Synthesis of symmetrical ketones from Grignard reagents and 1,1′-carbonyldiimidazole

Article abstract of DOI:10.1055/s-0029-1216815

Coupling reactions of 1,1′-carbonyldiimidazole with Grignard reagents provide a rapid and straightforward method for the synthesis of symmetrical ketones. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0029-1216815

2316
SHORT PAPER
Synthesis of Symmetrical Ketones from Grignard Reagents and
1,1¢-Carbonyldiimidazole
S
ynthesis of Symm
a
etrical
K
et
n
ones iela Bottalico, Vito Fiandanese, Giuseppe Marchese,* Angela Punzi
Dipartimento di Chimica, Università di Bari, Via Orabona 4, 70126 Bari, Italy
Fax +39(80)5442075; E-mail: marchese@chimica.uniba.it
Received 19 February 2009; revised 13 March 2009
N
N
Abstract: Coupling reactions of 1,1¢-carbonyldiimidazole with
Grignard reagents provide a rapid and straightforward method for
RMgX
R
R
N
N
the synthesis of symmetrical ketones.
O
O
Key words: Grignard reactions, coupling, acylations, 1,1¢-carbon-
yldiimidazole, ketones
1
2
Scheme 1
Ketones are highly useful intermediates in organic synthe- tone 2b (80%) were obtained when 2.3 equivalents of the
sis for carbon–carbon bond formation and functional Grignard reagent were added to 1 equivalent of 1 at –80 °C,
group interconversion. Therefore extensive efforts have and the reaction mixture was subsequently warmed to
been made towards the efficient synthesis of this impor- room temperature and kept at the same temperature for
tant functionality.1 One of the most straightforward meth- one hour (Table 1, entry 2).
ods for the synthesis of ketones is the coupling reaction of
carboxylic acids or their derivatives with organometallic
reagents. However, in spite of the inherent simplicity, its
synthetic usefulness is severely limited, mainly due to the
The scope of the reaction of 1,1¢-carbonyldiimidazole (1)
with regard to a variation of the Grignard reagent was then
investigated (Table 1). The reaction of 1 with phenyl- (en-
try 1), functionalized aryl- (entries 2–4), as well as hetaryl
simultaneous formation of undesired tertiary and/or sec-
Grignard reagents (entry 5) were successful and gave the
ondary alcohols.2 Thus, a number of techniques have been
desired ketones 2a–e in good yields when the abovemen-
tioned protocol was followed. The coupling reactions of
sterically hindered Grignard reagents also gave ketones 2f
and 2g in good yields (entries 6 and 7), but did not take
developed to suppress the formation of tertiary alco-
hol,1,3,4 and, in this regard, extensive efforts have been
made in our laboratory over recent years.5
In connection with this type of synthetic work and with place at low temperature, implying a lower reactivity of
the aim to explore other valuable carbonyl transfer re- these reagents. To obtain ketones 2f and 2g in comparable
agents, we considered it to be of interest to further inves- yields, 2.7 equivalents of the Grignard reagent were added
tigate the reactivity of acylazoles with organometallic at room temperature, and the reaction mixtures were
reagents. Indeed, as recently documented by Staab, Bauer, stirred for three hours at the same temperature. Although
and Schneider,6a acylazolides in general, and N-acylimi- our protocol required the use of a slight excess of the or-
dazoles in particular, are efficient acylating reagents.6 ganomagnesium reagent (2.3–2.7 equiv), tertiary alcohols
They have undergone reactions with various nucleophiles, 3 were either not obtained as the side products (entries 2,
including organometallic reagents, to give a wide range of 3, 6, and 7) or were limited at 2–7% (entries 1, 4, and 5),
carbonyl and carboxyl derivatives under mild conditions. an amount which, however, can easily be removed by col-
However, to the best of our knowledge, the synthesis of umn chromatography.
ketones directly from the reaction of 1,1¢-carbonyldiimi-
We also investigated the use of alkyl Grignard reagents in
the coupling reactions with 1 (Table 1, entries 8–12).
These reagents also reacted smoothly to afford the corre-
sponding ketones 2h–l in satisfactory yields. Neverthe-
dazole with alkyl and aryl Grignard reagents has not been
reported in the literature. This observation encouraged us
to consider the possibility to develop a simple and general
method for the synthesis of a variety of ketones starting
less, for the primary alkyl reagents a greater amount of
directly from Grignard reagents and 1,1¢-carbonyldiimi-
tertiary alcohol 3 formation (5–18%) took place. The ke-
dazole (CDI), as a milder and more easily handled substi-
tone 2/tertiary alcohol 3 product ratio was generally sen-
sitive to the temperature and the amount of excess
tute of the more toxic phosgene (Scheme 1).
The reaction of Grignard reagents with 1,1¢-carbonyldi- Grignard reagent used, and may be increased by using a
imidazole (1) was optimized for the coupling reaction of lower excess or two equivalents of Grignard reagent. Our
1 with 4-tolylmagnesium bromide. Superior yields of ke- study, however, for the present, was a comparison of the
relative performance of several Grignard reagents under
fixed conditions.
SYNTHESIS 2009, No. 14, pp 2316–2318
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Advanced online publication: 14.05.2009
DOI: 10.1055/s-0029-1216815; Art ID: T04309SS
© Georg Thieme Verlag Stuttgart · New York

