chemistry 2001
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Scheme 3 Reagents and conditions: i, C2H5MgI, Et2O; ii, POCl3, DMF
(4 equiv.), 80 ЊC, 2 h; iii, NH4OAc, 80 ЊC, 2 h.
However the reaction 3-phenylpentan-3-ol 16 with chloro-
methyleneiminium salt followed by subsequent reaction with
Vilsmeier reagent and ammonium acetate did not give the
expected 3,5-dimethyl-4-phenylpyridine 17 under our conditions.
Scheme 2
Similarly 2-(2-naphthyl)propan-2-ol
8 derived from 2-
acetylnaphthalene reacts with chloromethyleneiminium salt
followed by ammonium acetate to afford the corresponding
4-(2-naphthyl)nicotinaldehyde 9 in 43% yield.
Jutz et. al have reported that the reaction of 2-methylpropene
with excess of chloromethyleneiminium salt proceeds with
multiple iminoalkylations and that cyclisation of the imino-
alkylated intermediate induced by ammonium acetate leads to
the formation of [2,7]naphthyridine-4-carbaldehyde.7 Isoolefins
are known to undergo stepwise acetylations under Friedel–
Crafts conditions followed by treatment with liquid ammonia
to afford, e.g., 1,3,6,8-tetramethyl[2,7]naphthyridine along with
2,4,6-trimethylpyridine.10 Nevertheless, these methodologies
have not been further explored for the synthesis of naphthyr-
idines. We have examined the reactions of aliphatic tertiary
alcohols directly with chloromethyleneiminium salt and the
subsequent cyclisation of the intermediates in the presence of
ammonium acetate. Considering the prevalence of the [2,7]-
naphthyridine moiety in biologically active marine natural
alkaloids,11 the transformation of simple tertiary alcohols
into naphthyridine derivatives is valuable. Our survey of the
literature revealed that the chemistry of [2,7]naphthyridine
derivatives has been little explored, partly due to the difficult
and multistep synthesis of these compounds.12,13 We envisaged
that the reaction of tertiary alcohols with chloromethylene-
iminium salts would lead to the formation of the corresponding
alkene, which upon sequential multiple iminoalkylation fol-
lowed by ammonium acetate-mediated cyclisation should afford
substituted naphthyridines.
However, the reaction of 2-(2-pyridyl)propan-2-ol 10 with
chloromethyleneiminium salt followed by treatment with
ammonium acetate gave a rather complex product mixture
under these conditions from which 4-(2-pyridyl)pyridine-3-
carbaldehyde 11 could not be isolated.
We next examined the reactivity of 2-methyl-4-phenylbut-3-
en-2-ol 12, derived from benzalacetone, with Vilsmeier–Haack
reagent. The carbinol was treated with four equivalents of
Vilsmeier reagent and the product mixture was subjected to
cyclisation under similar conditions to afford a pale yellow
solid, having mp 66–67 ЊC, in 51% yield, which was identified as
4-styrylnicotinaldehyde 13.
tert-Butyl alcohol 18 was treated with six equivalents of
Vilsmeier reagent at room temperature for 15 hours, cooled to
0 ЊC, treated with solid ammonium acetate in excess (15 equiv.)
and the mixture again stirred at 0 ЊC for 1 more hour.
The reaction mixture after usual work-up and purification by
chromatography afforded [2,7]naphthyridine-4-carbaldehyde
207,14 in 18% yield.
Formation of 2-methylpropene from tert-butyl alcohol by the
elimination of water followed by iminoalkylation and loss of
The reactivity of 2-arylbutan-2-ols with chloromethylene-
iminium salt was also studied to further explore the generality
of this procedure. When 2-phenylbutan-2-ol 14a was treated
with Vilsmeier reagent prepared from POCl3 and DMF at 80
ЊC followed by treatment with NH4OAc, 5-methyl-4-phenyl-
nicotinaldehyde 15a was obtained in 55% yield (Scheme
3). Similarly the other 2-arylbutan-2-ols 14b–d afforded the
substituted nicotinaldehydes 15b–d.
