Synthesis of alkyl 2,5-dihydro-5-oxofuran-2-carboxylates via palladium-catalyzed carbonylative cyclization of β-bromovinyl aldehydes in alcohols

Article abstract of DOI:10.1016/j.jorganchem.2008.09.014

β-Bromovinyl aldehydes reacts with carbon monoxide and alcohols at 125 °C in the presence of a catalytic amount of a palladium catalyst along with a base to give the corresponding carbonylative cyclized alkyl 2,5-dihydro-5-oxofuran-2-carboxylates in good yields. A reaction pathway involving intramolecular addition of acylpalladium to formyl group is proposed as a key step of this catalytic process.

Full text of DOI:10.1016/j.jorganchem.2008.09.014

Journal of Organometallic Chemistry 693 (2008) 3677–3680
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Note
Synthesis of alkyl 2,5-dihydro-5-oxofuran-2-carboxylates via palladium-catalyzed
carbonylative cyclization of b-bromovinyl aldehydes in alcohols
*
Chan Sik Cho , Jun Uk Kim, Heung-Jin Choi
Department of Applied Chemistry, College of Engineering, Kyungpook National University, Daegu 702-701, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 15 May 2008
Received in revised form 29 August 2008
Accepted 2 September 2008
Available online 10 September 2008
b-Bromovinyl aldehydes reacts with carbon monoxide and alcohols at 125 °C in the presence of a cata-
lytic amount of a palladium catalyst along with a base to give the corresponding carbonylative cyclized
alkyl 2,5-dihydro-5-oxofuran-2-carboxylates in good yields. A reaction pathway involving intramolecular
addition of acylpalladium to formyl group is proposed as a key step of this catalytic process.
Ó 2008 Elsevier B.V. All rights reserved.
Keywords:
Alcohols
b-Bromovinyl aldehydes
Carbon monoxide
Carbonylative cyclization
Palladium catalyst
Lactones
1. Introduction
a palladium-catalyzed cyclization of b-bromovinyl aldehydes with
carbon monoxide and alcohols leading to alkyl 2,5-dihydro-5-
Palladium-catalyzed annulation reaction has been widely used
as a convenient tool for the synthesis of many carbo- and hetero-
cyclic compounds [1]. As part of our continuing studies directed to-
wards transition metal-catalyzed cyclization reactions, we recently
reported on the synthesis of several cyclic compounds using such a
palladium-catalyzed cyclization protocol. Among them, several
aldehydes such as b-bromovinyl aldehydes, 2-bromobenzaldehy-
des and 3-bromopyridine-4-carbaldehydes were found to be cou-
pled and cyclized with suitably functionalized alkenes in the
presence of a palladium catalyst to give benzenes, naphthalenes
and isoquinolines, respectively, via tandem Heck and aldol reac-
tions [2–4]. It is also reported by us that indazoles and pyrazoles
can be synthesized by palladium-catalyzed intramolecular car-
bon–nitrogen bond forming reaction of 2-bromobenzaldehydes
and b-bromovinyl aldehydes with arylhydrazines [5,6]. In connec-
tion with this report, 2-bromobenzaldehyde was found to be
cyclized with primary alcohols in the presence of a palladium
catalyst and a base under carbon monoxide pressure to afford
3-alkoxyisobenzofuran-1(3H)-ones [7]. The present work was dis-
closed during the course of the extension of this carbonylative
cyclization protocol to the reaction with b-bromovinyl aldehydes,
which are readily prepared from ketones via the bromo analogue
of Vilsmeier reaction (Scheme 1) [8]. Herein this report describes
oxofuran-2-carboxylates [9,10].
