Domino Methylenation/Hydrogenation of Aldehydes and Ketones by Combining Matsubara's Reagent and Wilkinson's Catalyst

Article abstract of DOI:10.1002/ejoc.201601137

The methylenation/hydrogenation cascade reaction of aldehydes or ketones through a domino process involving two ensuing steps in a single pot is realized. The compatibility of Matsubara's reagent and Wilkinson's complex give a combination that allows, under dihydrogen, the transformation of a carbonyl function into a methyl group. This new method is suitable to introduce an ethyl motif from aromatic and aliphatic aldehydes with total chemoselectivity and total retention of α-stereochemical purity. The developed procedure is also extended to the introduction of methyl groups from ketones.

Full text of DOI:10.1002/ejoc.201601137

A Journal of
Accepted Article
Title: Domino Methylenation-Hydrogenation of Aldehydes and Ketones by Combi-
ning Matsubara’s Reagent and Wilkinson’s Catalyst
´
Authors: Radhouan Maazaoui; Mar´ıa Pin-No; Kevin Gervais; Raoudha Abderrahim;
Franck Ferreira; Alejandro Perez-Luna; Fabrice Chemla; Olivier Jackowski
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201601137
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European Journal of Organic Chemistry
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Domino Methylenation–Hydrogenation of Aldehydes and Ketones
by Combining Matsubara’s Reagent and Wilkinson’s Catalyst
Radhouan Maazaoui,[a][b] María Pin–Nó,[a] Kevin Gervais,[a] Raoudha Abderrahim,[b] Franck Ferreira,[a]
Alejandro Perez-Luna,[a] Fabrice Chemla*[a], Olivier Jackowski*[a]
Dedication ((optional))
Abstract: The methylenation–hydrogenation cascade reaction of
aldehydes or ketones through a domino process involving two
ensuing steps in a single pot is related. The compatibility of
Matsubara’s reagent and Wilkinson’s complex afford a combination
that allows, under dihydrogen atmosphere, the transformation of
carbonyl function into a methyl group. This new method is suitable to
introduce an ethyl motif from aromatic and aliphatic aldehydes, with
total chemoselectivity and total retention of -stereochemical purity.
The developed procedure is also extended to the introduction of
methyl group from ketones.
lack of chemoselectivity of phosphorus ylide reagents between
aldehydes and ketones is another common limitation, and diene
formation from compounds presenting both aldehyde and ketone
moieties is generally observed. For all these drawbacks, the
availability of a more direct and selective method avoiding
intermediate purifications is required. Such a method could be
attained through a all-in-one-pot domino sequence involving two
subsequent steps.
To the best of our knowledge, only a single one-pot alternative
to Wittig methylenation–hydrogenation has been disclosed to
date:[8] it combines methylenation and hydrogenation both
catalyzed by rhodium complexes. However, the two processes
cannot be performed simultaneously and the methylenation
needs to be completed prior initiation of the hydrogenation
(Scheme 1, middle).
Introduction
Development of new synthetic processes that meet both
economic and environmental needs is one of the major
challenges in organic chemistry and its main source of
innovation. Finding new strategies that reduce the number of
In order to develop a true domino methylenation–hydrogenation
alternative method, we therefore examined the use of
methylenedizinc reagents:[9] these are known to be less basic
than Wittig reagents and we expected in this case the reaction
side products (zinc salts) generated through the methylenation
step would to be inert towards the hydrogenation catalyst.
Reagent such as Nysted’s reagent 1 and Matsubara’s reagent 2
[CH2(ZnI)2] present also the advantage of being chemoselective
between aldehydes and ketones and to react with -chiral
aldehydes without loss of the stereochemical integrity. For the
double bond reduction, we considered the commercially
available and widely used Wilkinson’s catalyst (ClRh(PPh3)3)[10]
(Scheme 1, bottom).
elementary operations required to achieve
a
given
transformation participates to this effort since it allows significant
waste diminution.[1] Thus, in this context, one-pot multiple
transformations have attracted an ever-increasing interest.[2,3]
Carbonyl methylenation is an important method for C–C bond
formation because the resulting alkene offers a valuable handle
for further elaboration. However, processes wherein the
generated alkene undergoes a subsequent transformation in the
same reaction media are scarce.[4] A case to the point is the
combination of aldehyde methylenation and hydrogenation. This
sequence is a common strategy to introduce an ethyl group from
aldehydes in multi-step synthesis of natural products,[5] bioactive
analogues[6] or key intermediates.[7] Typically, the transformation
is performed through a two-step/two-batch procedure involving a
Wittig-type reaction followed by
a
Pd- or Pt-catalyzed
hydrogenation (Scheme 1, top). But use of large volume of
solvent and elimination of phosphine oxide by-product are major
restrictions of this method. Another drawback is the basic
conditions met in the Wittig reaction that could lead to the loss of
-stereochemical purity by enolization of aldehydes. Finally, the
[a]
[b]