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silica gel using hexane–ethyl acetate (8 : 2) as eluent to give the
4-arylnicotinaldehydes7,9 3a–e, 9.
4-Phenylnicotinaldehyde 3a. Prepared by the reaction of 2-
phenylpropan-2-ol 2a (0.68 g, 5 mmol) with Vilsmeier reagent,
and subsequent treatment with ammonium acetate, as a solid
(0.54 g, 60%); mp 40–41 ЊC (lit.,9 40–41 ЊC).
4-(4-Methoxyphenyl)nicotinaldehyde 3b. Prepared by the
reaction of 2-(4-methoxyphenyl)propan-2-ol 2b (0.83 g, 5
mmol) with Vilsmeier reagent, and subsequent treatment with
ammonium acetate, as a pale brown solid (0.78 g, 66%); mp 82–
83 ЊC (Found: C, 73.02; H, 5.06; N, 6.44. C13H11NO2 requires C,
73.23; H, 5.20; N, 6.57%); νmax (KBr)/cmϪ1 2950, 2830, 1680,
1600, 1580, 1510, 1465 and 1380; δH (90 MHz) 3.90 (3H, s,
OCH3), 7.05 (2H, d, J 8, ArH), 7.30–7.50 (3H, m, ArH ϩ Py
5-H), 8.75 (1H, d, J 6.5, 6-H), 9.10 (1H, s, 2-H), 10.10 (1H, s,
CHO); δC (22.4 MHz) 54.71 (OCH3), 113.81, 123.96, 126.46,
127.89, 130.46, 149.11, 150.99, 152.60, 160.15 (aromatic),
HCl would afford the N,N-dimethylamino-substituted diene 22.
Further sequential iminoalkylations involving four equivalents
of chloromethyleneiminium salt would finally lead to the tris-
(iminium) salt 23, which on treatment with ammonium acetate
followed by aqueous basic work-up would afford the [2,7]-
naphthyridine-4-carbaldehyde 20.7 Similarly, the reaction of
2-methylbutan-2-ol 19 with Vilsmeier reagent prepared from
POCl3 and DMF, followed by treatment with ammonium acet-
ate, gave 5-methyl[2,7]naphthyridine-4-carbaldehyde 21 in 11%
yield. 1-Methylcyclohexanol 24 under similar conditions gave
8,9-dihydro-7H-benzo[de][2,7]naphthyridine 25 in 8% yield.
190.67 (C᎐O); m/z (GCMS) 213 (Mϩ, 100%), 212 (22.4), 170
᎐
(37.8), 142 (19.4).
4-(4-Methylphenyl)nicotinaldehyde 3c. Prepared by the reac-
tion of 2-(4-methylphenyl)propan-2-ol 2c (0.75g, 5 mmol) with
Vilsmeier reagent, and subsequent treatment with ammonium
acetate, as a brown liquid (0.6 g, 61%) (Found: C, 78.94; H,
5.51; N, 6.87. C13H11NO requires C, 79.17; H, 5.62; N, 7.10%);
νmax (film)/cmϪ1 3025, 2850, 1690, 1590, 1540, 1510, 1470 and
1390; δH (90 MHz) 2.40 (3H, s, CH3), 7.30 (4H, s, ArH), 7.36
(1H, d, J 6.5, 5-H), 8.75 (1H, d, J 6.5, 6-H), 9.12 (1H, s,
2-H), 10.10 (1H, s, CHO); δC (22.4 MHz) 21.00 (CH3), 125.00,
127.50, 128.00, 129.00, 132.00, 140.00, 150.00, 152.00, 153.00
In summary we have examined the reactions of a variety of
tertiary alcohols with a chloromethyleneiminium salt. These
studies reveal that the multiply iminoalkylated intermediates
derived from them could be cyclised using ammonium acet-
ate to afford substituted pyridines and naphthyridines having
functional groups for further synthetic transformations.
(aromatic), 191.50 (C᎐O); m/z (GCMS) 197 (Mϩ, 87.8%), 182
᎐
(100), 168 (32.7), 154 (19.4), 115 (18.4).
