Concise synthesis of α-(hydroxymethyl) alkyl and aryl vinyl ketones

Article abstract of DOI:10.1080/00397911.2011.592626

2,4-Diketoesters 2 have first been reported as starting materials for the synthesis of a new class of α-hydroxymethyl-α,β-unsaturated ketones 3. Thus, under heterogeneous liquid-liquid medium in the presence of concentrated aqueous potassium carbonate as a base, both aliphatic and aromatic 2,4-dioxoalkanoates 2 react with aqueous formaldehyde to afford the corresponding ketones 3 in fair to good yields. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397911.2011.592626

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Concise Synthesis of α-(Hydroxymethyl)
Alkyl and Aryl Vinyl Ketones
Jihène Ben Kraïem a & Hassen Amri a
a Laboratoire de Chimie Organique et Organométallique, Université
de Tunis El Manar, Faculté des Sciences, Campus Universitaire, Tunis,
Tunisia
Accepted author version posted online: 01 Feb 2012. Version of
record first published: 05 Sep 2012
To cite this article: Jihène Ben Kraïem & Hassen Amri (2013): Concise Synthesis of α-(Hydroxymethyl)
Alkyl and Aryl Vinyl Ketones, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 43:1, 110-117
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Synthetic Communications1, 43: 110–117, 2013
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2011.592626
CONCISE SYNTHESIS OF a-(HYDROXYMETHYL) ALKYL
AND ARYL VINYL KETONES
`
Jihene Ben Kra¨ıem and Hassen Amri
Laboratoire de Chimie Organique et Organometallique, Universite de Tunis
´
´
´
El Manar, Faculte des Sciences, Campus Universitaire, Tunis, Tunisia
GRAPHICAL ABSTRACT
Abstract 2,4-Diketoesters 2 have first been reported as starting materials for the synthesis
of a new class of a-hydroxymethyl-a,b-unsaturated ketones 3. Thus, under heterogeneous
liquid–liquid medium in the presence of concentrated aqueous potassium carbonate as a
base, both aliphatic and aromatic 2,4-dioxoalkanoates 2 react with aqueous formaldehyde
to afford the corresponding ketones 3 in fair to good yields.
Keywords 2,4-Diketoesters; a-hydroxymethyl-a,b-unsaturated ketones; Morita–Baylis–
Hillman reaction; Wittig–Horner reaction
INTRODUCTION
a-Hydroxyalkyl-a,b-unsaturated ketones 1 are the most versatile building
blocks in organic synthesis because their structure allows reactions with several
nucleophilic and electrophilic reagents, acids, and bases.[1–5] Therefore, many
approaches for the construction of these functional structures have been pro-
posed,[6–8] but most of these methods have many constraints such as availability
of the starting materials, simplicity, efficiency, and complexity of the reaction con-
ditions. However, the Baylis–Hillman reaction seems to be the most effective. This
method, also known as Morita–Baylis–Hillman reaction (MBHR), yields highly a-
functionalized vinyl ketones 1.[9–15] It can be defined as a coupling reaction between
alkyl (Me, Et) or phenyl vinyl ketones and large varieties of aldehydes in the presence
of a nucleophilic catalyst, usually a tertiary amine such as 1,4-diazabicyclo[2.2.2]oc-
tane or tertiary phosphine (Scheme 1).
Received April 15, 2011.
Address correspondence to Hassen Amri, Laboratoire de Chimie Organique et Organometallique,
´
Universite de Tunis El Manar, Faculte des Sciences, Campus Universitaire 2092, Tunis, Tunisia. E-mail:
´
hassen.amri@fst.rnu.tn
´
110

a-(HYDROXYMETHYL) ALKYL AND ARYL VINYL KETONES
111
Scheme 1. Baylis–Hillman synthesis of vinylic ketones 1.
Although the Baylis–Hillman reaction has had a great appeal because of its
facile method and use of several catalysts,[16–22] over recent years some major incon-
veniences remain, thus limiting its impact: (i) the reaction is very slow under normal
conditions (ii) the use of methyl vinyl ketone as the most frequently starting material
in this synthesis limits the diversity of the family of ketones, and (iii) this coupling
reaction did not give a wide range of a-hydroxymethyl-a,b-unsaturated ketones 3
(R1 ¼ H, R ¼ alkyl, aryl). Today, it seems that rare methods, including Baylis–
Hillman reaction,[23] succeeded in the synthesis of this class of compounds. These
limitations, which are a real challenge for organic chemists, prompted us to develop
a concise synthesis of these a-hydroxymethyl-a,b-unsaturated ketones 3 using a
low-cost and simple methodology.
RESULTS AND DISCUSSION
The starting materials of our synthetic sequence depicted in Scheme 2 were
available 2,4-dioxoalkanoates 2, easily obtained in a known oxaloylation of methyl
ketones in a coupling process with diethyl oxalate in a basic medium of NaH,
NaOEt, or NaOMe (Scheme 2).[24,25]
It would be very interesting to compare the CH-acidities of 2,4-dioxoalkano-
ates 2 and b-ketophosphonate, which react, in the presence of aqueous formaldehyde
in heterogenous conditions, and undergo the Wittig–Horner reaction, leading to the
bis-hydroxymethylated intermediate. Elimination affords the expected a-hydroxy-
methyl-a,b-unsaturated ketones 3[26–29] (Scheme 3).
Indeed, we found that the reaction of diketoesters 2 with a large excess
(4 equiv.) of aqueous formaldehyde occurs under heterogeneous liquid–liquid
conditions using highly concentrated (6–10 mol) aqueous solution of potassium car-
bonate in the absence of organic solvents. The reaction provides a family of enones
3a–i by the well-established tandem hydroxymethylation–cyclization–elimination
(Scheme 4).
Scheme 2. Direct synthesis of 2,4-diketoesters 2.