R. Maazaoui, M. Pin–Nó, K. Gervais, F. Ferreira, A. Perez-Luna, F.
Chemla, O. Jackowski
Institut Parisien de Chimie Moléculaire (IPCM),
Sorbonne Universités, UPMC Univ Paris 06, CNRS UMR 8232
CC 229, 4 place Jussieu, F-75252 Paris Cedex 05, France
E-mail: olivier.jackowski@upmc.fr; fabrice.chemla@upmc.fr
R. Maazaoui, R. Abderrahim
Laboratoire de Synthèse Hétérocyclique, Université de Carthage,
Faculté des Sciences de Bizerte, 7021 Jarzouna. Bizerte, Tunisia
Scheme 1. Methylenation–hydrogenation sequences.
Supporting information for this article is given via a link at the end of
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Naturally the viability of such an approach is directly related to
the compatibility of the methylenation reagent with the
hydrogenation catalyst, and this had to be verified first.
To our delight a reproducible 67% yield (entry 4) was obtained
under our former one-pot conditions (addition at –78 °C then
warming to 25 °C). Interestingly, the catalyst loading could be
diminished to 6.5 mol% without erosion of the yield (entry 5).
Our best result was obtained by carrying out the whole process
at 25 °C. Under these optimized conditions, alkane 4 could be
formed in significantly better 75% isolated yield (entry 6). The
use of only 3 mol% of this catalyst was however shown to be
detrimental (entry 7) as partial reduction was observed.
With these optimized conditions in hands, various aldehydes
were subjected to our all-in-one-pot domino conditions (Scheme
2). In the aromatic series, a range from 65% to 80% yield was
observed. Steric hindrance did not show any impact as
illustrated by comparison of the yields between alkanes 5 and 6
or 4 and 8. The influence of electronic effects on the aromatic
group was also investigated: aldehydes presenting either
electron-poor aromatic rings (compound 13) or electron-rich
ones (products 4, 8 and 9) gave the corresponding products in
similar yields (71–80%). On the other hand aliphatic aldehydes
were converted into the corresponding alkanes in slightly lower
yields (55–78%). Here again no impact of the steric hindrance
-mono-, di- or tri-substituted aldehydes were
Results and Discussion
To explore this one-pot domino approach, we focused first on
the commercially available Nysted’s reagent 1[11] (Table 1). The
transformation of the aldehyde moiety into an ethyl group was
first attempted by a sequential addition. At 0 °C, reagent 1 was
added to aldehyde 3 in the presence of BF3·OEt2 (1 equiv) and
the mixture was warmed to 25 °C. The complete consumption of
3 was observed within 2 h. The reaction flask was then flushed
with H2 (1 atm) and Wilkinson’s catalyst (10 mol%) was
introduced. Alkane 4 was isolated in 58% yield after 48 h (entry
1). In a second experiment, at 0 °C all reagents (aldehyde 3,
BF3·Et3O and Wilkinson’s catalyst) were introduced in the flask,
previously flushed with H2 (1 atm), and the resulting mixture
gradually allowed to warm to 25 °C. Alkane 4 was isolated in a
lower 27% yield (entry 2). Pleasingly, adding all reagents at –
78 °C prior to warming the mixture to 25 °C led to the formation
of alkane 4 in a 62% yield (entry 3), showing the viability of our
one-pot domino approach. However confronted to a lack of
reproducibility of these results (attributed to the heterogeneity of
Nysted’s reagent 1), we decided to turn to THF-soluble
Matsubara reagent 2[12] known to be a methylenating reagent of
aldehydes that does not require Lewis acid activation. [13]
transformed into the corresponding alkanes 10–12 in
comparable (69–81%) yields.
Table 1. Optimization studies.
Entry
1
Reaction Conditions
Yield (%)[a]
58
1 (1 equiv), BF3·Et2O (1 equiv), 0 °C then 2 h at 25 °C,
then H2 (1 atm), ClRh(PPh3)3 (10 mol%), 48 h
1 (1 equiv), BF3·Et2O (1 equiv), H2 (1 atm), ClRh(PPh3)3
(10 mol%), 0 °C to 25 °C, 48 h
2
3
4
5
6
7
27
62[b]
67
1 (1 equiv), BF3·Et2O (1 equiv), H2 (1 atm), ClRh(PPh3)3
(10 mol%),–78 °C to 25 °C, 48 h
2 (1 equiv), H2 (1 atm), ClRh(PPh3)3 (10 mol%), –78 °C
to 25 °C, 48 h
2 (1 equiv), H2 (1 atm), ClRh(PPh3)3 (6.5 mol%), –78 °C
to 25 °C, 48 h
66
2 (1.2 equiv), H2 (1 atm), ClRh(PPh3)3 (6.5 mol%),
25 °C, 48 h
75
2 (1.2 equiv), H2 (1 atm), ClRh(PPh3)3 (3 mol%), 25 °C,
48 h
28[c]
[a] Isolated yield. [b] not reproducible. [c] 50% of 2,3-dimethoxystyrene was
isolated.