4-(4-Chlorophenyl)nicotinaldehyde 3d. Prepared by the reac-
tion of 2-(4-chlorophenyl)propan-2-ol 2d (0.85 g, 5 mmol) with
Vilsmeier reagent, and subsequent treatment with ammonium
acetate, as a pale yellow solid (0.68 g, 63%) mp 75–76 ЊC
(Found: C, 65.93; H, 3.59; N, 6.36. C12H8ClNO requires C,
66.22; H, 3.70; N, 6.44%); νmax (KBr)/cmϪ1 3050, 2875, 1690,
1580, 1470 and 1390; δH (90 MHz) 7.20–7.70 (5H, m, ArH ϩ Py
5-H), 8.80 (1H, d, J 6.5, 6-H), 9.12 (1H, s, 2-H), 10.10 (1H, s,
CHO); δC (22.4 MHz) 124.17, 127.87, 128.59, 130.38, 133.15,
Experimental
Melting points are uncorrected and were obtained on a Buchi-
530 melting point apparatus. IR spectra were recorded on a
Shimadzu IR-470 spectrometer. NMR spectra were recorded in
deuteriochloroform (internal standard TMS) on JEOL EX90,
Bruker WM200 or Bruker WM300 spectrometers; 1H spectra at
90, 200 or 300 MHz and 13C spectra at 22.4, 50.3 or 75.5 MHz,
respectively, and coupling constants are given in Hz. Electron-
impact mass spectra were obtained on a Finnigan-MAT 312
spectrometer. GCMS were obtained on a Hewlett Packard
5890 Series II GC connected to a 5890 mass-selective detector.
Solvents were dried and distilled before use: N,N-dimethyl-
formamide from P2O5; diethyl ether from Na. Organic extracts
were dried over anhydrous Na2SO4.
135.24, 149.53, 150.13, 153.08 (aromatic), 190.13 (C᎐O); m/z
᎐
(GCMS) 217 (Mϩ, 100%), 182 (73.5), 154 (21.4), 126 (23.5).
4-(4-Bromophenyl)nicotinaldehyde 3e. Prepared by the reac-
tion of 2-(4-bromophenyl)propan-2-ol 2e (1.08 g, 5 mmol) with
Vilsmeier reagent, and subsequent treatment with ammonium
acetate, as a brown solid (0.79 g, 60%); mp 80–82 ЊC (Found: C,
54.58; H, 2.91; N, 5.21. C12H8BrNO requires C, 54.99; H, 3.08;
N, 5.34%); νmax (KBr)/cmϪ1 2849, 1696, 1593, 1471 and 1392; δH
(300 MHz) 7.20 (2H, d, J 8.5, ArH), 7.28 (1H, d, J 5.1, 5-H),
7.57 (2H, d, J 8.5, ArH), 8.71 (1H, d, J 5.1, 6-H), 9.02 (1H, s, 2-
H), 9.96 (1H, s, CHO); δC (75.5 MHz) 124.56, 124.99, 128.76,
131.42, 132.52, 134.39, 150.54, 151.23, 153.99 (aromatic),
Reactions of 2-arylpropan-2-ols 2, 8 with Vilsmeier reagent
followed by ammonium acetate: Synthesis of 4-arylnicotin-
aldehydes 3, 9
Vilsmeier reagent was prepared by mixing ice-cold, dry DMF
(50 mL) and POCl3 (1.87 mL, 20 mmol). The mixture was then
stirred for 15 minutes at room temperature. The 2-arylpropan-
2-ol 2a–e or 8 (5 mmol) obtained from the Grignard reaction
was dissolved in dry DMF and added over about 15 minutes at
0–5 ЊC. The reaction mixture was stirred for 10 minutes at room
temperature and heated to 80 ЊC for 2 hours with stirring. After
the heating excess of solid ammonium acetate (15 equiv., 5.8 g)
was added to the reaction mixture and heating was continued
with stirring at 80 ЊC for two hours more. The mixture was then
added to cold, saturated aq. K2CO3 (500 mL) and extracted
with diethyl ether (3 × 50 mL). The organic layer was washed
with water, dried over anhydrous Na2SO4, and evaporated to
afford the crude product, which was chromatographed over
191.09 (C᎐O); m/z (EI) 265 (Mϩ ϩ 2, 61.9%), 264 (Mϩ ϩ 1,
᎐
55.8), 263 (Mϩ, 73.2), 184 (24), 183 (100), 155 (49.9), 154 (37.9),
127 (62.1), 106 (30.3), 77 (37.9), 64 (31.8), 50 (22.7).
