Cobalt-catalysed addition of allylidene dipivalate to aldehydes. A formal homoaldol condensation

Article abstract of DOI:10.1002/adsc.200505212

A Co(I)-catalysed condensation of allylidene dipivalate with aldehydes to give (Z)-4-hydroxybut-1-enyl pivalates in 62 to 87% isolated yields, is reported. Reactions are run in acetonitrile at 0 or 25°C depending on the nature of the aldehyde, and exploit

Full text of DOI:10.1002/adsc.200505212

UPDATE
DOI: 10.1002/adsc.200505212
Cobalt-Catalysed Addition of Allylidene Dipivalate to
Aldehydes. A Formal Homoaldol Condensation
Marco Lombardo,* Sebastiano Licciulli, Filippo Pasi, Gaetano Angelici,
Claudio Trombini*
`
Dipartimento di Chimica “G. Ciamician”, Universita degli Studi di Bologna, via Selmi 2, 40126, Bologna, Italy
Fax: (þ39)-(0)51-209-9456; e-mail: marco.lombardo@unibo.it, claudio.trombini@unibo.it
Received: May 23, 2005; Accepted: September 9, 2005
Supporting Information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: A Co(I)-catalysed condensation of allyli-
dene dipivalate with aldehydes to give (Z)-4-hy-
droxybut-1-enyl pivalates in 62 to 87% isolated
yields, is reported. Reactions are run in acetonitrile
at 0 or 258C depending on the nature of the alde-
hyde, and exploiting the Co(II)/Zn(0) redox couple
for the preparation of the catalytic Co(I) species.
propanal or propionate homoenolate 4. There are exam-
ples where the highly susceptible aldehyde function is
protected as acetal,[3] but, more frequently, the homoe-
nolate ion is masked in the form of a heterosubstituted
allyl-metal complex 5. Significant examples are based
on allyl-titanium complexes carrying nitrogen[4] or oxy-
gen[5] substituents on the metallated allyl terminus.
Keywords: Allylidene dipivalate; catalysis; cobalt(I);
homoaldol reaction; g-hydroxy carbonyl compounds;
regioselectivity
In the frame of a research project aimed at exploiting
3-halopropenyl esters as three-carbon homologating
agents in organic synthesis,[6] we developed a catalytic
Introduction
Designing novel synthons to be efficiently applied in route to the homoaldol reaction based on the Cr(III)-
broad scope reactions is a topic in the field of molecular Mn(0) redox couple and on 3-chloropropenyl pivalate
engineering devoted to the development of alternative 6 as the precursor of the homoenolate species, that is
synthetic pathways. An example is offered by three-car- an ester-substituted allyl-chromium(III) complex 7
bon homologating agents containing a nucleophilic cen- (Scheme 2).[7] Under the reported conditions, a good
tre on carbon 3 relative to the heteroatom[1] (d3 syn- control of regioselectivity was achieved: isolated yields
thons), among which synthetic equivalents of the homo-
enolate anion 4 are important building blocks in organic
synthesis.[2] The reaction of 4 with aldehydes, the homo-
aldol reaction, opens a route to g-substituted butano-
lides 1 or butyrolactols 2 via adducts 3, according to
the disconnective approach reported in Scheme 1.
Much effort has been devoted in the last decades to
the design of organometallic d3 synthons mimicking
Scheme 1.
Scheme 2.
Adv. Synth. Catal. 2005, 347, 2015 – 2018
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2015