Scheme 2. One-pot domino methylenation–hydrogenation from aldehydes.
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Importantly, as the methylenation using 2 is known to be
chemoselective,[13a,b] our one-pot domino procedure tolerates the
presence of ketone moieties. As illustrated by the formation of
products 13–15, substrates bearing both an aldehyde and a
ketone moiety undergo methylenation–hydrogenation of the
aldehyde by leaving the ketone intact. By comparison, Wittig
methylenation of such substrates usually affords not only the
desired methylenated products but also diene side products.[14]
Finally, we verify that our conditions also allow the
transformation of enolizable chiral aldehydes without loss of
chiral integrity. While Wittig reaction is likely to induce aldehyde
isomerization, no epimerization occurs with 2.[13a,13b,15] Thus,
(2S)-2-methyl,3-trityloxypropanal (99% ee) afforded alkane 16 in
78% yield and identical ee (99%).
Our conditions thus offer a new easy method to transform
aldehydes into ethyl group with a great chemoselectivity and a
total retention of the -stereochemical information of the
aldehyde. To gain insight into the interplay of the different
elements of our system, we carried out several control
experiments with 2-naphthaldehyde 17 (Scheme 3). In a first
experiment, the methylenation step was monitored by in situ
IR[16] analysis in presence of Wilkinson’s catalyst under H2
atmosphere. The methylenation step was observed to be fast as
95% conversion of 17 was achieved within 20 min and alkene 18
was isolated in 85% yield (eq. 1). Another control experiment
was conducted by mixing Wilkinson’s catalyst and 2 for 2 h
under H2 prior to the addition of alkene 18 (eq. 2). Product 5 was
obtained in 80% yield, thus proving that the mixture of
Wilkinson's catalyst and 2 is still active for the hydrogenation
process. In the last experiment, a mixture of Wilkinson’s catalyst
and 2 was stirred under H2 for 2 h and thus aldehyde 17 was
added (eq. 3).
In this case, alcohol 19 was isolated in 60% yield as the major
product and starting material 17 was recovered in 33% yield.
This last result indicates that under these conditions, no
organometallic species was still able to carry out any
methylenation process. These results denote that, even though
degradation of organometallic species 2 occurs in the presence
of the Wilkinson’s catalyst, the kinetics of the methylenation step
override reagent decomposition. Thanks to this kinetic difference
the one-pot domino approach is possible.
Extension of this domino procedure was thus envisioned to
ketones. In this case, it has been reported that the use of -TiCl3
or TiCl4 as a Lewis acid is necessary for the methylenation
step.[9,13] Hence, our investigation was carried out in a all-in-one-
pot manner with -Tetralone (1 equiv) in the presence of TiCl4
(1.2 equiv),[17] reagent 2 (1.1 equiv.) and ClRh(PPh3)3 (7 mol%)
at 25 °C under H2 (1 atm). As expected alkane 20 was formed
and isolated in 86% yield (Scheme 4). The scope of this domino
system was consequently evaluated for a variety of ketones
(Scheme 4). Aliphatic ketones were transformed in good yields:
alkanes 21 and 22 were obtained in respectively 70% and 82%
yields from the corresponding aliphatic ketones. Ketoesters
could also be converted as illustrated by product 23 isolated in
62 % yield. However, from easily enolizable ketone such as -
Tetralone known to afford a low yield,[13a] a 73:27 mixture of
alkane 24 and alkene 25 was isolated in 78 % yield. Alkene 25
was assumed to result from the double bond migration into the
cycle from the exocyclic primarily formed methylenation product.
Hydrogenation was also revealed to be sensitive to the steric
hindrance of the ketone. Alkane 26 was indeed obtained in
mixture with alkene 27 (26:27 = 80:20) in 85% yield, even with
12 mol% of catalyst loading.
Scheme 4. One-pot domino methylenation–hydrogenation process from
ketones.
Scheme 3. Interplay of the different elements of the domino process.
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4-Ethylbromobenzene (7)
The representative procedure
A
was
followed
using 4-
Bromobenzaldehyde (78 mg, 0.5 mmol), Wilkinson’s catalyst (30 mg, 6.5
mol%) and a 0.50 M soln of 2 in THF (1.2 mL, 0,6 mmol). Column
chromatography on silica gel (pentane) yielded 7 (71 mg, 76%). 1H NMR
(400 MHz, CDCl3):  (ppm) = 7.42 (d, J = 8.4 Hz, 2 H), 7.09 (d, J = 8.6
Hz, 2 H), 2.63 (q, J = 7.6 Hz, 2 H), 1.25 (t, J = 7.6 Hz, 3 H). 13C NMR
(101 MHz, CDCl3):  (ppm) = 143.2, 131.4, 129.7, 119.4, 28.4, 15.6.