4-(2-Naphthyl)nicotinaldehyde 9. Prepared by the reaction of
2-(2-naphthyl)propan-2-ol 8 (0.93 g, 5 mmol) with Vilsmeier
reagent, and subsequent treatment with ammonium acetate, as
a yellow solid (0.51 g, 43%); mp 103–104 ЊC (Found: C, 81.92;
H, 4.61; N, 5.88. C16H11NO requires C, 82.38; H, 4.75; N,
6.00%); νmax (KBr)/cmϪ1 3050, 2825, 1680, 1580, 1480 and 1380;
δH (200 MHz) 7.34–7.59 (4H, m, ArH ϩ Py 5-H), 7.83–7.99
(4H, m, ArH), 8.82 (1H, d, J 5.1, 6-H), 9.18 (1H, s, 2-H), 10.10
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(1H, s, CHO); δC (50.3 MHz) 124.57, 126.21, 126.85, 127.05,
4-(4-Methoxyphenyl)-5-methylnicotinaldehyde 15b. Prepared
127.48, 127.96, 128.37, 128.44, 129.16, 132.04, 132.52, 132.90,
by the reaction of 2-(4-methoxyphenyl)butan-2-ol 14b (0.9 g,
5 mmol) with Vilsmeier reagent, and subsequent treatment with
ammonium acetate, as a brown liquid (0.65 g, 56.5%) (Found:
C, 73.61; H, 5.63; N, 5.93. C14H13NO2 requires C, 73.99; H,
5.77; N, 6.16%); νmax (film)/cmϪ1 2950, 2850, 1690, 1600, 1570,
1510, 1460 and 1390; δH (90 MHz) 2.30 (3H, s, PyCH3), 4.00
(3H, s, OCH3), 7.10–7.40 (4H, m, ArH), 8.85 (1H, s, 6-H), 9.15
(1H, s, 2-H), 10.50 (1H, s, CHO); δC (75.5 MHz) 16.20 (CH3),
55.32 (OCH3), 115.63, 131.94, 131.96, 139.73, 140.18, 144.67,
149.54, 151.72, 153.07 (aromatic), 190.88 (C᎐O); m/z (EI) 233
᎐
(Mϩ, 84.3%), 232 (60.6), 205 (70.1), 204 (61.9), 177 (22.4), 176
(34.8), 152 (18.3), 151 (26), 40 (100).
Reaction of 2-methyl-4-phenylbut-3-en-2-ol 12 with Vilsmeier
reagent followed by ammonium acetate: Synthesis of
4-(phenylvinyl)nicotinaldehyde 13
148.53, 154.06, 156.74 (aromatic), 195.16 (C᎐O); m/z (EI) 227
᎐
Vilsmeier reagent was prepared by mixing ice-cold, dry DMF
(50 mL) and POCl3 (1.87 mL, 20 mmol). The mixture was then
stirred for 15 minutes at room temperature. 2-Methyl-4-
phenylbut-3-en-2-ol 12 (5 mmol) obtained from the Grignard
reaction was dissolved in dry DMF and was added during
about 15 minutes at 0–5 ЊC. The reaction mixture was stirred for
10 minutes at room temperature and heated to 80 ЊC for 2 hours
with stirring. After the heating, excess of solid ammonium
acetate (15 equiv., 5.8g) was added to the reaction mixture and
heating at 80 ЊC with stirring was continued for two hours more.