2. Results and discussion
The results of several attempted carbonylative cyclization of 2-
bromocyclohex-1-enecarbaldehyde (1a) under various conditions
are listed in Table 1. In contrast to the report on palladium-cata-
lyzed synthesis of 3-alkoxy phthalides from 2-bromobenzaldehyde
via carbonylative cyclization [7], treatment of 1a in EtOH in the
presence of PdCl2(PPh3)2 along with Et3N under carbon monoxide
pressure (20 atm) afforded ethyl 1,3,4,5,6,7-hexahydro-3-
oxoisobenzofuran-1-carboxylate (2a) in 66% yield with concomi-
tant formation of 4,5,6,7-tetrahydroisobenzofuran-1(3H)-one (3)
(9% yield), no ethoxy substituted carbonylative cyclized product
4 being formed (entry 1). The reaction was monitored until 1a
had disappeared on TLC, which occurred within 1 h. In a separate
experiment, we confirmed that similar treatment of 2-bromobenz-
aldehyde (5) under the employed reaction conditions afforded 3-
ethoxyisobenzofuran-1(3H)-one (6) in 59% isolated yield as sole
carbonylative cyclized product with 89% conversion of 2-bromo-
benzaldehyde (Scheme 2). This result indicates that 1a is more sus-
ceptible to further carbonylation than 2-bromobenzaldehyde. All
examined palladium precursors such as PdCl2, Pd(OAc)2 and
Pd(dba)2 combined with PPh3 and Pd(PPh3)4 under the employ-
ment of Et3N as base were revealed to be as similarly effective
as that using PdCl2(PPh3)2 (entries 1–5). The product yield and
* Corresponding author. Tel.: +82 53 950 5586; fax: +82 53 950 6594.
E-mail address: cscho@knu.ac.kr (C.S. Cho).
0022-328X/$ - see front matter Ó 2008 Elsevier B.V. All rights reserved.
doi:10.1016/j.jorganchem.2008.09.014

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C.S. Cho et al. / Journal of Organometallic Chemistry 693 (2008) 3677–3680
Table 2
Palladium-catalyzed synthesis of lactones 2a
b-Bromovinyi aldehydes 1
Lactones 2
CO2R
Isolated yield (%)
CHO
66
61
80
Scheme 1.
O
Br
O
distribution were not significantly affected by the kind of palla-
dium precursor. However, when the reaction was performed with
other bases K2CO3 and NaOAc combined with PdCl2(PPh3)2, the
cyclization did not occur effectively towards 2a, whereas 3 was
produced as main carbonylative cyclized product (entries 6 and 7).
Having reaction conditions being established, various b-bromo-
vinyl aldehydes were subjected to react with carbon monoxide and
alcohols in order to investigate the reaction scope and several rep-
resentative results are summarized in Table 2. b-Bromovinyl alde-
hyde 1a was readily tethered with an array of straight and
branched primary alcohols and carbon monoxide to give the corre-
sponding alkyl 1,3,4,5,6,7-hexahydro-3-oxoisobenzofuran-1-car-
boxylates (2a–c) in the range of 61–80% yields. Here again,
simple carbonylative cyclized product 3 was produced in 5–9%
yields. Higher reaction rate and yield were observed with branched
primary alcohol. However, when the reaction of 1a was carried out
in other alcohols such as MeOH and (CF3)2CHOH under the em-
ployed conditions, no carbonylative cyclized esters like 2 were pro-
duced. With cyclic b-bromovinyl aldehydes (1a–d) having various
ring sizes, the carbonylative cyclized esters (2a, d–f) were also
formed in similar yields and the ring size of 1a–d had no relevance
to the product yield. In the reaction with 2-bromo-5-methylcyclo-
hex-1-enecarbaldehyde (1e) and 2-bromo-5-pheylcyclohex-1-ene-
carbaldehyde (1f), the carbonylative cyclized products 2g and h
were obtained as diastereomeric mixtures. However, similar treat-
ment of 1-bromo-3,4-dihydronaphthalene-2-carbaldehyde scar-
cely afforded the corresponding carbonylative cyclized ester,
2a R = Et
1a
2b R = Bu
2c R = iBu
CO2Et
CHO
O
O
58
59
Br
1b
2d
2e
CO2Et
CHO
O
O
Br
1c
CO2Et
CHO
O
63
Br
O
1d
2f
CO2Et
CHO
O
O
73b
Br
1e
2g
CO2Et
Ph
CHO
Br
Ph
O
62b
O
1f
2h
a
Reaction conditions: 1 (0.5 mmol), PdCl2(PPh3)2 (0.02 mmol), Et3N (4 mmol),
CO (20 atm), alcohol (10 mL), 125 °C, for 1 h.
b
Scheme 2.
Mixture of diastereomers (1:1).