¨
J. B. KRAIEM AND H. AMRI
112
Scheme 3. Synthesis of a-hydroxymethylated enones from b-ketophosphonates.
The viability of this protocol has been anticipated as suitable nucleophiles
differentiate between the two kinds of carbonyl group in 2. Accordingly, the more
electrophilic C-2 carbonyl was found to be chemoselectively more reactive than
C-4 one, providing pure ketones 3a–i[30] in good yields and in a very short reaction
time (Table 1).
As reported in Table 1, reaction coupling of all diketoesters 2 with aqueous for-
maldehyde under the simple experimental procedure described does not seem to be
affected by the aliphatic or aromatic group of the starting materials 2 except
=
2,4-diketoester 2d (R Ph-CH2), showing a particular ability to undergo a second
hydroxymethylation reaction at the C-5 carbon atom followed by dehydration, lead-
ing to the highly conjugated ketone 3d, which can be used as a powerful synthon for
the synthesis of several cyclopentenones[31,32](Scheme 5).
To optimize our method, various bases including NaH, RONa, NaOH, and
KOH have been used in various solvents, but the reaction was not reproducible
and only moderate yields of 3 were obtained. One should note that the synthesis
of a-hydroxymethyl methyl vinyl ketone (HMVK) 3a has been reported[33] through
high-temperature pyrolysis of 1,1,1-tris-hydroxymethyl acetone and hydroxymethy-
lation of methyl vinyl ketone[34] with formaldehyde and Ph3P as catalyst. Both synth-
eses involve difficulties and poor yields (<30%). Hence, our original method, which
offers the possibility to access to the uncommon 2-hydroxymethyl-but-1-ene-3-one
3a with a practical yield (86%), is significant.
Scheme 4. First simple synthesis of a-(hydroxymethyl) alkyl and aryl vinylketones 3.

a-(HYDROXYMETHYL) ALKYL AND ARYL VINYL KETONES
Table 1. a-(Hydroxymethyl) vinylketone 3 from 2,4-diketoester 2
113
2,4-Diketoester 2
Yield (%)a a-Hydroxymethyl vinyl ketone 3 Time (h) Yield (%)a
85
1
86
78
76
1.5
2
82
81
74
95
90
2
3
73
52
56
2.5
88
87
3
3
58
52
85
2
51
aYields refer to the pure isolated products characterized by 1H, 13C NMR, IR, and HRMS.
CONCLUSION
In conclusion, we have developed a simple, efficient, and original method for
the synthesis of a wide range of a-hydroxymethyl alkyl and aryl vinyl ketones 3,
under very friendly conditions (room temperature and ambient atmosphere). We
propose a simple experimental procedure, in good yields, with a short reaction time
and easy workup.