The mixture was then added to cold, saturated aq. K2CO3 (500
mL) and extracted with diethyl ether (3 × 50 mL). The organic
layer was washed with water, dried over anhydrous Na2SO4, and
evaporated to afford the crude product, which was chromato-
graphed over silica gel, using hexane–ethyl acetate (8 : 2) as
eluent, to give 4-(phenylvinyl)nicotinaldehyde 13 as a pale yel-
low solid (0.52 g, 51%); mp 66–67 ЊC (Found: C, 80.03; H, 5.19;
N, 6.57. C14H11NO requires C, 80.36; H, 5.30; N, 6.69%); νmax
(KBr)/cmϪ1 1680, 1620, 1590, 1490, 1440, 1410, 1310, 1230 and
1190; δH (90 MHz) 7.20–7.80 (7H, m, ArH ϩ Py 5-H ϩ vinylic
H), 8.15 (1H, d, J 16, vinylic H), 8.75 (1H, d, J 5.1, 6-H), 8.95
(1H, s, 2-H), 10.30 (1H, s, CHO); δC (22.4 MHz) 119.87, 122.05,
127.12, 127.30, 128.67, 129.12, 135.66, 137.03, 145.98, 153.14,
(Mϩ, 100), 212 (18.3), 184 (58.1), 168 (19.8), 156 (25.1), 154
(19.5), 128 (26).
5-Methyl-4-(4-methylphenyl)nicotinaldehyde 15c. Prepared by
the reaction of 2-(4-methylphenyl)butan-2-ol 14c (0.82 g,
5 mmol) with Vilsmeier reagent, and subsequent treatment with
ammonium acetate, as a brown liquid (0.55 g, 52%) (Found: C,
79.17; H, 5.93; N, 6.52. C14H13NO requires C, 79.59; H, 6.20; N,
6.63%); νmax (film)/cmϪ1 1692, 1581, 1463, 1387, 1268 and 1157;
δH (300 MHz) 2.05 (3H, s, C6H4CH3), 2.32 (3H, s, PyCH3), 7.01
(2H, d, J 7.7, ArH), 7.20 (2H, d, J 7.7, ArH), 8.53 (1H, s, 6-H),
8.83 (1H, s, 2-H), 9.67 (1H, s, CHO); δC (75.5 MHz) 15.74
(PyCH3), 20.23 (CH3), 127.84, 127.95, 128.38, 129.66, 131.25,
137.71, 145.77, 151.02, 153.43 (aromatic), 190.67 (C᎐O); m/z
᎐
(EI) 211 (Mϩ, 100%), 210 (68.5), 196 (77.5), 182 (24.6), 168
(46.1), 167 (39.1), 139 (18).
4-(4-Chlorophenyl)-5-methylnicotinaldehyde 15d. Prepared by
the reaction of 2-(4-chlorophenyl)butan-2-ol 14d (0.92 g,
5 mmol) with Vilsmeier reagent, and subsequent treatment with
ammonium acetate, as a pale brown solid (0.62 g, 54%); mp 78–
79 ЊC (Found: C, 67.03; H, 4.26; N, 5.84. C13H10ClNO requires
C, 67.40; H, 4.35; N, 6.05%); νmax (KBr)/cmϪ1 1690, 1494, 1391,
1265 and 1092; δH (300 MHz) 2.31 (3H, s, PyCH3), 7.01 (2H, d,
J 7.9, ArH), 7.11 (2H, d, J 7.9, ArH), 8.53 (1H, s, 6-H), 8.83
(1H, s, 2-H), 9.58 (1H, s, CHO); δC (75.5 MHz) 17.15 (PyCH3),
129.03, 129.51, 130.69, 132.55, 132.68, 135.49, 147.71, 150.89,
154.89 (aromatic and vinylic), 191.59 (C᎐O); m/z (EI) 208 (Mϩ,
᎐
100%), 207 (45.4), 180 (19.4), 179 (84), 152 (21.1), 151 (39.6),
105 (18.2).