Table 1
Optimization of conditions for the reaction with 1aa
CO2Et
OEt
O
CHO
cat. [Pd], CO
O
+
O
EtOH, 125 oC
Br
O
O
O
1a
2a
3
4
Entry
Pd catalysts
Bases
Isolated yield (%)
2a
3
1
2
3
4
5
6
7
PdCl2(PPh3)2
PdCl2/2PPh3
Pd(OAc)2/2PPh3
Pd(dba)2/2PPh3
Pd(PPh3)4
Et3N
Et3N
Et3N
Et3N
Et3N
K2CO3
66
54
54
63
64
0
9
9
9
12
16
17
33
PdCl2(PPh3)2
PdCl2(PPh3)2
NaOAc
16
a
Reaction conditions: 1a (0.5 mmol), palladium catalyst (0.02 mmol), base (4 mmol), EtOH (10 mL), CO (20 atm), 125 °C, for 1 h.

C.S. Cho et al. / Journal of Organometallic Chemistry 693 (2008) 3677–3680
3679
instead, simple carbonylative cyclized product like 3 was produced
in 20% yield.
seems to be due to temporary destruction of the aromatic o-pheny-
lene group for such a metallotropic process [12,15].
The present reaction, consistent with the product formed,
seems to proceed via a pathway shown in Scheme 3. Oxidative
addition of a carbon–bromide bond of 1a to palladium(0) produces
vinylpalladium(II) intermediate 8, which is followed by the inser-
tion of carbon monoxide into a carbon–palladium bond of 8 to give
acylpalladium species 9. Subsequent intramolecular addition of
acylpalladium bond of 9 to neighboring formyl C@O produces cy-
clized alkylpalladium species 10, which triggers further carbon
monoxide insertion to produce acylpalladium 11 and ethanolysis
to give 2a. The mechanistic acylpalladium addition to ketones is
known on palladium-catalyzed carbonylative cyclization of (Z)-b-
3. Conclusion
In summary, it has been shown that b-bromovinyl aldehydes
undergoes carbonylative cyclization with carbon monoxide and
alcohols in the presence of a catalytic amount of a palladium
catalyst along with a base to give alkyl 2,5-dihydro-5-oxofuran-
2-carboxylates in good yields. We believe that the present
reaction will work as a useful two-step procedure for the construc-
tion of a lactone framework from ketones. Synthetic applications
using the mechanistic metallotropic process are currently under
investigation.
iodoenones leading to c-lactones [11,12].
For the formation of lactone 3, adventitious water was sus-
pected as the source of hydrogen. It seems that intermediate 10
undergoes a metallotropic shift to give a furanyl contributor 13
via an alkylpalladium intermediate 12, which is trapped by H2O
to afford enol 14 (Scheme 4). We confirmed in a separate experi-
ment that similar treatment of 1a in EtOH along with the addition
of H2O (0.1 mL) afforded an increased yield of 3 (25%) with an de-
creased yield of 2a (46% yield) compared with the result shown in
entry 1 of Table 1 [13]. These results clearly indicate that H2O
works as a hydrogen source for the formation of 3. It appears that
adventitious water is also a hydrogen source in the synthesis of
lactones like 3 via palladium-catalyzed carbonylative cyclization
of b-bromovinyl aldehydes in an aprotic solvent [14]. As shown
in Scheme 2, no observation of lactone 7 in the reaction with 5
4. Experimental
1H and 13C NMR (400 and 100 MHz) spectra were recorded on a
Bruker Avance Digital 400 spectrometer using TMS as an internal
standard. The isolation of pure products was carried out via thin
layer chromatography (silica gel 60 GF254, Merck). b-Bromovinyl
aldehydes 1 were synthesized from the corresponding ketones
by treatment of PBr3/DMF/CHCl3 [8]. Commercially available
organic and inorganic compounds were used without further
purification.
4.1. General procedure for palladium-catalyzed carbonylative
cyclization of b-bromovinyl aldehydes with carbon monoxide and
alcohols
To a 50 mL stainless steel autoclave were added b-bromovinyl
aldehyde 1 (0.5 mmol), PdCl2(PPh3)2 (0.014 g, 0.02 mmol), Et3N
(0.405 g, 4 mmol) and alcohol (10 mL). After the system was
flushed and then pressurized with carbon monoxide to 20 atm,
the reaction mixture was allowed to react at 125 °C for 1 h. The
reaction mixture was filtered through a short silica gel column
(ethyl acetate–hexane mixture) to eliminate inorganic salts. Re-
moval of the solvent left a crude mixture, which was separated
by thin layer chromatography (silica gel, ethyl acetate–hexane
mixture) to give carbonylative cyclized product 2. All products pre-
pared by the above procedure were characterized spectroscopically
as shown below.