¨
J. B. KRAIEM AND H. AMRI
114
Scheme 5. Uncommon bis-hydroxymethylation–elimination of 2,4-diketoester 2d.
EXPERIMENTAL
All reactions were monitored by thin-layer chromatography (TLC) on silica-gel
plates (Fluka Kieselgel 60 F ). For column chromatography, Fluka Kieselgel
254
1
(70–230 mesh) was used. H and 13C NMR spectra (fully decoupled) were recorded
on a Bruker AMX 300 in CDCl3 as solvent and tetramethylsilane (TMS) as the inter-
nal standard. Infrared (IR) spectra were recorded with a Perkin-Elmer Paragon 1000
Fourier transform (Ft)–IR spectrophotometer. Mass spectrometry was performed
on an Autospec 200, Micromass (Waters) instrument.
Preparation of Ethyl 2,4-Dioxoalkanoates 2
A mixture of diethyl oxalate (83 mmol) and aryl or alkyl ketone (83 mmol) was
added dropwise to a stirred solution of NaOEt (2.3 g of sodium in 40 mL of absolute
ethanol) at 0 ꢀC. The resulting salt was stirred at room temperature for 24 h. The
reaction was quenched with aqueous H2SO4 and extracted with ethyl acetate. The
combined organic layers were washed with saturated NaHCO3, dried over MgSO4,
and concentrated under vacum. Purification on silica gel (AcOEt=hexane, 2:8) pro-
vided the desired product 2.
2,4-Dioxo-4-phenylethyl butanoate 2e. Yield (17.35 g, 95%) as a yellow
1
solid, mp 101–102 ꢀC; nmax (liquid film) 2985, 1737, 1596, 1283 cmꢁ1. H NMR
(300 MHz, CDCl3): 7.62 (2H, d, J ¼ 7.50 Hz), 7.53 (1H, t, J ¼ 7.4 Hz), 7.47 (2H, t,
J ¼ 7.5 Hz), 7.00 (1H, s), 4.40 (2H, q, J ¼ 7.0 Hz), 1.41 (3H, t, J ¼ 7.0 Hz); 13C
NMR (75 MHz, CDCl3): 197.9, 169.7, 162.0, 134.7, 133.6, 128.7, 127.7, 97.8, 62.0,
14.0. HRMS (ES) m=z calcd. for C12H12O4 220.0736; found 220.0738.
Synthesis of a-Hydroxymethyl Alkyl and Aryl Vinyl Ketones 3
A gelatinous solution of potassium carbonate (6–10 M, 10 mmol) was added at
room temperature to a magnetically stirred mixture of 2,4-diketoester 2 (5 mmol)
and 30% aqueous formaldehyde (20 mmol). The heterogeneous reaction mixture
was stirred at room temperature for the time indicated in Table 1, and then treated

a-(HYDROXYMETHYL) ALKYL AND ARYL VINYL KETONES
115
with water. The solution was then extracted three times with 25 mL of ether. The
combined organic layers were dried over anhydrous MgSO4, filtered, and evaporated
under reduced pressure. The crude product was purified by column chromatography
on silica gel (EtOAc=hexane, 3:7) to afford ketones 3.
3-(Hydroxymethyl)but-3-en-2-one 3a. Yield (0.43 g, 86%) as a yellow oil;
1
nmax (liquid film) 3320, 1640, 1520 cmꢁ1; H NMR (300 MHz, CDCl3): 6.13 (1H,
s), 6.06 (1H, s), 4.32 (2H, s), 2.53 (1H, OH), 2.37 (3H, s); 13C NMR (75 MHz,
CDCl3): 200.3, 147.3, 126.0, 63.2, 25.9. HRMS (ES) m=z calcd. for C5H8O2
100.0524; found 100.0528.
2-(Hydroxymethyl)pent-1-en-3-one 3b. Yield (0.46 g, 82%) as orange-
1
yellow oil; nmax (liquid film) 3330, 1650, 1480 cmꢁ1; H NMR (300 MHz, CDCl3):
6.12 (1H, s), 6.01 (1H, s), 4.31 (2H, s), 3.09 (1H, OH), 2.75 (2H, q, J ¼ 7.5 Hz),
1.10 (3H, t, J ¼ 7.5 Hz); 13C NMR (75 MHz, CDCl3): 201.9, 146.7, 124.6, 62.2,
31.0, 8.07. HRMS (ES) m=z calcd. for C6H10O2 114.0681; found 114.0680.
2-(Hydroxymethyl)-5-phenylpent-1-en-3-one 3c. Yield (0.76 g, 81%) as
1
yellow oil; nmax (liquid film) 3325, 1660, 1470 cmꢁ1; H NMR (300 MHz, CDCl3):
7.29–7.17 (5H, m), 6.09 (1H, s), 6.0 (1H, s), 4.32 (2H, s), 3.04 (2H, t, J ¼ 7.5 Hz),
2.92 (2H, t, J ¼ 7.5 Hz), 2.24 (1H, OH); 13C NMR (75 MHz, CDCl3): 201.4, 146.8,
140.9, 126.6, 128.3, 126.2, 125.1, 62.5, 39.6, 22.6; HRMS (ES) m=z calcd. for
C12H14O2 190.0994; found 190.0993.
2-(Hydroxymethyl)-4-phenylpentA-1,4-dien-3-one 3d. Yield (0.68 g, 73%)
as yellow oil; nmax (liquid film) 3320, 1690, 1500 cmꢁ1; 1H NMR (300 MHz, CDCl3):
7.32–7.20 (5H, m), 6.22 (1H, s), 6.10 (1H, s), 5.97 (1H, s), 5.77 (1H, s), 4.52 (2H, s),
1.93 (1H, OH); 13C NMR (75 MHz, CDCl3): 199.3, 147.6, 146.7, 132.3, 128.6, 128.5,
126.9, 125.8, 62.5. HRMS (ES) m=z calcd. for C12H12O2 188.0837; found 188.0840.
2-(Hydroxymethyl)-1-phenylprop-2-en-1-one 3e. Yield (0.42 g, 52%) as
1
yellow oil; nmax (liquid film) 3300, 1650, 1445 cmꢁ1; H NMR (300 MHz, CDCl3):
7.74 (2H, d, J ¼ 7.5 Hz), 7.54 (1H, t, J ¼ 7.4 Hz), 7.45 (2H, t, J ¼ 7.5 Hz), 6.15 (1H,
s), 5.81 (1H, s), 4.50 (2H, s), 2.77 (1H, m); 13C NMR (75 MHz, CDCl3): 197.9,
146.23, 137.2, 132.4, 129.3, 128.2, 127.3, 63.0; mass (70 eV) m=z (rel. intensity): 51
(35), 77 (89), 105 (100), 116 (13), 144 (9), 161 (96). HRMS (ES) m=z calcd. for
C10H10O2 162.0681; found 162.0683.
2-(Hydroxymethyl)-1-p-tolylprop-2-en-1-one 3f. Yield (0.49 g, 56%) as yel-
low oil; nmax (liquid film) 3300, 1630, 1455 cmꢁ1; 1H NMR (300 MHz, CDCl3): 7.67
(2H, d, 2J ¼ 8.1 Hz), 7.25 (2H, d, 2J ¼ 8.1 Hz), 6.10 (1H, s), 5.77 (1H, s), 4.48 (2H, s),
2.77 (1H, OH), 2.41 (3H, s); 13C NMR (75 MHz, CDCl3): 197.7, 146.3, 143.4, 134.6,
129.6, 129.03, 126.5, 62.3, 21.6. HRMS (ES) m=z calcd. for C11H12O2 176.0837;
found 176.0839.
2-(Hydroxymethyl)-1-(4-methoxyphenyl)prop-2-en-1-one 3g. Yield
(0.55 g, 58%) as yellow oil; nmax (liquid film) 3310, 1645, 1475 cmꢁ1 1H NMR
;
2
2
(300 MHz, CDCl3): 7.82 (2H, d, J ¼ 8.1 Hz), 6.95 (2H, d, J ¼ 8.1 Hz), 6.06 (1H,
s), 5.74 (1H, s), 4.48 (2H, s), 3.88 (3H, s), 2.41 (1H, OH); 13C NMR (75 MHz,