Reactions of 2-arylbutan-2-ols 14 with Vilsmeier reagent
followed by ammonium acetate: Synthesis of 4-aryl-5-
methylnicotinaldehydes 15
155.15 (aromatic), 191.45 (C᎐O); m/z (EI) 233 (Mϩ ϩ 2, 32%),
᎐
232 (Mϩ ϩ 1, 33.4), 231 (Mϩ, 100), 230 (56.4), 196 (70.9), 192
(24.6), 168 (33.2), 167 (47), 140 (17.7), 139 (33.3), 119 (42.4).
Vilsmeier reagent was prepared by mixing ice-cold, dry DMF
(50 mL) and POCl3 (1.87 mL, 20 mmol). The mixture was then
stirred for 15 minutes at room temperature. A carbinol 14a–d
(5 mmol) obtained from the Grignard reaction was dissolved in
dry DMF and added during about 15 minutes at 0–5 ЊC. The
reaction mixture was stirred for 10 minutes at room temper-
ature and heated to 80 ЊC for 2 hours with stirring. Solid
ammonium acetate was added to the reaction mixture in excess
(15 equiv., 5.8 g) and the mixture was further heated at 80 ЊC for
2 more hours before being added to cold, saturated aq. K2CO3
(300 mL) and extracted with diethyl ether (3 × 50 mL). The
organic layer was washed with water, dried over anhydrous
Na2SO4, and evaporated to give the crude product, which was
chromatographed using hexane–ethyl acetate (8 : 2) as eluent to
give the corresponding 4-aryl-5-methylnicotinaldehyde 15a–d.
Reactions of aliphatic and alicyclic tertiary alcohols 18, 19 and
24 with Vilsmeier reagent followed by ammonium acetate:
Synthesis of substituted [2,7]naphthyridines 20, 21 and 25
Vilsmeier reagent was prepared by mixing ice-cold, dry DMF
(50 mL) and POCl3 (11.2 mL, 120 mmol). The mixture was then
stirred for 15 minutes at room temperature. The tertiary alcohol
(20 mmol) was dissolved in dry DMF and added during about
15 minutes at 0–5 ЊC. The reaction mixture was stirred for 15
hours at room temperature and cooled in ice, solid ammonium
acetate was added to the reaction mixture in excess (15 equiv.,
23 g), and the mixture was again stirred for 2 hours more before
being added to cold, saturated aq. K2CO3 (500 mL) and
extracted with diethyl ether (3 × 50 mL). The organic layer
was washed with water, dried over anhydrous Na2SO4, and
evaporated to give the crude product, which was chromato-
graphed using hexane–ethyl acetate (4 : 6) as eluent to give the
substituted [2,7]naphthyridine.
5-Methyl-4-phenylnicotinaldehyde 15a. Prepared by the reac-
tion of 2-phenylbutan-2-ol 14a (0.76 g, 5 mmol), with Vilsmeier
reagent, and subsequent treatment with ammonium acetate, as
a pale brown solid (0.54 g, 55%); mp 65–66 ЊC (Found: C, 78.84;
H, 5.51; N, 6.87. C13H11NO requires C, 79.17; H, 5.62; N,
7.10%); νmax (KBr)/cmϪ1 3050, 2850, 1680, 1575, 1435, 1380 and
1260; δH (200 MHz) 2.17 (3H, s, CH3), 7.22–7.31 (2H, m, ArH),
7.45–7.60 (3H, m, ArH), 8.68 (1H, s, 6-H), 8.98 (1H, s, 2-H),
9.79 (1H, s, CHO); δC (50.3 MHz) 17.08 (CH3), 129.09, 129.36,
[2,7]Naphthyridine-4-carbaldehyde 20. Prepared by the reac-
tion of tert-butyl alcohol 18 (1.47 g, 20 mmol) with Vilsmeier
reagent, and subsequent treatment with ammonium acetate, as
a white crystalline solid (0.57 g, 18%); mp 215–216 ЊC (lit.,14
215–216 ЊC); νmax (KBr)/cmϪ1 3356, 2850, 1695, 1626, 1585,
1555, 1497, 1433, 1381, 1355, 1309, 1253, 1215, 1192, 1115,
1082, 1033, 943, 900, 840, 711, 789, 740 and 676 (ref. 7); δH (300
MHz) 7.28 (1H, d, J 5.6, 5-H), 8.96 (1H, d, J 5.6, 6-H), 9.17
(1H, s, 8-H), 9.54 (1H, s, 1-H), 9.60 (1H, s, 3-H), 10.42 (1H, s,
132.38, 134.21, 147.30, 152.06, 155.08 (aromatic), 191.85 (C᎐O);
᎐
m/z (EI) 197 (Mϩ, 100%), 196 (98.9), 168 (50.5), 167 (45),
139 (27.3), 115 (59.6).
