Transition-metal-catalyzed chemoselective methylenation of dicarbonyl substrates

Article abstract of DOI:10.1021/jo800777w

(Chemical Equation Presented) Rhodium- and copper-catalyzed methylenation reactions with trimethylsilyldiazomethane, triphenylphosphine, and 2-propanol were used to react chemoselectively with aldehydes, alkoxymethylketones, and triftuoromethylketones in substrates also containing a less reactive carbonyl group. Terminal alkenes were obtained in high yields, and no protecting group was necessary in the methylenation process.

Full text of DOI:10.1021/jo800777w

using the Oshima-Lombardo reagent has been extensively
studied.4 Indeed ketoaldehyde substrates produced both monoalk-
enes resulting from the methylenation of either the aldehyde or
the ketone moiety. Despite significant advantages, several
drawbacks remain associated with such a reaction, including
the use of stoichiometric amount of expensive and/or toxic
metals. We have recently disclosed a novel transition-metal-
catalyzed methylenation reaction of carbonyl compounds using
trimethylsilyldiazomethane, triphenylphosphine, and 2-propanol.5,6
Mechanistic studies revealed that methylenetriphenylphospho-
Transition-Metal-Catalyzed Chemoselective
Methylenation of Dicarbonyl Substrates
He´le`ne Lebel,* Michae¨l Davi, and Grzegorz T. Stokłosa
De´partement de Chimie, UniVersite´ de Montre´al, PaVillon
´
Roger Gaudry, 2900 Boul. Edouard-Montpetit, Montre´al,
Que´bec, Canada H3T 1J4
helene.lebel@umontreal.ca
7
rane was the active species; this completely salt-free ylide
reacted with high chemoselectivity.5e However, no systematic
investigation has been published so far for the chemoselectivity
of the methylenation reaction using a phosphorus ylide reagent.
In this paper, we describe the use of bis-hydrocinnamate
derivatives as a conserved backbone to thoroughly study the
reactivity of ketones and aldehydes under various methylenation
reaction conditions using methylenetriphenylphosphorane.
We have previously reported that the rhodium-catalyzed
methylenation with trimethylsilyldiazomethane, triphenylphos-
phine, and 2-propanol of ketoaldehyde substrates 1 and 3
produced exclusively the corresponding monoalkene (2 and 4,
respectively) resulting from the aldehyde methylenation (eqs 1
and 2).5e Conversely, when methylenetriphenylphosphorane was
generated from methyltriphenylphosphonium bromide and
sodium hexamethyldisilazide, 15-30% of the corresponding
diene was observed leading to lower yields for the desired
product.
ReceiVed April 17, 2008
Rhodium- and copper-catalyzed methylenation reactions with
trimethylsilyldiazomethane, triphenylphosphine, and 2-pro-
panol were used to react chemoselectively with aldehydes,
alkoxymethylketones, and trifluoromethylketones in sub-
strates also containing a less reactive carbonyl group.
Terminal alkenes were obtained in high yields, and no
protecting group was necessary in the methylenation process.
Nucleophilic additions to carbonyl compounds typically
follow the reactivity order of aldehydes > ketones > esters
.amides . carboxylic acids.1 Such an order can be perturbed
by coordination of the carbonyl group with a Lewis acid.2 A
number of scattered examples of chemoselective olefination
reactions with carbonyl compounds have been previously
published,3 whereas only a few systematic studies were reported.
Among them, the chemoselectivity of the methylenation reaction
To further investigate the chemoselectivity of the methyl-
enation reaction, we have prepared a series of bis-hydrocin-
namate derivatives containing various carbonyl groups. Such
substrates (7-13) display a conserved backbone, and thus each
(1) Saito, S.; Yamamoto, H. In Modern Carbonyl Chemistry; Otera, J., Ed.;
Wiley-VCH: Weinheim, 2000; pp 33-67.
(2) (a) Asao, N.; Asano, T.; Yamamoto, Y. Angew Chem., Int. Ed. 2001, 40,
3206–3208, and references therein. (b) Yamamoto, H.; Maruoka, K.; Araki, Y.
Tetrahedron Lett. 1988, 29, 3101–3104.