Marco Lombardo et al.
UPDATE
of (Z)-4-hydroxy-alk-1-enyl pivalates 8 varied in the tion of acrolein with pivalic anhydride, and played the
40–60% interval and regioisomer ratios in favour of 8 role of the precursor of the new propanal homoenolate
ranged from 72/28 to 90/10.
equivalent 10 or 11 (Scheme 3).
Here we report the development of an improved pro-
Avery simple synthetic protocol was developed: 9 and
cedure for the synthesis of adducts 8, which displayed an aldehyde are poured into a freshly prepared solution
the following features:
of anhydrous CoBr2[12] (30% with respect to the limiting
(i) it was again mechanistically based on the insertion reactant, the aldehyde) in acetonitrile, then zinc powder
of a low-valent metal to a suitable substituted allyl- is added to the solution. The addition of zinc metal im-
ic precursor, rather than on more expensive and mediately fosters the reaction cascade depicted in
critical protocols requiring the use of organolithi- Scheme 3. Temperature is the key factor to achieve a
um or organomagnesium derivatives,
complete control of regiochemistry. To this purpose,
(ii) it exploited a less environmentally toxic and dan- the overall process is run at 08C or at 20–258C, depend-
gerous metal than chromium, one of the top prior- ing on the nature of the aldehyde. More reactive aliphat-
ity pollutants according to the US Environmental ic aldehydes (runs 7–11) need cooling to 08C to undergo
Protection Agency,[8]
(iii)it required milder reaction conditions, and
regioselective nucleophilic attack from the less hindered
terminus of 11 (Table 1, runs 7–11), while complete re-
(iv) it attained better yields and virtually complete re- gioselectivity is attained at 258C using the less reactive
gioselectivity.
aromatic aldehydes (runs 1–6).
A transient Co(I) species, likely stabilised by acetoni-
trile ligands in its coordination sphere, in the presence of
9 undergoes insertion into the carbon-oxygen bond,
rather than over-reduction to inactive Co metal by ex-
Results and Discussion
En route to new synthetic equivalents 5 of the homoeno- cess of zinc metal, or dismutation to Co(0) and Co(II).
late ion, our attention was attracted on one hand by acy- The resulting intermediate 10, an allylic Co(III) com-
lals, on the other by recent studies from the groups of plex, should be reduced, on pure electrochemical
[9]
Perichon and Gosmini[10] on the generation of Co(I) grounds,[13] to the allylic Co(II) complex 11[14] by the ex-
´
species in acetonitrile, by exploiting the Co(II)/Zn(0) re- cess of Zn(0).[15] The interaction of 11 with the aldehyde
dox couple. Since Co(I) proved to oxidatively add to the takes place at the less hindered terminus of the allylic
carbon-halogen bond of aryl halides and to the carbon- moiety, giving the Co(II) adduct 12. Generation of the
acetate bond of allyl acetate,[11] we tested the reaction of easily reducible CoBr2 may take place via transmetala-
allylidene dipivalate (9) with aldehydes in the presence tion of 12 with ZnBr2, thus completing the catalytic cy-
of the redox couple Co(II)/Zn(0), and eventually we cle. Configurationally pure (Z)-4-hydroxy-alk-1-enyl
succeeded in attaining a new catalytic version of the ho- pivalates (8) are formed as the sole products.
moaldol reaction. The acylal 9 was obtained by the reac-
Scheme 3.
2016
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ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2005, 347, 2015 – 2018