SHORT PAPER
Synthesis of Symmetrical Ketones
2317
Table 1 Synthesis of Symmetrical Ketones 2a
performed on a Varian 3900 gas chromatograph equipped with a
Supelco capillary column (SLB-5ms, 30 m × 0.25 mm i.d.). GC-MS
analysis was performed on a Shimadzu GC-MS-QP5000 gas chro-
matograph–mass spectrometer equipped with a Supelco capillary
column (SLB-5ms, 30 m × 0.25 mm i.d.). 1H NMR (400 MHz) and
13C NMR (100.6 MHz) spectra of samples in CDCl3 were recorded
on a Varian Inova spectrometer.
N
N
R
R
R
R
R
RMgBr
THF
N
N
+
O
OH
O
1
2
3
Entry
R
Temp
Ratio
2/3b
2
Yieldc
(%)
Ketones 2a–l; General Procedure
A freshly prepared THF soln of RMgBr (2.85 mmol) was added
dropwise, under N2, to a stirred soln of CDI (1; 1.24 mmol) in anhyd
THF (6 mL) at –80 °C. The resulting mixture was stirred at the same
temperature for 30 min, then warmed to r.t. After 1 h, the reaction
mixture was quenched with aq NH4Cl and extracted with EtOAc.
The organic extracts were washed with H2O, dried (Na2SO4), and
concentrated under vacuum. The residue was purified by column
chromatography (silica gel, PE–EtOAc, 95:5); this gave ketones
2a–l. All products except 2k are known and commercially avail-
able, and were characterized spectroscopically. Spectroscopic data
for the known compounds 2a7, 2b8, 2c7, 2f7, and 2g9 can be found in
the literature.
1
2
Ph
–80 °C to r.t.
–80 °C to r.t.
–80 °C to r.t.
–80 °C to r.t.
–80 °C to r.t.
r.t.
98:2
2a
2b
2c
2d
2e
2f
65
80
72
65
71
73
67
55
73
72
72
75
4-tolyl
100:0
100:0
93:7
3
4-MeOC6H4
4-FC6H4
2-thienyl
2-tolyld
4
5
97:3
6
100:0
100:0
85:15
82:18
95:5
7
1-naphthyld
hexyl
r.t.
2g
2h
2i
Bis(4-fluorophenyl)methanone (2d)10
8
–80 °C to r.t.
–80 °C to r.t.
–80 °C to r.t.
–80 °C to r.t.
–80 °C to r.t.
1H NMR (400 MHz, CDCl3): d = 7.82–7.75 (m, 4 H), 7.17–7.09 (m,
9
octyl
4 H).
13C NMR (100 MHz, CDCl3): d = 193.7, 165.3 (d, J = 254.4 Hz),
133.6 (d, J = 3.0 Hz), 132.4 (d, J = 9.2 Hz), 115.5 (d, J = 21.9 Hz).
10
11
12
decyl
2j
dodecyl
cyclohexyl
89:11
100:0
2k
2l
Bis(2-thienyl)methanone (2e)10
1H NMR (400 MHz, CDCl3): d = 7.88 (dd, J = 3.8, 1.0 Hz, 2 H),
7.67 (dd, J = 5.0, 1.0 Hz, 2 H), 7.16 (dd, J = 5.0, 3.8 Hz, 2 H).
a Reagents and conditions: RMgBr (2.3 equiv), –80 °C, 30 min, then
r.t., 1 h.
13C NMR (100 MHz, CDCl3): d = 178.7, 142.8, 133.5, 133.1, 127.9.
b The 2/3 ratio of the product mixture was determined by GC analysis.
c Yields of products purified by column chromatography.
d Reagents and conditions: RMgBr (2.7 equiv), r.t., 3 h.
Tridecan-7-one (2h)10
1H NMR (400 MHz, CDCl3): d = 2.33 (t, J = 7.4 Hz, 4 H), 1.55–1.45
(m, 4 H), 1.29–1.15 (m, 12 H), 0.82 (t, J = 6.8 Hz, 6 H).
13C NMR (100 MHz, CDCl3): d = 211.5, 42.7, 31.6, 28.9, 23.8, 22.4,
We have also investigated the possibility of obtaining un-