(4) (a) Matsubara, S.; Oshima, K.; Utimoto, K. J. Organomet. Chem. 2001,
617, 39–46. (b) Matsubara, S.; Mizuno, T.; Otake, Y.; Kobata, M.; Utimoto, K.;
Takai, K. Synlett 1998, 1369–1371. (c) Okazoe, T.; Hibino, J.; Takai, K.; Nozaki,
H. Tetrahedron Lett. 1985, 26, 5581–5584.
(5) (a) Lebel, H.; Paquet, V.; Proulx, C. Angew. Chem., Int. Ed. 2001, 40,
2887–2890. (b) Grasa, G. A.; Moore, Z.; Martin, K. L.; Stevens, E. D.; Nolan,
S. P.; Paquet, V.; Lebel, H. J. Organomet. Chem. 2002, 658, 126–131. (c) Lebel,
H.; Paquet, V. Org. Lett. 2002, 4, 1671–1674. (d) Lebel, H.; Guay, D.; Paquet,
V.; Huard, K. Org. Lett. 2004, 6, 3047–3050. (e) Lebel, H.; Paquet, V. J. Am.
Chem. Soc. 2004, 126, 320–328. (f) Paquet, V.; Lebel, H. Synthesis 2005, 1901–
1905. (g) Lebel, H.; Davi, M.; Diez-Gonzalez, S.; Nolan, S. P. J. Org. Chem.
2007, 72, 144–149.
(6) For recent examples of application in total synthesis, see: (a) Kwon, M. S.;
Woo, S. K.; Na, S. W.; Lee, E. Angew. Chem., Int. Ed. 2008, 47, 1733–1735.
(b) Zhang, H.; Reddy, M. S.; Phoenix, S.; Deslongchamps, P. Angew. Chem.,
Int. Ed. 2008, 47, 1272–1275. (c) Lebel, H.; Parmentier, M. Org. Lett. 2007, 9,
3563–3566.
(3) Selected examples: (a) Olpp, T.; Bruckner, R. Angew. Chem., Int. Ed.
2006, 45, 4023–4027. (b) Trost, B. M.; Dirat, O.; Gunzner, J. L. Angew. Chem.,
Int. Ed. 2002, 41, 841–843. (c) Mergott, D. J.; Frank, S. A.; Roush, W. R. Org.
Lett. 2002, 4, 3157–3160. (d) Kahnberg, P.; Lee, C. W.; Grubbs, R. H.; Sterner,
O. Tetrahedron 2002, 58, 5203–5208. (e) Oesterreich, K.; Klein, I.; Spitzner,
D. Synlett 2002, 1712–1714. (f) Faure, S.; Piva, O. Tetrahedron Lett. 2001, 42,
255–259. (g) Kim, D.; Lee, J.; Chang, J.; Kim, S. Tetrahedron 2001, 57, 1247–
1252. (h) Colombo, M. I.; Zinczuk, J.; Mischne, M. P.; Ruveda, E. A.
Tetrahedron: Asymmetry 2001, 12, 1251–1253. (i) Nicolaou, K. C.; King, N. P.;
Finlay, M. R. V.; He, Y.; Roschangar, F.; Vourloumis, D.; Vallberg, H.; Sarabia,
F.; Ninkovic, S.; Hepworth, D. Bioorg. Med. Chem. 1999, 7, 665–697. (j) Hsu,
P.-Y.; Lee, Y.-C.; Liao, C.-C. Tetrahedron Lett. 1998, 39, 659–662. (k) Paquette,
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B. W.; Cote, B.; Coleman, P. J.; Dias, L. C.; Tyler, A. N. Angew. Chem., Int.
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6828 J. Org. Chem. 2008, 73, 6828–6830
10.1021/jo800777w CCC: $40.75 2008 American Chemical Society
Published on Web 07/29/2008

TABLE 1. Chemoselective Methylenation of Dicarbonyl
Substrates
SCHEME 1. Preparation of Dicarbonyl Substrates
SCHEME 2. Preparation of Ketoaldehyde 13
carbonyl group has a similar steric environment. These substrates
are prepared by desymmetrization of diol 5, which is obtained
in three steps from 1,4-dibromobenzene via a double Heck
reaction, followed by a reduction (Scheme 1).
The functionalization of aldehyde 6 by Grignard addition,
followed by oxidation, deprotection and oxidation produced
ketoaldehydes substrates 7-9 in 47-74% overall yields.