Conclusions
In summary, an efficient all-in-one-pot domino process has been
developed to perform the transformation of a carbonyl moiety
into a methyl group through a methylenation and [Rh]-catalyzed
double bond hydrogenation cascade. This new method allows
the introduction of an ethyl motif with total chemoselectivity and
total preservation of -stereochemical information from various
aldehydes. Aromatic and aliphatic aldehydes produced the
corresponding alkanes in good yields. Extension of the process
to ketones in the presence of TiCl4 represents also a new
pathway to introduce the methyl pattern into molecules. This
procedure confirms the prospect of domino methylenation–
alkene transformation cascades by the combination of gem-
organodizinc species and Rh catalysts.
1,2-Dimethoxy-4-ethylbenzene (8)
The representative procedure
A
was followed using 3,4-
Dimetoxybenzaldehyde (83 mg, 0.5 mmol), Wilkinson’s catalyst (30 mg,
6.5 mol%) and a 0.50 M soln of 2 in THF (1.2 mL, 0,6 mmol). Column
chromatography on silica gel (pentane/diethyl ether 100/0 to 90/10)
yielded 8 (60 mg, 71%). 1H NMR (400 MHz, CDCl3):  (ppm) = 6.80 (d, J
= 8.6 Hz, 1 H), 6.76-6.72 (m, 2 H), 3.88 (s, 3 H), 3.85 (s, 3 H), 2.61 (q, J
= 7.6 Hz, 2H), 1.24 (t, J = 7.6 Hz, 3 H). 13C NMR (101 MHz, CDCl3):

(ppm) = 148.8, 147.0, 134.0, 119.5, 111.4, 111.3, 55.9, 55.8, 28.5,
15.8.
1-Ethylferrocene (9)
The
representative
procedure
A
was
followed
using
Ferrocenecarboxaldehyde (107 mg, 0.5 mmol), Wilkinson’s catalyst (30
mg, 6.5 mol%) and a 0.50 M soln of 2 in THF (1.2 mL, 0,6 mmol).
Column chromatography on silica gel (pentane/diethyl ether 100/0 to
90/10) yielded 9 (86 mg, 80%). 1H NMR (400 MHz, CDCl3):  (ppm)
4.14-4.03 (m, 10 H), 2.34 (t, J = 7.5 Hz, 2 H), 1.18 (t, J = 7.5 Hz, 3 H).
13C NMR (101 MHz, CDCl3):  (ppm) = 91.4, 68.61 67.6, 67.2, 22.4,
14.7.
Experimental Section
Representative Procedure
A for the Domino Methylenation–
Hydrogenation of aldehydes: Aldehyde (0.5 mmol) was dissolved in
dry THF (1 mL) and the flask was flushed with H2 (1 atm). At 25 °C under
vigorous stirring, were successively added the Wilkinson’s catalyst (6.5
mol%) and a 0.50 M soln of 2 in THF (0,6 mmol, 1.2 mL). After total
consumption of alkene (24 h), the mixture was directly purified by flash
column chromatography over silica gel to give desired compound. All
compounds were obtained as oils.
2-Methoxy-2,6-dimethylnonane (10)
The representative procedure A was followed using 3,7-Dimethyl-7-
methoxyactanal (93 mg, 0.5 mmol), Wilkinson’s catalyst (30 mg, 6.5
mol%) and a 0.50 M soln of 2 in THF (1.2 mL, 0,6 mmol). Column
chromatography on silica gel (pentane/diethyl ether 100/0 to 90/10)
yielded 10 (65 mg, 69%). 1H NMR (400 MHz, CDCl3):  (ppm) = 6.73 (d,
J = 7.9 Hz, 1 H), 6.66 (d, J = 1.6 Hz, 1 H), 6.60 (dd, J = 7.8, 1.6 Hz, 1 H),
5.92 (s, 2 H), 2.57 (dd, J = 13.5, 6.2 Hz, 1 H), 2.30 (dd, J = 13.5, 8.0 Hz,
1 H), 1.66-1.52 (m, 1 H), 1.48-1.33 (m, 1 H), 1.22-1.12 (m, 1 H), 0.92 (t, J
= 7.4 Hz, 3 H), 0.86 (d, J = 6.6 Hz, 3 H). 13C NMR (101 MHz, CDCl3):
1,2-Dimethoxy-3-ethylbenzene (4)
The representative procedure
A
was followed using 2,3-
Dimetoxybenzaldehyde (83 mg, 0.5 mmol), Wilkinson’s catalyst (30 mg,
6.5 mol%) and a 0.50 M soln of 2 in THF (1.2 mL, 0,6 mmol). Column
chromatography on silica gel (pentane/diethyl ether 100/0 to 90/10)
yielded 4 (63 mg, 75%). 1H NMR (400 MHz, CDCl3):  (ppm) = 1.99-
1.89 (m, 3 H), 1.75-1.59 (m, 6 H), 1.45 (d, J = 2.9 Hz, 6 H), 1.10 (q, J =
7.6 Hz, 2 H), 0.79 (t, J = 7.6 Hz, 3 H). 13C NMR (101 MHz, CDCl3): 
(ppm) = 42.2, 37.5, 36.9, 32.4, 29.0, 7.0.