symmetrical substituted ketones. Two different Grignard
reagents were added sequentially to 1,1¢-carbonyldiimida-
zole (1). However, the addition of one equivalent of phe-
nylmagnesium bromide at –80 °C followed, after 30
minutes, by the addition of one equivalent of 4-tolylmag-
13.9.
Heptadecan-9-one (2i)11
1H NMR (400 MHz, CDCl3): d = 2.33 (t, J = 7.4 Hz, 4 H), 1.56–1.46
(m, 4 H), 1.22 (br s, 20 H), 0.83 (t, J = 6.8 Hz, 6 H).
13C NMR (100 MHz, CDCl3): d = 211.6, 42.7, 31.8, 29.3, 29.2, 29.1,
nesium bromide yielded a mixture of symmetrical and un- 23.8, 22.6, 14.0.
symmetrical substituted ketones in comparable amounts
Henicosan-11-one (2j)11
(GC analysis). In an effort to expand the scope of this pro-
cess further, studies on the extension of this strategy to the
synthesis of unsymmetrical substituted ketones are cur-
rently under investigation.
1H NMR (400 MHz, CDCl3): d = 2.34 (t, J = 7.4 Hz, 4 H), 1.57–1.47
(m, 4 H), 1.22 (br s, 28 H), 0.84 (t, J = 6.8 Hz, 6 H).
13C NMR (100 MHz, CDCl3): d = 211.7, 42.8, 31.9, 29.6, 29.5, 29.4,
29.3, 29.2, 23.9, 22.7, 14.1.
In conclusion, we have described a new protocol for the
direct acylation of Grignard reagents, without additional Pentacosan-13-one (2k)12
1H NMR (400 MHz, CDCl3): d = 2.36 (t, J = 7.6 Hz, 4 H), 1.52–1.49
transition-metal catalysts or organic ligands. Aliphatic,
aromatic, and heteroaromatic ketones have been synthe-
sized in satisfactory yields by use of a stable and easily ac-
cessible acylating agent. We believe that this protocol
provides a practical alternative to the existing methods
available for the synthesis of ketones by reaction of their
corresponding carboxylic acid derivatives with organo-
metallic reagents.
(m, 4 H), 1.23 (br s, 36 H), 0.86 (t, J = 6.8 Hz, 6 H).
13C NMR (100 MHz, CDCl3): d = 211.8, 42.8, 31.9, 29.7, 29.6, 29.6,
29.5, 29.4, 29.3, 29.3, 23.9, 22.7, 14.1.
MS (EI, 70 eV): m/z (%) = 252 (2), 213 (8), 197 (31), 169 (2), 152
(5), 127 (3), 123 (3), 109 (6), 96 (11), 95 (10), 85 (14), 83 (10), 71
(42), 69 (14), 59 (19), 58 (44), 57 (66), 55 (43), 43 (100), 41 (56).
Dicyclohexylmethanone (2l)10
1H NMR (400 MHz, CDCl3): d = 2.48–2.37 (m, 2 H), 1.80–1.66 (m,
8 H), 1.65–1.56 (m, 2 H), 1.35–1.06 (m, 10 H).
Macherey-Nagel silica gel 60 (particle size 0.040–0.063 mm) was
used for column chromatography and Macherey-Nagel aluminum
sheets with silica gel 60 F254 were used for TLC. GC analysis was
13C NMR (100 MHz, CDCl3): d = 217.0, 49.1, 28.5, 25.8, 25.7.
Synthesis 2009, No. 14, 2316–2318 © Thieme Stuttgart · New York

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D. Bottalico et al.
SHORT PAPER
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Acknowledgment
This work was financially supported by the University of Bari.
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