Trifluoromethylketone 10 was further elaborated from ke-
toaldehyde 7. In addition, aldehyde 6 was derived to lead to
ketoaldehyde 11 and diketone 12. Similar chemical steps were
used to prepare ketoaldehyde 13 from aldehyde 6 (Scheme 2),
by exchange of protecting groups (see Supporting Information
for details).
a Isolated yields. b CuCl (5 mol%), 0.1
M in THF at 60 °C.
c RhCl(PPh3)3 (2.5 mol%), 0.1 M in THF at 23 °C. d Ph3PCH3Br (1.1
equiv), NaHMDS (1.1 equiv), 0.1 M in THF at 23 °C. e Eight percent
isolated yields of the diene. f Approximately 30% isolated yields of the
diene.
was formed under these reaction conditions, using either copper
chloride or Wilkinson’s catalyst. The more expensive rhodium
catalyst gave yields slightly higher than those using copper
chloride, and the reaction was run at room temperature. A good
chemoselectivity was also observed for the reaction of ketoal-
dehydes 7 and 8 with methylenetriphenylphosphorane generated
by deprotonation of methyltriphenylphosphonium bromide to
produce monoalkene 14 and 15 in 77% and 62% yields,
respectively (entries 1 and 2). However, in the case of substrates
containing an activated ketone, such as an aromatic ketone or
an alkoxymethylketone, such reaction conditions led to a
substantial amount of the corresponding diene. Conversely, only
With these substrates in hand, both the copper- and the
rhodium-catalyzed methylenation reactions were tested and
compared to the reaction with methylenetriphenylphosphorane
generated by deprotonation of methyltriphenylphosphonium
bromide (Table 1).
In all cases, a high chemoselectivity was observed for the
transition-metal-catalyzed methylenation reactions, as no diene
J. Org. Chem. Vol. 73, No. 17, 2008 6829

a solution of trimethylsilyldiazomethane in THF (0.82 mL, 1.40
mmol). Gas evolution was observed, and the resulting dark orange
mixture was stirred at room temperature. After 2 h, the solvent
was removed under reduced pressure, and the residue was purified
by flash chromatography on silica gel.
Catalytic Methylenation using CuCl as Catalyst. To a solution
of CuCl (5 mg, 0.05 mmol) and triphenylphosphine (288 mg, 1.10
mmol) in THF (10 mL (0.1 M)) at 25 °C, was added 2-propanol
(84 µL, 1.1 mmol) followed by the aldehyde (1.00 mmol) and the
trimethylsilyldiazomethane ether solution (0.82 mL, 1.40 mmol).
The resulting mixture was then heated at 60 °C and stirred until
the reaction showed completion by TLC analysis. Aqueous 3%
H2O2 (10 mL) was added, and the organic layer was washed with
ether (3 × 20 mL). The combined organic layers were washed with
brine (2 × 20 mL) and then dried over MgSO4. The solvent was
removed under reduced pressure, and the crude alkene was purified
by flash chromatography on silica gel.
the monoalkene product was isolated when the methylenetriph-
enylphosphorane was generated from trimethylsilyldiazomethane
and triphenylphosphine. Methylenation reactions catalyzed by
copper chloride produced monoalkene 16-18 in 58-72%
yields, whereas 74-83% isolated yields were obtained with
Wilkinson’s catalyst (entries 3-5). In the case of diketone
substrates containing an activated ketone, such as an alkoxym-
ethylketone or a trifluoromethylketone, all reaction conditions
provided exclusively the monoalkene product (entries 6 and 7).
The difference in the chemoselectivity of methylenetriph-
enylphosphorane generated from the transition metal decom-
position of trimethylsilyldiazomethane versus the deprotonation
of methyltriphenylphosphonium bromide is quite intriguing. In
both cases the same ylide reagent has been identified as the
reactive species, suggesting that the difference in reactivity is
due to byproduct formed during the generation of the ylide.
The only byproduct obtained when the methylenetriphenylphos-
phorane is generated from trimethylsilyldiazomethane, triph-
enylphosphine, and 2-propanol is the highly volatile and inert
2-propyloxytrimethylsilane. In contrast, the deprotonation of
methyltriphenylphosphonium bromide provides a bromide salt
as byproduct, which can play a role as a Lewis acid catalyst. It
has been previously shown that lithium salts can have a
pronounced effect on E:Z ratio in Wittig olefination, whereas
sodium and potassium salts had little effect.8 However, in the
cases of chemoselective methylenation reactions, it appears that
not only are soluble lithium salts able to activate the more basic
carbonyl moiety (presumably by Lewis acid type activation),
but sodium and potassium salts can also alter chemoselectivi-
ties.9 This is in contrast to the chemoselectivity afforded by
completely salt-free methods of producing methylenetriph-
enylphosphorane.
