1,2-Addition of α,α,α-trichlorotoluene to ketones via a Mg Barbier reaction in DMF: New route to cycloalk-1-en-1-yl and alk-1-en-1-yl phenyl ketones

Article abstract of DOI:10.1080/00397910701198971

The reductive cyclocondensation of α,α,α-trichlorotoluene to enolisable ketones enables the preparation of (cyclo)alken-1-en-1-yl phenyl ketones via the formation of an intermediate chlorooxirane. Copyright Taylor & Francis Group, LLC.

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1,2‐Addition of α,α,α‐Trichlorotoluene
to Ketones via a Mg Barbier Reaction in
DMF: New Route to Cycloalk‐1‐en‐1‐yl and
Alk‐1‐en‐1‐yl Phenyl Ketones
Akima Aaziz a , Sylvain Oudeyer a , Eric Léonel a , Jean Paul Paugam a
&
Jean‐Yves Nédélec a
a Laboratory of Electrolysis , Catalysis and Organic Synthesis , Thiais, France
Published online: 13 Oct 2010.
To cite this article: Akima Aaziz , Sylvain Oudeyer , Eric Léonel , Jean Paul Paugam & Jean‐Yves Nédélec
(2007) 1,2‐Addition of α,α,α‐Trichlorotoluene to Ketones via a Mg Barbier Reaction in DMF: New Route to
Cycloalk‐1‐en‐1‐yl and Alk‐1‐en‐1‐yl Phenyl Ketones, Synthetic Communications: An International Journal for
Rapid Communication of Synthetic Organic Chemistry, 37:7, 1147-1154, DOI: 10.1080/00397910701198971
To link to this article: http://dx.doi.org/10.1080/00397910701198971
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Synthetic Communicationsw, 37: 1147–1154, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701198971
1,2-Addition of a,a,a-Trichlorotoluene to
Ketones via a Mg Barbier Reaction in DMF:
New Route to Cycloalk-1-en-1-yl and Alk-1-
en-1-yl Phenyl Ketones
´
Akima Aaziz, Sylvain Oudeyer, Eric Leonel,
´ ´
Jean Paul Paugam, and Jean-Yves Nedelec
Laboratory of Electrolysis, Catalysis and Organic Synthesis,
Thiais, France
Abstract: The reductive cyclocondensation of a,a,a-trichlorotoluene to enolisable
ketones enables the preparation of (cyclo)alken-1-en-1-yl phenyl ketones via the
formation of an intermediate chlorooxirane.
Keywords: 1-benzoyl (cyclo)alkenes, chlorooxiranes, enones, Mg Barbier reaction,
PhCCl3 activation
The synthesis of cycloalk-1-en-1-yl phenyl ketones by benzoylation of
cycloalkenes and subsequent dehydrohalogenation (i.e., Friedel–Crafts
[1]
acylation of olefins), first reported by Wieland and Bettag
in 1922, has
been frequently investigated thereafter to improve the yields in a,b-
unsaturated ketones, which are no more than 65%.[2–15] More recently,
1-benzoylcyclopentene was prepared as the major regioisomer by a
palladium-catalyzed cross-carbonylation of phenyl iodide with cyclopentene.[16]
1-Halocycloalkenes are alternatively used as substrate. They are converted
into 1-lithiocycloalkenes to react either with benzaldehyde, leading to
cycloalk-1-en-1-yl benzyl alcohols, which are further oxidized,[17–21] or with
benzonitrile followed by heating in the presence of hydrochloric acid.[6,22]
Received in the U.K. May 8, 2006
Address correspondence to Jean Paul Paugam, Laboratory of Electrolysis, Catalysis
and Organic Synthesis, UMR 7582, CNRS – University Paris 12, 2, rue Henri Dunant,
B.P. 28, F-94320 Thiais, France. E-mail: paugam@glvt-cnrs.fr
1147