¨
J. B. KRAIEM AND H. AMRI
116
CDCl3): 196.7, 163.4, 146.4, 131.9, 129.8, 125.3, 113.6, 63.5, 55.5. HRMS (ES) m=z
calcd. for C11H12O3 192.0786; found 192.0786.
1-(4-Fluorophenyl)-2-(hydroxymethyl)prop-2-en-1-one 3h. Yield (0.46 g,
1
52%) as yellow oil; nmax (liquid film) 3315, 1645, 1460 cmꢁ1; H NMR (300 MHz,
3
4
3
CDCl3): 7.72 (2H, dd, JH-H ¼ 7.2 Hz, JH-F ¼ 3.7 Hz), 7.23 (2H, t, JH-H ¼ 3JH-F
-
¼ 7.2 Hz), 6.14 (1H, s), 5.77 (1H, s), 4.5 (2H, s), 2.80 (1H, OH); 13C NMR
(75 MHz, CDCl3): 196.3, 167.2 (1JC-F ¼ 252.75 Hz), 146.4, 133.5 (4JC-F ¼ 3 Hz),
132.1 (3JC-F ¼ 9 Hz), 126.5, 115.6 (2JC-F ¼ 21.75 Hz), 62.7. HRMS (ES) m=z calcd.
for C10H9FO2 180.0587; found 180.0581.
2-(Hydroxymethyl)-1-(4-nitrophenyl)prop-2-en-1-one 3i. Yield (0.52 g,
1
51%) as yellow oil; nmax (liquid film) 3325, 1650, 1450 cmꢁ1; H NMR (300 MHz,
2
2
CDCl3): 8.32 (2H, d, J ¼ 8.1 Hz), 7.83 (2H, d, J ¼ 8.1 Hz), 6.34 (1H, s), 5.89 (1H,
s), 4.65 (2H, s), 1.9 (1H, OH); 13C NMR (75 MHz, CDCl3): 195.8, 149.9, 146.2,
142.6, 130.1, 123.6, 63.8. HRMS (ES) m=z calcd. for C10H9NO4 207.0532; found
207.0530.
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