(ppm) = 147.5, 145.5, 135.7, 122.0, 109.6, 108.0, 100.8, 43.2, 34.0,
29.2, 19.0, 11.6
5-(2-methylbutyl)-1,3-benzodioxole (11)
The representative procedure A was followed using 2-Methyl-3-(3,4-
methylenedioxyphenyl)-propanal (96 mg, 0.5 mmol), Wilkinson’s catalyst
(30 mg, 6.5 mol%) and a 0.50 M soln of 2 in THF (1.2 mL, 0,6 mmol).
Column chromatography on silica gel (pentane/diethyl ether 100/0 to
90/10) yielded 11 (69 mg, 70%). 1H NMR (400 MHz, CDCl3):  (ppm)
6.73 (d, J = 7.9 Hz, 1 H), 6.66 (d, J = 1.6 Hz, 1 H), 6.60 (dd, J = 7.8, 1.6
Hz, 1 H), 5.92 (s, 2 H), 2.57 (dd, J = 13.5, 6.2 Hz, 1 H), 2.30 (dd, J = 13.5,
8.0 Hz, 1 H), 1.66-1.52 (m, 1 H), 1.48-1.33 (m, 1 H), 1.22-1.12 (m, 1 H),
0.92 (t, J = 7.4 Hz, 3 H), 0.86 (d, J = 6.6 Hz, 3 H). 13C NMR (101 MHz,
CDCl3):  (ppm) = 147.5, 145.5, 135.7, 122.0, 109.6, 108.0, 100.8, 43.2,
34.0, 29.2, 19.0, 11.6.
1-Ethylnaphthalene (5)
The representative procedure A was followed using 1-Naphthaldehyde
(78 mg, 0.5 mmol), Wilkinson’s catalyst (30 mg, 6.5 mol%) and a 0.50 M
soln of 2 in THF (1.2 mL, 0,6 mmol). Column chromatography on silica
gel (pentane) yielded 5 (61 mg, 77%). 1H NMR (400 MHz, CDCl3):

(ppm) = 8.16-8.10 (m, 1 H), 7.92 (d, J = 7.6 and 2.0 Hz, 1 H), 7.77 (d,
J = 8.0 Hz, 1 H), 7.63-7.43 (m, 3 H), 7.43-7.37 (m, 1 H), 3.18 (q, J = 7.5
Hz, 2 H), 1.46 (t, J = 7.5 Hz, 3 H). 13C NMR (101 MHz, CDCl3):  (ppm) =
140.4, 134.0, 131.9, 128.9, 126.5, 125.8, 125.5, 125.0, 123.9, 26.0, 15.2.
2-Ethylnaphthalene (6)
The representative procedure A was followed using 2-Naphthaldehyde
(92 mg, 0.5 mmol), Wilkinson’s catalyst (30 mg, 6.5 mol%) and a 0.50 M
soln of 2 in THF (1.2 mL, 0,6 mmol). Column chromatography on silica
gel (pentane) yielded 6 (59 mg, 75%). 1H NMR (400 MHz, CDCl3):
(ppm) = 7.86-7.79 (m, 3 H), 7.69-7.64 (m, 1 H), 7.51-7.41 (m, 2 H), 7.39
(dd, J = 8.4, 1.8 Hz, 1 H), 2.86 (qd, J = 7.5, 0.8 Hz, 2 H), 1.37 (t, J = 7.6
Hz, 3 H). 13C NMR (101 MHz, CDCl3):  (ppm) = 141.9, 133.9, 132.1,
127.9, 127.7, 127.6, 127.2, 126.0, 125.7, 125.1, 29.2, 15.7.
1-Ethyladamantane (12)
The
representative procedure
A
was
followed
using 1-
Adamantanecarboxaldhyde (82 mg, 0.5 mmol), Wilkinson’s catalyst (30
mg, 6.5 mol%) and a 0.50 M soln of 2 in THF (1.2 mL, 0,6 mmol).
Column chromatography on silica gel (pentane) yielded 12 (68 mg, 81%).
1H NMR (400 MHz, CDCl3):  (ppm) = 1.99-1.89 (m, 3 H), 1.75-1.59 (m,
6 H), 1.45 (d, J = 2.9 Hz, 6 H), 1.10 (q, J = 7.6 Hz, 2 H), 0.79 (t, J = 7.6
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European Journal of Organic Chemistry
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Hz, 3 H). 13C NMR (101 MHz, CDCl3):  (ppm) = 42.2, 37.5, 36.9, 32.4,
29.0, 7.0.