4.1.1. Ethyl 1,3,4,5,6,7-hexahydro-3-oxoisobenzofuran-1-carboxylate
(2a)
Oil; 1H NMR (CDCl3) d 1.32 (t, J = 7.5 Hz, 3H), 1.69–1.81 (m, 4H),
2.24–2.26 (m, 2H), 2.28–2.42 (m, 2H), 4.22–4.34 (m, 2H), 5.25 (s,
1H); 13C NMR (CDCl3) d 14.50, 20.47, 21.63, 21.81, 23.71, 62.68,
80.47, 128.07, 158.79, 166.57, 173.00. Anal. Calc. for C11H14O4: C
62.85; H 6.71. Found: C 62.58; H 6.62%.
Scheme 3.
4.1.2. Butyl 1,3,4,5,6,7-hexahydro-3-oxoisobenzofuran-1-carboxylate
(2b)
Oil; 1H NMR (CDCl3) d 0.94 (t, J = 7.5 Hz, 3H), 1.34–1.43 (m, 2H),
1.62–1.78 (m, 6H), 2.24–2.26 (m, 2H), 2.34–2.37 (m, 2H), 4.22 (t,
J = 6.8 Hz, 2H), 5.25 (s, 1H); 13C NMR (CDCl3) d 13.97, 19.34,
20.47, 21.64, 21.82, 23.70, 30.81, 66.47, 80.52, 128.06, 158.79,
166.66, 173.00. Anal. Calc. for C13H18O4: C 65.53; H 7.61. Found:
C 65.27; H 7.47%.
4.1.3. Isobutyl 1,3,4,5,6,7-hexahydro-3-oxoisobenzofuran-1-
carboxylate (2c)
Oil; 1H NMR (CDCl3) d 0.94 (d, J = 7.0 Hz, 6H), 1.69–1.81 (m, 4H),
1.93–2.03 (m, 1H), 2.25–2.31 (m, 2H), 2.33–2.42 (m, 2H), 3.95–4.04
(m, 2H), 5.26 (s, 1H); 13C NMR (CDCl3) d 19.28, 20.49, 21.66, 21.84,
Scheme 4.

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C.S. Cho et al. / Journal of Organometallic Chemistry 693 (2008) 3677–3680
23.72, 28.02, 72.49, 80.54, 128.13, 158.72, 166.64, 172.95. Anal.
Calc. for C13H18O4: C 65.53; H 7.61. Found: C 65.36; H 7.48%.
172.04 (172.11). Anal. Calc. for C17H18O4: C 71.31; H 6.34. Found:
C 71.14; H 6.25%.
4.1.4. Ethyl 3,4,5,6,7,8-hexahydro-3-oxo-1H-cyclohepta[c]furan-1-
carboxylate (2d)
Acknowledgements
Oil; 1H NMR (CDCl3) d 1.30 (t, J = 7.5 Hz, 3H), 1.61–1.70 (m, 4H),
1.78–1.84 (m, 2H), 2.43–2.50 (m, 4H), 4.23–4.31 (m, 2H), 5.15 (s,
1H); 13C NMR (CDCl3) d 14.51, 25.52, 26.94, 26.96, 28.33, 30.84,
62.70, 80.27, 130.70, 160.21, 166.90, 174.07. Anal. Calc. for
C12H16O4: C 64.27; H 7.19. Found: C 64.22; H 7.14%.
This research was supported by Kyungpook National University
Research Fund (2008).
References
[1] (a) E. Negishi (Ed.), Handbook of Organopalladium Chemistry for Organic
Synthesis, vol. II, Wiley, New York, 2002, pp. 2309–2712;
(b) J. Tsuji, Palladium Reagents and Catalysis, Wiley, Chichester, 1995;
(c) H.M. Colquhoun, D.J. Thompson, M.V. Twigg, Carbonylation: Direct
Synthesis of Carbonyl Compounds, Plenum Press, New York, 1991.
