Facile conversion of pyridine propargylic alcohols to enones: Stereochemistry of protonation of allenol

Article abstract of DOI:10.1016/j.tetlet.2005.06.087

The conversion of 4-pyridyl propargylic alcohols 1 to the (E)-propenones 3 and propynones 2 occurs under mild reaction conditions, pyridinium chloride in methanol at room temperature. (Z)-4-Pyridyl propenones 11 are detected as initial products when large

Full text of DOI:10.1016/j.tetlet.2005.06.087

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 5683–5685
Facile conversion of pyridine propargylic alcohols to enones:
stereochemistry of protonation of allenol
Ramazan Erenler and Jean-Franc¸ois Biellmann*
Institute of Chemistry, Academia Sinica, Nankang 115, Taipei, Taiwan
Received 10 May 2005; revised 10 June 2005; accepted 17 June 2005
Available online 6 July 2005
Abstract—The conversion of 4-pyridyl propargylic alcohols 1 to the (E)-propenones 3 and propynones 2 occurs under mild reaction
conditions, pyridinium chloride in methanol at room temperature. (Z)-4-Pyridyl propenones 11 are detected as initial products when
large substituents such as trimethylsilyl, tert-butyl and phenyl are attached at C-3 of the propynols and these (Z)-enones 11 are iso-
merised to the (E)-isomers 3 under the reaction conditions. In the presence of deuterated solvent, both hydrogens at the double bond
of enone 3d are deuterated. An allenol is proposed as intermediate whose preferential protonation occurs at the less hindered side
giving the (Z)-enone. The propargylic alcohols, pyridin-2-yl 12 and quinolin-4-yl 5, are converted to (E)-enones 13 and 7,
respectively.
Ó 2005 Elsevier Ltd. All rights reserved.
In a synthetic scheme, we planned to use alcohols of the
type 1-(pyridin-4-yl)prop-2-yn-1-ol and found that they
are not well documented. Only one reference mentions
the compound 1d as a pink solid that slowly decomposes
(NMR in CDCl3).1 Based on the reported transforma-
tion of quinine to quinotoxine under acid–base cataly-
sis,2 we suspected that the acidic deuterochloroform
may contribute to the instability of this propargylic
alcohol. Soon we found out that this alcohol 1d was
more stable in THF solution. Since pyridine hydrochloride
R
R
R
H
(E)
O
O
HO
O
+
+
rt
N
N
N
N
1
2
3
4
Comp.
Reaction condition
MeOH, PyHCl
Yld (%)
49
a R = CH3
15
-
-
-
b R = Ph
MeOH, PyHCl
MeOH, PyHCl
10
55
75
c R = t-butyl
d R = SiMe3
e R = SiMe3
12
26
15
MeOH, PyHCl
CH2Cl2
52
28
-
8
Keywords: Isomerisation; Propargylic alcohol; Enone; Ynone; Heterocyclic; Pyridinium chloride.
*
Corresponding author. Tel.: +886 9 27298484; fax: +886 2 27831237; e-mail: jfb@chem.sinica.edu.tw
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.06.087

5684
R. Erenler, J.-F. Biellmann / Tetrahedron Letters 46 (2005) 5683–5685
R
R
R
H
N
HO
O
O
PyHCl
+
MeOH,rt
N
N
7
5
6
Comp.
Yld (%)
a R = CH3
30
-
36
55
b R = SiMe3
is a good acid–base catalyst,3 we treated the propargylic
alcohol 1d in methanol with pyridine hydrochloride in
catalytic amount (5% molar ratio) and found that
greater yields of the reaction products were obtained
in methanol than those in chloroform and dichloro-
methane. We isolated two ketones ynone 2d and (E)-
enone 3d by chromatography.4 Besides the ynone 2d
and enone 3d, the saturated ketone 4e5 was obtained
in the reaction of alcohol 1d in dichloromethane
(without addition of pyridinium hydrochloride). We
explored the generality of this transformation by varia-
tion of the acetylenic substituent. The three alcohols 1a,
1b and 1c underwent the same transformation and the
results are presented as well as those obtained for the
1-(quinolin-4-yl)but-2-yn-1-ol 5a and compound 5b.
enone 11. The approach of the acid cis to the large sub-
stituent as trimethylsilyl, phenyl or t-butyl is strongly
hindered and the protonation occurs at the opposite face
leading to the (Z)-enone 11. When the reactions were
followed by NMR, the (Z)-enones 11b, 11c and 11d were
detected initially. These (Z)-enone 11 gave rise to the
(E)-enone 3 by acid isomerisation. With methyl substi-
tuted 1a, the (Z) enone 11a was not detected. When
the reaction with 1d was carried out in MeO2H, the
two vinylic hydrogens of enone 3d are deuterated.
Hence, these two deuteriums must be derived from the
deuterated methanol. The protonation of allenol and re-
lated species such as allenyl ethers has been described to
give at least some (Z) isomer.7 A less likely explanation
could be that the isomerisation of methyl (Z)-enone 11a
(R = Me) to the (E)-enone 3a is faster than that of the
other (Z)-enones 11b, 11c and 11d. The isomerisation
of the propargylic alcohol, 3-(trimethylsilyl)-1-phenyl-
prop-2-yn-1-ol, was not detected under these conditions
even on longer reaction times and higher temperature.
So the activation of the propargylic proton by formation
of the pyridinium salt is crucial.
The mechanism shown below was considered. Isomeri-
sation of propargylic alcohols to enones has been
described in numerous instances with acid–base (under
harsher conditions) or metallic catalysts.6 It is surprising
that the reaction of propargylic alcohol 1 goes to com-
pletion under much milder reaction conditions at room
temperature in 5 h. So a special feature facilitates the
reaction and this is the protonation of the nitrogen to
salt 8 which loses the propargylic proton under base
catalysis to give the anhydro base 9. The protonation
at the terminal position of the triple bond of 9 with
the loss of the proton at the nitrogen gives allenol 10.
The protonation of the allenol 10 at the enolic position
gives enone 3. Model examination of this protonation
suggested that the less hindered direction gives the (Z)-
The related allylic alcohols at C-4 of pyridine are not
more described than the propargylic ones. It is men-
tioned where the preparation of the allylic alcohol was
attempted by addition of the vinylic Grignard reagent
to isonicotinaldehyde and the 1-(pyridin-4-yl)propan-1-
one was isolated.8 However, another substituted allylic
alcohol is mentioned without comments about its
stability.9
H
R
Base
R
H
H+
R
R
(E)
H
(Z)
O
C
H
C
O
H+
H
HO
HO
C
HO
H
R
N
N
N
N
N
10
11
3
H
H
8
9