1.74 (m, 1 H), 1.59-1.52 (m, 1 H), 1.31 (d, J = 7.0 Hz, 3 H). 13C NMR (75
MHz, CDCl3):  (ppm) = 142.3, 137.0, 129.1, 128.2, 125.7, 125.5, 32.6,
31.6, 30.1, 23.0, 20.6.
4’-Ethylacetophenone (13)
The
representative procedure
A
was
followed
using 4-
8-Methyl-1,4-dioxaspiro[4.5]decane (21)
Acetylbenzaldehyde (74 mg, 0.5 mmol), Wilkinson’s catalyst (30 mg, 6.5
mol%) and a 0.50 M soln of 2 in THF (1.2 mL, 0,6 mmol). Column
chromatography on silica gel (pentane/diethyl ether 100/0 to 95/5)
yielded 10 (51 mg, 65%). 1H NMR (400 MHz, CDCl3):  (ppm) = 7.89 (d,
J = 8.3 Hz, 2 H), 7.28 (d, J = 8.1 Hz, 2 H), 2.71 (q, J = 7.6 Hz, 2 H), 2.58
(s, 3 H), 1.26 (t, J = 7.6 Hz, 3 H). 13C NMR (101 MHz, CDCl3):  (ppm)
The representative procedure
B
was followed using 1,4-
dioxaspiro[4.5]decan-8-one (78 mg, 0.5 mmol), Wilkinson’s catalyst (33
mg, 7 mol%), a 1 M soln of TiCl4 in CH2Cl2 (0.6 mL, 0,6 mmoL) and a
0.50 M soln of 2 in THF (1.05 mL, 0.55 mmol). Column chromatography
on silica gel (pentane/diethyl ether 100/0 to 70/30) yielded 22 (56 mg,
70%). 1H NMR (400 MHz, CDCl3) :  (ppm) =3.90 (s, 4 H), 1.74-1.57 (m,
4 H), 1.55-1.44 (m, 2 H), 1.39 (tdd, J = 9.9, 7.1, 5.0 Hz, 1 H), 1.20 (tdd, J
= 13.9, 11.2, 3.5 Hz, 2 H), 0.88 (d, J = 6.5 Hz, 3 H). 13C NMR (101 MHz,
CDCl3):  (ppm) = 109.1, 64.3, 64.2, 34.7, 32.4, 31.5, 21.7.
1-Phenyl-1-hexanone (14)
The representative procedure A was followed using 4-Benzoylpentanal
(88 mg, 0.5 mmol), Wilkinson’s catalyst (30 mg, 6.5 mol%) and a 0.50 M
soln of 2 in THF (1.2 mL, 0,6 mmol). Column chromatography on silica
gel (pentane/diethyl ether 100/0 to 95/5) yielded 14 (50 mg, 55%). 1H
2-Methylpropoxy-benzene (22)
The representative procedure B was followed using 1-Phenoxyacetone
(75 mg, 0.5 mmol), Wilkinson’s catalyst (33 mg, 7 mol%), a 1 M soln of
TiCl4 in CH2Cl2 (0.6 mL, 0,6 mmoL) and a 0.50 M soln of 2 in THF (1.05
mL, 0.55 mmol). Column chromatography on silica gel (pentane/diethyl
ether 100/0 to 95/5) yielded 23 (63 mg, 82%). 1H NMR (400 MHz,
CDCl3) :  (ppm) = 7.35-7.26 (m, 2 H), 6.99-6.84 (m, 3 H), 3.73 (d, J =
6.5 Hz, 2 H), 2.10 (heptuplet, J = 6.6 Hz, 1 H), 1.04 (d, J = 6.7 Hz, 6 H).
13C NMR (101 MHz, CDCl3):  (ppm) = 159.4, 129.5, 120.5, 114.7, 74.4,
28.4, 19.4.
NMR (400 MHz, CDCl3):  (ppm)
7.90-7.85 (m, 2 H), 7.49-7.44 (m, 1
H), 7.44-7.33 (m, 2 H), 2.86 (t, J = 8.0 Hz, 2 H), 1.70-1.60 (m, 2 H), 1.32-
1.25 (m, 4 H), 0,83 (t, J = 8.0 Hz, 3 H). 13C NMR (101 MHz, CDCl3):

(ppm) = 200.6, 137.2, 132.9, 128.6, 128.1, 38.6, 31.6, 24.1, 22.6, 14.0.