2586
J. Chem. Soc., Perkin Trans. 1, 2001, 2583–2587

View Article Online
CHO); δC (75.5 MHz) 117.22, 123.34, 123.93, 135.61, 150.32,
Lucknow for providing spectral and analytical data. A. D. T.
153.23, 155.56, 158.51 (aromatic), 191.81 (C᎐O); m/z (EI) 158
thanks Mahatma Gandhi University for a Junior Research
Fellowship.
᎐
(Mϩ, 100%), 157 (45.5), 129 (73.7), 103 (25.3), 75 (22.2).
5-Methyl[2,7]naphthyridine-4-carbaldehyde 21. Prepared by
the reaction of 2-methylbutan-2-ol 19 (1.76 g, 20 mmol) with
Vilsmeier reagent, and subsequent treatment with ammonium
acetate, as a pale yellow solid (0.376 g, 11%); mp 181–182 ЊC
(Found: C, 69.42; H, 4.57; N, 16.21. C10H8N2O requires C,
69.76; H, 4.68; N, 16.27%); νmax (KBr)/cmϪ1 2962, 1683, 1601,
1261, 1097 and 1023; δH (300 MHz) 2.72 (3H, s, CH3), 8.65 (1H,
s, 6-H), 9.05 (1H, s, 8-H), 9.28 (1H, s, 1-H), 9.46 (1H, s, 3-H),
10.86 (1H, s, CHO); δC (75.5 MHz) 21.69 (CH3), 118.90, 123.38,
126.07, 127.66, 150.02, 150.46, 152.12, 158.28 (aromatic),
References
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191.29 (C᎐O); m/z (EI) 172 (Mϩ, 100%), 171 (56), 155 (72.9),
᎐
149 (30), 144 (61.4), 143 (44.8).
8,9-Dihydro-7H-benzo[de][2,7]naphthyridine 25. Prepared by
the reaction of 1-methylcyclohexanol 24 (2.28 g, 20 mmol) with
Vilsmeier reagent, and subsequent treatment with ammonium
acetate, as a reddish brown semi-solid (0.268 g, 8%) (Found: C,
77.16; H, 5.81; N, 16.33. C11H10N2 requires C, 77.62; H, 5.92;
N, 16.46%); νmax (film)/cmϪ1 2932, 1612, 1545, 1432, 1382, 1270
and 1119; δH (300 MHz) 2.05 (2H, quintet, J 6.2, CH2CH2CH2),
2.99 (4H, t, J 6.2, CH2CH2CH2), 8.44 (2H, s, 3-H and 6-H), 9.17
(2H, s, 1-H and 8-H); δC (75.5 MHz) 21.28 (CH2CH2CH2),
25.59 (CH2CH2CH2), 121.63 (C-8a), 127.59 (C-4 and C-5),
134.75 (C-4a), 142.89 (C-3 and C-6), 149.09 (C-1 and C-8); m/z
(EI) 171 (Mϩ ϩ 1, 91.3%), 170 (Mϩ, 100), 169 (25.5), 84 (22.4),
73 (49.3).
11 F. Guillier, F. Nivoliers, A. Godard, F. Marsais and G. Queguiner,
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Acknowledgements
We thank Dr Mathew George, Dr Satheesh K. Nair and CDRI,
J. Chem. Soc., Perkin Trans. 1, 2001, 2583–2587
2587