R. Erenler, J.-F. Biellmann / Tetrahedron Letters 46 (2005) 5683–5685
5685
rt. After 5 h, the usual extraction with CH2Cl2 was
performed. By column chromatography (silica, hexane/
EtOAc, 4:1) we separated two products: 3-(trimethylsilyl)-
1-(pyridine-4-yl)prop-2-yn-1-one 2d: Yellow liquid (26%),
1H NMR (400 MHz, CDCl3): d 0.30 (s, 9H), 7.87 (dd,
J = 6.0, 3.0 Hz, 2H), 8.81 (dd, J = 6.0, 3.0 Hz, 2H); 13C
NMR (100 MHz, CDCl3): d À0.7, 100.1, 103.2, 122.1,
142.1, 150.9, 176.7; UV/vis (CH2Cl2), kmax (e) = 237
(6610); Ms (FAB+), 204 [M++H]. Anal. Calcd for
C11H13NOSi: C, 64.98; H, 6.44; N, 6.89. Found: C,
64.95; H, 6.41; N, 6.85. (E)-3-(trimethylsilyl)-1-(pyridine-
4-yl)prop-2-en-1-one 3d: Colourless liquid (52%), 1H
We prepared the propargylic alcohol at C-2 12. The
treatment of this alcohol 12 with pyridinium chloride
gives the enone 13 in an yield of 42%. The same reason-
ing as for alcohols 1 applies here. It has been reported
that heating of the related allylic alcohol, 1-(pyridin-2-
yl)prop-2-en-1-ol, in chloroform at 110 °C for
two days gave 1-(pyridin-2-yl)propan-1-one and that the
intermediate was trapped.10
TMS
TMS
NMR (400 MHz, CDCl3):
d 0.11(s, 9H), 7.05 (d,
HO
O
J = 18.8 Hz, 1H), 7.25 (d, J = 18.8 Hz, 1H), 7.60 (dd,
J = 6.0, 2.0 Hz, 2H), 8.70 (dd, J = 6.0, 2.0 Hz, 2H); 13C
NMR (100 MHz, CDCl3): d À1.8, 121.8, 137.4, 143.9,
150.7, 152.7, 189.9; UV/vis (CH2Cl2), kmax (e) = 195
(2900), 231 (4500), 277(2300); Ms (EI): 205 [M+]. Anal.
Calcd for C11H15NOSi: C, 64.34; H, 7.36; N, 6.82. Found:
C, 64.30; H, 7.34; N, 6.85.
N
N
PyHCl
MeOH, rt
13
12
5. Sheldrake, P.; Tyrrell, E.; Mintias, S.; Shahrid, I. Synth.
Commun. 2003, 33, 2263–2267.
6. Acid–base: Nineham, W.; Raphael, R. A. J. Chem. Soc.
1949, 118–121; Ishikawa, T.; Mizuta, T.; Hagiwara, K.;
Aikawa, T.; Kudo, T.; Seito, S. J. Org. Chem. 2003, 68,
3702–3705; Coelho, A.; Sotelo, E.; Fraiz, N.; Yanez, M.;
Laguna, R.; Cano, E.; Ravina, E. Bioorg. Med. Chem.
Lett. 2004, 14, 321–324; , Palladium: Arcadi, A.; Cacchi,
S.; Marinelli, F.; Misiti, D. Tetrahedron Lett. 1988, 29,
1457–1460; Saiah, M. K. E.; Pellicciari, R. Tetrahedron
Lett. 1995, 36, 4497–4500; Lu, X.; Ji, J.; Guo, C.; Shen, W.
J. Organomet. Chem. 1992, 428, 259–266; Ruthenium:
Trost, B. M.; Livingston, R. C. J. Am. Chem. Soc. 1995,
117, 9586–9587.
The ynones 2 and 6 originate from oxidation and were
found even when the reaction was carried out under
nitrogen. But the saturated ketone 4e was observed only
when the reaction was carried out in CH2Cl2. The dis-
mutation of 1 to equal amount of ynone 2 and saturated
ketone 4 does not seem to occur in the presence of pyrid-
inium hydrochloride.
References and notes
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Tetrahedron 1983, 39, 949–960; Vanderwal, C. D.; Vos-
berg, D. A.; Sorensen, E. J. Org. Let. 2001, 3, 4307–4310;
Sestrick, M. R.; Miller, M.; Hegedus, L. S. J. Am. Chem.
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2. Rabe, P.; Schuler, W. Chem. Ber. 1948, 81, 139–153;
Turner, R. B.; Woodward, R. B. The Chemistry of
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8. Massiot, G. Bull. Soc. Chim. Belg. 1990, 99, 717–728.
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2633–2648.
4. To a solution of product 1d (0.97 mmol) in MeOH
(4.0 mL) was added pyridinhydrochloride (49 lmol) at