1-Phenyl-1-heptanone (15)
The representative procedure
A
was followed using 6-Oxo-6-
phenylhexanal (95 mg, 0.5 mmol), Wilkinson’s catalyst (30 mg, 6.5
mol%) and a 0.50 M soln of 2 in THF (1.2 mL, 0,6 mmol). Column
Benzyl isobutyrate (23)
chromatography on silica gel (pentane/diethyl ether 100/0 to 95/5)
The representative procedure B was followed using Benzyl pyruvate (75
mg, 0.5 mmol), Wilkinson’s catalyst (33 mg, 7 mol%), a 1 M soln of TiCl4
in CH2Cl2 (0.6 mL, 0,6 mmoL) and a 0.50 M soln of 2 in THF (1.05 mL,
0.55 mmol). Column chromatography on silica gel (pentane/diethyl ether
100/0 to 80/20) yielded 24 (63 mg, 82%). 1H NMR (400 MHz, CDCl3) :
1
yielded 15 (63 mg, 65%). H NMR (400 MHz, CDCl3):  (ppm)
4
(d, J = 8.0 Hz, 2 H), 7.59-7.50 (m, 1 H), 7.50-7.39 (m, 2 H), 2.93 (t, J =
8.0 Hz, 2 H), 1.78-1.66 (m, 2 H), 1.42-1.25 (m, 6 H), 0,88 (t, J = 8.0 Hz, 3
H). 13C NMR (101 MHz, CDCl3):  (ppm) = 200.5, 137.2, 132.9, 128.6,
128.1, 38.7, 31.7, 29.1, 24.4, 22.6, 14.1.

(ppm) = 7.39-7.31 (m, 5 H), 5.12 (s, 2 H), 2.61 (hept, J = 7.0 Hz, 1 H),
1.19 (d, J = 7.0 Hz, 6 H). 13C NMR (101 MHz, CDCl3):  (ppm) = 176.9,
136.4, 128.6, 128.1, 128.0, 66.1, 34.1, 19.1.
(2R)-1-Triphenylmethoxy-2-methylbutane (16)
The representative procedure A was followed using (2S)-2-Methyl-3-
triphenylmethoxypropanal (165 mg, 0.5 mmol), Wilkinson’s catalyst (30
mg, 6.5 mol%) and a 0.50 M soln of 2 in THF (1.2 mL, 0,6 mmol).
Column chromatography on silica gel (pentane/diethyl ether 100/0 to
90/10) yielded 16 (130 mg, 78%). 1H NMR (400 MHz, CDCl3):  (ppm) =
7.51-7.46 (m, 6 H), 7.31 (t, J = 7.4 Hz, 5 H), 7.29-7.20 (m, 3 H), 2.99 (dd,
J = 8.7, 6.0 Hz, 1 H), 2.91 (dd, J = 8.7, 6.3 Hz, 1 H), 1.74-1.64 (m, 1 H),
1.57-1.47 (m, 1 H), 1.24-1.15 (m, 1 H), 0.97 (d, J = 6.7 Hz, 3 H), 0.84 (t, J

(24) and 2-Methyl-3,4-dihydronaphthalene (25)
The representative procedure B was followed using -Tetralone (73 mg,
0.5 mmol), Wilkinson’s catalyst (33 mg, 7 mol%), a 1 M soln of TiCl4 in
CH2Cl2 (0.6 mL, 0,6 mmoL) and a 0.50 M soln of 2 in THF (1.05 mL, 0.55
mmol). Column chromatography on silica gel (pentane) yielded a 73/27
mixture of 25 and 26 (58.5 mg, 78%). 1H NMR (400 MHz, CDCl3) :  =
7.15-7.04 (m, 3.72 H, 25 + 26), 6.99-6.95 (m, 0.27 H, 26), 6.23 (d, J = 1.5
Hz, 0.27 H, 26), 2.90-2.78 (m, 2.72 H, 25), 2.42 (ddd, J = 16.5, 10.6, 1.3
Hz, 0.71 H, 26), 2.29-2.22 (m, 0.58 H, 26), 1.95-1.80 (m, 2.35 H, 25 + Me
26), 1.46-1.37 (m, 0.72 H, 25), 1.08 (d, J = 6.5 Hz, 2.19 H, Me 25). 13C
NMR (75 MHz, CDCl3):  = 138.3, 137.1, 136.8, 135.2, 134.2, 129.2,
129.0, 127.3, 126.5, 126.1, 125.9, 125.6, 125.5, 125.2, 122.9, 38.3, 31.7,
29.4, 29.0, 28.2, 23.6, 22.1.
= 7.5 Hz, 3 H). 13C NMR (101 MHz, CDCl3):  (ppm)
4.8, 128.9,
127.8, 126.9, 86.2, 68.3, 35.7, 26.6, 17.1, 11.5. HRMS (ESI) m/z
calculated for C24H26NaO+ 353.1876; found 353.1883.
Representative Procedure
B for the Domino Methylenation–
Hydrogenation of ketones: To a solution of ketone (0.5 mmol) and
Wilkinson catalyst (7 mol%) in dry CH2Cl2 (0.5 mL) under H2 (1 atm),
were successively added at 25 °C a 1 M soln of TiCl4 in CH2Cl2 (0.6
mmoL) and a 0.5 M soln of 2 in THF (0,55 mmol). After 20 h under
vigorous stirring, the mixture was purified by flash column
chromatography (silica gel, pentane/diethyl ether as eluent 100/0 to
50/50) to give desired compound. All compounds were obtained as oils.