[2] C.S. Cho, D.K. Lim, J.Q. Zhang, T.-J. Kim, S.C. Shim, Tetrahedron Lett. 45 (2004)
5653.
[3] C.S. Cho, D.B. Patel, S.C. Shim, Tetrahedron 61 (2005) 9490.
[4] C.S. Cho, D.B. Patel, J. Mol. Cat. A: Chem. 260 (2006) 105.
[5] C.S. Cho, D.K. Lim, N.H. Heo, T.-J. Kim, S.C. Shim, Chem. Commun. (2004) 104.
[6] C.S. Cho, D.B. Patel, Tetrahedron 62 (2006) 6388.
4.1.5. Ethyl 1,3,4,5,6,7,8,9-octaahydro-3-oxocycloocta[c]furan-1-
carboxylate (2e)
Oil; 1H NMR (CDCl3) d 1.30 (t, J = 7.2 Hz, 3H), 1.56–1.60 (m, 4H),
1.71–1.76 (m, 3H), 1.83–1.89 (m, 1H), 2.29–2.36 (m, 1H), 2.47–2.55
(m, 3H), 4.24–4.39 (m, 2H), 5.03 (s, 1H); 13C NMR (CDCl3) d 14.29,
22.48, 25.06, 25.20, 26.16, 26.25, 26.78, 64.33, 100.49, 131.34,
158.39, 168.57, 171.94. Anal. Calc. for C13H18O4: C 65.53; H 7.61.
Found: C 65.33; H 7.54%.
[7] (a) S.C. Shim, D.Y. Lee, L.H. Jiang, T.J. Kim, S.-D. Cho, J. Heterocyclic Chem. 32
(1995) 363;
4.1.6. Ethyl 1,3,4,5,6,7,8,9,10,11,12,13-dodecahydro-3-
oxocyclododeca[c]furan-1-carboxylate (2f)
(b) C.S. Cho, D.K. Lim, T.-J. Kim, S.C. Shim, J. Chem. Res. (S) (2002) 550.
[8] (a) R.M. Coates, P.D. Senter, W.R. Baker, J. Org. Chem. 47 (1982) 3597;
(b) J.K. Ray, M.K. Haldar, S. Gupta, G.K. Kar, Tetrahedron 56 (2000) 909;
(c) Y. Zhang, J.W. Herndon, Org. Lett. 5 (2003) 2043;
Oil; 1H NMR (CDCl3) d 1.25–1.50 (m, 15H), 1.57–1.64 (m, 2H),
1.69–1.75 (m, 2H), 2.33–2.41 (m, 4H), 4.23–4.36 (m, 2H), 5.04 (s,
1H); 13C NMR (CDCl3) d 13.80, 20.99, 21.79, 22.10, 22.72, 23.99,
24.21, 24.53, 24.59, 24.94, 25.00, 63.93, 99.97, 132.37, 157.27,
168.66, 171.22. Anal. Calc. for C17H26O4: C 69.36; H 8.90. Found:
C 69.18; H 8.81%.
(d) S.K. Mal, D. Ray, J.K. Ray, Tetrahedron Lett. 45 (2004) 277;
(e) D. Ray, S.K. Mal, J.K. Ray, Synlett (2005) 2135;
(f) S. Some, B. Dutta, J.K. Ray, Tetrahedron Lett. 47 (2006) 1221;
(g) D. Ray, J.K. Ray, Tetrahedron Lett. 48 (2007) 673.
[9] (a) For our reports on palladium-catalyzed carbonylative cyclization C.S. Cho,
J.W. Lee, D.Y. Lee, S.C. Shim, T.J. Kim, Chem. Commun. (1996) 2115;
(b) C.S. Cho, D.Y. Chu, D.Y. Lee, S.C. Shim, T.-J. Kim, W.T. Lim, N.H. Heo, Synth.