1148
A. Aaziz et al.
Yields in 1-benzoylcycloalkenes are, respectively, ca. 50 and 70%. 1-Iodocy-
cloalkenes have also been involved in a palladium-catalyzed cross-coupling
with tributylphenylstannane in the presence of carbon monoxide.[23]
Other routes, which are more specific and/or rarely used, have been
described in the literature.[24–38] Thus, cyclanones are involved as reagents
for the preparation of cycloalk-1-en-1-yl phenyl ketones via a-chlorooxiranes
resulting from the nucleophilic addition of dichlorophenylmethylide derived
from the deprotonation of a,a-dichlorotoluene by lithium diisopropylamide
(LDA)[39] or from the electrochemical reduction of a,a,a-trichlorotoluene
at a mercury pool cathode.[40,41]
This communication reports a new, efficient, easy method for the conver-
sion of cyclanones to cycloalk-1-en-1-yl phenyl ketones, based on the works
[40,41]
by Larson[39] and Schafer
and involving the magnesium reduction of
¨
a,a,a-trichlorotoluene in N,N-dimethylformamide (DMF).
We have already described[42,43] the preparation of methyl 2-chloro-
2-phenylcyclopropanecarboxylate from methyl acrylate and PhCCl3 by
using the same Mg Barbier reaction in DMF (Scheme 1).
These reaction conditions first applied to the coupling between cyclohex-
anone and PhCCl3 led to the products shown in Scheme 2.
Compounds 2 and 3 are very likely derived from the first formed a-chlor-
ooxirane, in keeping with the mechanism proposed in Larson’s study,[39]
whereas compounds 4 and 5 result respectively from the reductive dimeriza-
tion of 2 and from the reduction of 3. This further reduction actually occurs
after the complete consumption of PhCCl3, due to the remaining Mg used in
excess. To prevent the formation of 4 and 5, we found it convenient to filter
the reaction mixture at the near consumption of PhCCl3. Also, the selectivity
in 2 vs. 3 could be improved by heating this filtered reaction mixture at 608C
for ca. 1 h. This allowed us to obtain 2 in 63% yield. In a final optimization
step, we found that the excess of Mg had to be preferably even larger (i.e.,
50 mmol) providing the reaction was conducted at 2208C, and the crude
mixture was filtered then heated after completion, as indicated previously.
Under these reaction conditions (see Experimental), 2 was isolated in 75%
yield (Scheme 3), along with less than 5% of 3 and no traces of 4 and 5.
These reaction conditions have then been applied to the condensation
of a,a,a-trichlorotoluene with various cyclanones and without further
Scheme 1.

Mg Barbier Reaction in DMF
1149
Scheme 2.
optimization. Results are reported in Table 1. In all cases, 1-benzoylcyclo-
alkene is the major product with isolated yields in the range of 40–75%.
The corresponding 1-benzoyl-1-chlorocycloalkane (5–15%) can be usually
dehydrohalogenated by simple heating.
Applied to dialkyl or alkyl phenyl ketones, the reductive condensation of
a,a,a-trichlorotoluene in this reaction leads to a,b-unsaturated ketones sub-
stituted at the a- and eventually at the b-position. As described for cyclanones,
the formation of these enones can be explained from 2-chlorooxiranes as inter-
mediates (Scheme 4).
Yields are in the range of 36–56% as indicated in Table 2. The low yield
in entry 3 (Table 2) is due to the lack of heating after the reaction is completed
in order to prevent the formation of by-products of high molecular weight,
which could come from self-condensation of 12 (m/z ¼ 446). It is worth
noting that a Friedel–Crafts acylation used to prepare compounds 10, 11, or
12 would need the involvement of an unsymmetrical olefin, and then the
question of regioselectivity would arise. Actually, Friedel–Crafts acylation
is only used with symmetrical olefins.[44] On the contrary, access to a,b-
unsaturated ketones having different substituents at the a- and b- positions
involves multistep processes.[45–48]
The reactions described here are based on Mg Barbier reaction, which is
only efficient in DMF. Such solvent specificity is not fully elucidated, nor the
very nature, anion or carbene, of the reactive intermediate derived from a,a,a-
trichlorotoluene. From a synthetic point of view, the approach is efficient to
prepare 1-benzoyl (cyclo)alkenes from cyclic or acyclic ketones. A possible
extension of this study could involve aryl aldehydes, which could open
access to unsymmetrical desyl chlorides.
Scheme 3.