2-Phenyl-hexane (26) and 2-Phenyl-1-hexene (27)
The representative procedure B was followed using Valerophenone (81
mg, 0.5 mmol), Wilkinson’s catalyst (33 mg, 7 mol%), a 1 M soln of TiCl4
in CH2Cl2 (0.6 mL, 0,6 mmoL) and a 0.50 M soln of 2 in THF (1.05 mL,
0.55 mmol). Column chromatography on silica gel (pentane) yielded a
80/20 mixture of 27 and 28 (71 mg, 85%). 1H NMR (400 MHz, CDCl3) :
= 7.45-7.17 (m, 5.38 H, 27 + 28), 5.28 (s, 0.19 H, 28), 5.07 (s, 0.19 H,
28), 2.69 (h, J = 7.1 Hz, 0.79 H, 27), 2.53 (t, J = 7.5 Hz, 0.39 H, 28),
1.67-1.09 (m, 8.63 H, 27 + 28), 0.95-0.83 (m, 3 H, CH3 nBu 27 + 28). 13
NMR (75 MHz, CDCl3):  = 148.9, 148.1, 141.7, 128.4, 128.4, 127.4,
127.1, 126.3, 125.9, 112.1, 40.1, 38.3, 35.2, 30.6, 30.1, 22.9, 22.6, 22.5,
14.2, 14.1.
α-Methyltetralin (20)
The representative procedure B was followed using -Tetralone (73 mg,
0.5 mmol), Wilkinson’s catalyst (33 mg, 7 mol%), a 1 M soln of TiCl4 in
CH2Cl2 (0.6 mL, 0,6 mmoL) and a 0.50 M soln of 2 in THF (1.05 mL, 0.55
mmol). Column chromatography on silica gel (pentane) yielded 21 (65
mg, 86%). 1H NMR (400 MHz, CDCl3) :  (ppm) = 7.21 (d, J = 7.3 Hz, 1
H), 7.17-7.03 (m, 3 H), 2.92 (m, 1 H), 2.77 (m, 2 H), 1.99-1.83 (m, 2 H),
C
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European Journal of Organic Chemistry
10.1002/ejoc.201601137
FULL PAPER
J. Am. Chem. Soc., 2010, 132, 17452; d) M. Sada, M. Uchiyama, S.
Matsubara, Synlett 2014, 25, 2831.
[14] H. Lebel, M. Davi, G. T. Stoklosa, J. Org. Chem., 2008, 73, 6828.
[15] a) D. A. Evans, H. A. Rajapakse, A. Chiu, D. Stenkamp, Angew. Chem.
Int. Ed. 2002, 41, 4573; b) K. P. Shelly, L. Weiler, Can. J. Chem 1988,
66, 1359; (c) L. Lombardo, Tetrahedron Lett. 1982, 23, 4293.
[16] See supporting information.
Acknowledgements
The authors wish to thank Omar Khaled from IPCM for HRMS
analysis and University of Carthage for financial support.
[17] The optimal reported protocol to convert ketones into alkenes involves
a 2/TiCl4 = 2:1 ratio in order to convert TiCl4 into TiCl2 or TiCl3. A 2/TiCl4
= 1:1 ratio only affords 26% of the alkene.[13a-c] Conversely, in our
conditions, a 2/ TiCl4 = 1:1.1 ratio is optimal: the combination of TiCl4
and Wilkinson’s catalyst under H2 atmosphere could perhaps lead to in
situ formation of TiCl2 or TiCl3 more suitable for the methylenation
reaction.
Keywords: Methylenation–Hydrogenation cascade • Domino
process • Chemoselectivity • Matsubara’s reagent • Wilkinson’s
catalyst
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European Journal of Organic Chemistry
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FULL PAPER
Entry for the Table of Contents
FULL PAPER
Domino Process
ClRh(PPh3)3
ZnI
Domino cascade transformation
Radhouan Maazaoui, María Pin–Nó,
Kevin Gervais, Raoudha Abderrahim,
Franck Ferreira, Alejandro Perez-Luna,
Fabrice Chemla*, Olivier Jackowski*
H or R'
O
H or R'
IZn
H2
+
R
R
Me
Page No. – Page No.
The transformation of carbonyl moiety into a methyl group through a all-in-one-pot
domino methylenation–hydrogenation cascade is available thanks to the
combination of Matsubara’s reagent and Wilkinson’s complex under H2
atmosphere. This new method is suitable for the introduction of an ethyl motif from
aromatic and aliphatic aldehydes, as well as for the introduction of a methyl pattern
from ketones.
Domino Methylenation–
Hydrogenation of Aldehydes and
Ketones by Combining Matsubara’s
Reagent and Wilkinson’s Catalyst
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