1-(Benzyloxy)-4-(4-(but-3-enyl)phenyl)butan-2-one (17). The
title compound was prepared from 3-(4-(4-(benzyloxy)-3-oxobu-
tyl)phenyl)propanal (11) (120 mg, 0.39 mmol) according to the
general procedure using CuCl as catalyst (reaction time 16 h). The
desired alkene 17 (86 mg, 72%) was obtained as a colorless oil
after flash chromatography (2% EtOAc/hexanes). Rf 0.35 (10%
EtOAc/hexanes). IR (neat) 2925, 2856, 1723, 1437, 1102, 913 cm-1
.
1H NMR (400 MHz, CDCl3) δ 7.37-7.30 (m, 5H), 7.09 (s, 4H),
5.85 (ddt, J ) 17, 10, 7 Hz, 1H), 5.03 (d, J ) 17 Hz, 1H), 4.97 (d,
J ) 10 Hz, 1H), 4.55 (s, 2H), 4.02 (s, 2H), 2.90-2.86 (m, 2H),
2.80-2.76 (m, 2H), 2.69-2.65 (m, 2H), 2.37-2.32 (m, 2H). 13C
NMR (75 MHz, CDCl3) δ 208.0, 139.6, 138.1, 138.0, 137.0, 128.5,
128.4, 128.2, 127.9, 127.8, 114.8, 75.1, 73.3, 40.6, 35.4, 34.8, 28.8.
HRMS (CI) calcd for C21H24NaO2 [M + Na]+ 331.1668, found
331.1679.
4-(4-(But-3-enyl)phenyl)-1-(tert-butyldimethylsilyloxy)-
butan-2-one (18). The title compound was prepared from 3-(4-
(4-(tert-butyldimethylsilyl)-3-oxobutyl)phenyl)propanal (13) (103
mg, 0.21 mmol) according to the general procedure using Wilkin-
son’s catalyst (reaction time 2 h). The desired alkene 18 (80 mg,
78%) was obtained as a colorless oil after flash chromatography
(2% EtOAc/hexanes). Rf 0.40 (10% EtOAc/hexanes). IR (neat)
2929, 2856, 1718, 1252, 1154, 1101, 845, 777 cm-1. 1H NMR (300
MHz, CDCl3) δ 7.11 (s, 4H), 5.86 (ddt, J ) 17, 10, 7 Hz, 1H),
5.04 (d, J ) 17 Hz, 1H), 4.98 (d, J ) 10 Hz, 1H), 4.14 (s, 2H),
2.92-2.78 (m, 4H), 2.70-2.65 (m, 2H), 2.39-2.32 (m, 2H), 0.91
(s, 9H), 0.07 (s, 6H). 13C NMR (75 MHz, CDCl3) δ 210.2, 139.5,
138.3, 138.1, 128.4, 128.2, 114.8, 69.4, 39.8, 35.5, 34.9, 28.8, 25.7,
18.2, -5.5. HRMS (CI) calcd for C19H31O3Si [M + H]+ 357.1856,
found 357.1854.
In conclusion, this systematic study illustrates the power of
copper- and rhodium-catalyzed methylenation with trimethyl-
silyldiazomethane, triphenylphosphine, and 2-propanol in
chemoselective reactions with dicarbonyl substrates. Although
methylenetriphenylphosphorane is the active reagent in this
process (as in the Wittig reaction through deprotonation of
methyltriphenylphosphonium bromide), the absence of salts
profoundly affected the chemical behavior of this reagent and
thus led to highly chemoselective reactions with a variety of
dicarbonyl substrates.
Experimental Section
Acknowledgment. This research was supported by NSERC
(Canada), the Canada Foundation for Innovation, Boehringer
Ingelheim (Canada) Lte´e, Merck Frosst Canada and the Uni-
versite´ de Montre´al.
Catalytic Methylenation using Wilkinson’s Catalyst. To a
solution of chlorotris(triphenylphosphine)rhodium (23 mg, 0.025
mmol) and triphenylphosphine (288 mg, 1.10 mmol) in THF (10
mL) was added 2-propanol (75.0 µL, 1.00 mmol) followed by the
aldehyde (1.00 mmol). To the resulting red mixture was then added
Supporting Information Available: Experimental proce-
dures and characterization data and spectra (1H and 13C NMR)
for new compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
(8) Reitz, A. B.; Nortey, S. O.; Jordan, A. D., Jr.; Mutter, M. S.; Maryanoff,
B. E. J. Org. Chem. 1986, 51, 3302–3308.
(9) See Table S1 in Supporting Information for the methylenation reaction
of ketoaldehyde 11 using various bases to generate the phosphorous ylide from
methyltriphenylphosphonium bromide.
JO800777W
6830 J. Org. Chem. Vol. 73, No. 17, 2008