Commun. 27 (1997) 4141;
4.1.7. Ethyl 1,3,4,5,6,7-hexahydro-6-methyl-3-oxoisobenzofuran-1-
carboxylate (2g)
(c) C.S. Cho, L.H. Jiang, S.C. Shim, Synth. Commun. 28 (1998) 849;
(d) C.S. Cho, L.H. Jiang, D.Y. Lee, S.C. Shim, H.S. Lee, S.-D. Cho, J. Heterocyclic
Chem. 34 (1997) 1371;
(e) C.S. Cho, L.H. Jiang, S.C. Shim, Synth. Commun. 29 (1999) 2695;
(f) C.S. Cho, D.Y. Baek, H.Y. Kim, S.C. Shim, D.H. Oh, Synth. Commun. 30 (2000)
1139.
Oil; diastereoisomeric mixture; 1H NMR (CDCl3) d 1.06 (d,
J = 6.5 Hz, 3/2H), 1.07 (d, J = 6.5 Hz, 3/2H), 1.31 (t, J = 7.0 Hz, 3/
2H), 1.32 (t, J = 7.0 Hz, 3/2H), 1.80–2.00 (m, 4H), 2.16–2.26 (m,
1H), 2.34–2.50 (m, 2H), 4.23–4.32 (m, 2H), 5.22 (s, 1H); 13C NMR
(CDCl3) d 14.53 (x2), 20.14 (20.32), 21.31 (21.35), 28.51 (28.54),
29.91 (29.96), 31.54 (31.87), 62.68 (62.72), 80.25 (80.38), 127.91
(127.98), 158.57 (158.67), 166.57 (x2), 172.74 (x2). Anal. Calc. for
C12H16O4: C 64.27; H 7.19. Found: C 64.21; H 7.05%.
[10] (a) For our recent reports on palladium catalysis C.S. Cho, J. Mol. Cat. A: Chem.
240 (2005) 55;
(b) C.S. Cho, J. Organomet. Chem. 690 (2005) 4094;
(c) C.S. Cho, J.U. Kim, Tetrahedron Lett. 48 (2007) 3775;
(d) C.S. Cho, W.X. Ren, J. Organomet. Chem. 692 (2007) 4182.
[11] C. Copéret, T. Sugihara, G. Wu, I. Shimoyama, E. Negishi, J. Am. Chem. Soc. 117
(1995) 3422.
[12] (a) For intramolecular nucleophilic addition of aryl- and vinylpalladiums to
ketones and aldehydes L.G. Quan, V. Gevorgyan, Y. Yamamoto, J. Am. Chem.
Soc. 121 (1999) 3545;
4.1.8. Ethyl 1,3,4,5,6,7-hexahydro-3-oxo-6-phenylisobenzofuran-1-
carboxylate (2h)
(b) V. Gevorgyan, L.G. Quan, Y. Yamamoto, Tetrahedron Lett. 40 (1999)
4089;
Oil; diastereoisomeric mixture; 1H NMR (CDCl3) d 1.30 (t,
J = 7.0 Hz, 3/2H), 1.31 (t, J = 7.0 Hz, 3/2H), 1.76–1.90 (m, 1H),
2.09–2.13 (m, 1H), 2.30–2.54 (m, 3H), 2.67–2.75 (m, 1H), 2.90–
3.00 (m, 1H), 4.28 (q, J = 7.0 Hz, 2H), 5.28–5.30 (m, 1H), 7.20–
7.27 (m, 3H), 7.32–7.36 (m, 2H); 13C NMR (CDCl3) d 14.16 (x2),
20.58 (x2), 28.85 (29.09), 30.79 (31.29), 39.46 (39.57), 62.41
(62.44), 79.69 (79.91), 126.75 (126.76), 126.85 (x2), 127.75
(127.82), 128.76 (x2), 144.35 (x2), 158.04 (158.12), 166.07 (x2),
(c) L.G. Quan, M. Lamrani, Y. Yamamoto, J. Am. Chem. Soc. 122 (2000) 4827.
[13] We also confirmed in a separate experiment that treatment of 1a in BuOH with
further addition of D2O (0.5 mL) under the employed conditions afforded ca.
1
79% deuterated 3 [13C NMR d 71.89 (t, JC–D = 22.9 Hz)] was formed in 36%
yield along with 2b (36% yield).
[14] C.S. Cho, H.S. Shim, Tetrahedron Lett. 47 (2006) 3835.
[15] A reviewer suggested that observation of oxidation products derived from b-
hydrogen elimination of alcohol should be described. However, GLC analysis
attempt to detect an aldehyde from crude mixture met with failure.