1150
A. Aaziz et al.
Table 1. Cycloalk-1-en-1-yl phenyl ketone formation from cyclanones and a,a,a-
trichlorotoluene by Mg Barbier reaction in DMF
Isolated
yield
(%)
Entry
1
Cyclanone
Benzoylcycloalkene Compound
References
2
75
[1, 2, 4, 5,
7, 10, 12,
13, 18, 19,
23, 25–29,
37–39]
2
3
6
7
60
57
[20, 21, 30,
32, 41]
[3, 8, 11,
12, 14, 16,
24, 33–37,
40, 41]
4
5
8
9
40
43
[6, 14, 17,
19, 22]
[9, 15, 19]
EXPERIMENTAL
Typical Experimental Procedure
Magnesium grits (50–100 mesh) (50 mmol) are suspended in DMF (40 mL)
in a three-neck flask fitted with a thermometer and a dropping funnel and
cooled at 2208C under an argon atmosphere. Half of the solution containing
cyclanone or aliphatic ketone (10 mmol), a,a,a-trichlorotoluene (12 mmol),
and DMF (5 mL) is rapidly introduced in the flask. The beginning of the
reaction is clearly indicated by the temperature rising up to 08C and the
Scheme 4.

Mg Barbier Reaction in DMF
1151
Table 2. a,b-Unsaturated ketone formation by Mg Barbier reaction in the presence of
aliphatic ketones and a,a,a-trichlorotoluene
Isolated
a,b-Unsaturated
ketone
yield
(%)
Entry
1
Aliphatic ketone
Compound
References
[41, 44]
10
56 (E/Z:
77/23)a
2
3
11
12
53
[41, 45, 46]
[47]
36 (E/Z:
20/80)a
aDetermined by GC and 1H NMR: references [44] (entry 1), [47] (entry 3).
mixture turning yellow. The remaining reactants were then added within 5 min,
and the reaction is allowed to proceed until almost the complete consumption of
the a,a,a-trichlorotoluene (about 3–4% GC). Then the reaction mixture is
filtered on a Buchner funnel and heated at 608C for about 1 h. The crude
product is poured into a cold mixture of aq. HCl (6 M, 50 mL) and Et2O
(50 mL). The layers are separated and extracted with Et2O (three portions of
25 mL). The combinated Et2O extracts are washed with saturated aq.
NaHCO3 solution and brine, dried (MgSO4), and evaporated. Products are
isolated by column chromatography on silica gel (230–400 mesh) using
1
pentane/Et2O (95%:5%) as eluent and characterized by H and 13C NMR,
GC-MS, and IR analysis. All isolated products show satisfactory physical
characteristics and spectroscopic data in keeping with the literature.
CAS registry numbers of isolated products are as follows: 2: [17040-65-2]
1-benzoylcyclohex-1-ene, 6: [33809-30-2] 1-benzoyl-4-tert-butylcyclohex-1-
ene, 7: [21573-70-6] 1-benzoylcyclopent-1-ene, 8: [100883-18-9] 1-benzoyl-
cylohept-1-ene, 9: [67788-08-03] 1-benzoylcyclooct-1-ene, 10: [30272-58-
3] (E)-2-ethyl-1-phenylbut-2-en-1-one and [30248-91-0] (Z)-2-ethyl-1-
phenylbut-2-en-1-one, 11: [4452-11-3] (E)-1,2-diphenylprop-2-en-1-one, and
12: [38384-58-6] (E)-1,2-diphenylbut-2-en-1-one and [54444-14-3] (Z)-1,2-
diphenylbut-2-en-1-one.
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