Cobalt-Catalysed Addition of Allylidene Dipivalate to Aldehydes
UPDATE
Table 1. Co(II)-catalysed synthesis of (Z)-4-hydroxy-alk-1-
enyl pivalates 8 in CH3CN.
Conclusion
A simple and economic approach to (Z)-4-hydroxy-alk-
1-en-1-yl pivalates 8, interesting protected forms of ho-
moaldols, has been developed, based on the use of acylal
9 and of the redox couple Co(II)/Zn(0). Reactions are
run in acetonitrile at 0–258C and look attractive for
scaling-up studies, provided that the exothermic reac-
tion associated to the initial redox processes is properly
managed (see Experimental Section).
Further studies are in progress in order to: (i) ascertain
which factors, other than temperature, could affect re-
gioselectivity, (ii) check the effect of modified acylal
structures, for instance, by changing the ester moieties,
and (iii) acquire insight about the true structure of the
catalytically active species by suitable computational
Run RCHO
t [h] T [8C] 8, Yield [%]
1
2
3
4
5
6
7
8
9
Benzaldehyde
6
6
6
6
6
6
6
6
25
25
25
25
25
25
0
8a, 87
8b, 80
8c, 70
8d, 67
8e, 66
8f, 68
8g, 82
8h, 70
8i, 67
8j, 62
8k, 67
4-Methoxybenzaldehyde
4-Chlorobenzaldehyde
4-Methylbenzaldehyde
1-Naphthaldeyde
2-Furancarboxaldehyde
2-Methylpropanal
3-Phenylpropanal
Cyclohexanecarboxaldehyde 6
0
0
10 Octanal
11 Dodecanal
6
6
0
0
Table 1 collects a series of preliminary results, where approaches.
isolated yields of 8 lie in the 62–87% range. Products
8 can be easily hydrolysed to 5-substituted butyrolactols;
Experimental Section
indeed, stirring 8a and 8 h with 3 equivalents of K2CO3 in
9:1 methanol/water for 2 h at 258C is sufficient to
quantitatively convert the two starting materials into
cis-trans mixtures of 5-phenyltetrahydrofuran-2-ol[16]
or 5-(2-phenylethyl)-tetrahydrofuran-2-ol,[17] respec-
tively. Moreover, the (Z)-configuration of the double
bond of 8 looks promising, in terms of possible diaster-
eocontrol, for subsequent epoxidation or dihydroxyla-
tion processes. Work to this purpose is in progress.
With the aim to broaden the scope of the reaction, we
checked the reactivity of acylal 9 toward an imine, in the
presence of Co(I). An acceptable conversion (50%) was
obtained with N-benzylidene p-toluensulfonamide (13),
but a full reversal of regioselectivity in the addition of 9
to 13 was observed, affording the adduct 14 in a virtually
pure anti diasetreoselectivity (Scheme 4).
In order to unambiguously assign the anti stereorela-
tionship between the newly formed stereocentres, 14
was converted into the cyclic oxazolidine 15 (Scheme 5).
The shielding (0.8–1.0 ppm) of the internal vinylic pro-
ton of 15 caused by the spatial proximity of the phenyl
ring proved the cis substitution in 15, thus confirming
the anti stereochemistry of 14.
Allylidene Dipivalate (9)
Two drops of H2SO4 were added to a solution of pivalic anhy-
dride (90 mmol, 18.3 mL) in CH2Cl2 (100 mL). A solution of
freshly distilled acrolein (6.56 mL, 100 mmol) in CH2Cl2
(10 mL) was added drop by drop, at a rate slow enough to main-
tain the solution at room temperature. The reaction mixture
was stirred at room temperature for 6 h and filtered through
a short pad of K2CO3. The solvent was removed at reduced
pressure and the residue distilled (bp 78–808C/6 mmHg) to af-
ford 9 as a clear liquid; yield: 16.3 g (67.5 mmol, 75%).
Synthesis of (Z)-4-Hydroxyalk-1-enyl Pivalate (8);
General Procedure
Commercial CoBr2 ·2 H2O (0.076 g, 0.3 mmol) was flamed un-
der a positive argon pressure until the colour turns from purple
to bright green. Anhydrous CoBr2 was dissolved in freshly distil-
led acetonitrile (2 mL), giving a deep blue solution. To this sol-
ution, acylal 9 (0.34 mL, 1.4 mmol) and the aldehyde (1 mmol)
were added, the solution retaining the original blue colour.
The temperature was set at 0 or 258C with an ice or oil bath,
and commercial zinc powder (0.85 g, 1.3 mmol) was added.
An initial exothermic reaction was observedwhile theheteroge-
neous solution turned reddish brown. The reaction mixture was
vigorouslystirredatthesametemperaturefor6hours, quenched
with saturated aqueous NaHCO3 solution (1 mL) and salts were
removed by filtration on a short pad of Celiteꢁ. The filtered sol-
ution was dried over Na2SO4, evaporated at reduced pressure
and the residue was purified by flash-chromatography on silica
eluting with cyclohexane/ethyl acetate mixtures.
Scheme 4.
Cobalt-Catalysed Reaction of Allylidene Dipivalate
(9) with N-Benzylidene-p-toluenesulfonamide (13);
Synthesis of 1-Phenyl-1-(tosylamino)but-3-en-2-yl
Pivalate (14)
To a blue solution of CoBr2 (0.065 g, 0.3 mmol) in acetonitrile
(3 mL) prepared as previously described, were added in turn
Scheme 5.
Adv. Synth. Catal. 2005, 347, 2015 – 2018
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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2017

Marco Lombardo et al.
UPDATE
acylal 9 (0.34 mL, 1.4 mmol) and the N-benzylidene-p-tolue-
nesulfonamide (13)[18] (0.26 g, 1 mmol). The temperature was
set at 258C with an oil bath, and commercial zinc powder
(0.13 g, 2 mmol) was added with vigorous stirring. The reaction
mixture was stirred at the same temperature for 12 hours,
quenched with saturated aqueous NH4Cl solution (2 mL) and
salts are removed by filtration on a short pad of Celiteꢁ. The fil-
tered solution was extracted two times with ethyl acetate, dried
over Na2SO4 and evaporated at reduced pressure. The residue
was purified by flash-chromatography on silica eluting with cy-
clohexane/ethyl acetate 9:1 to afford aminol 14; yield: 0.2 g
(0.5 mmol, 50%).
[4] a) C. Gaul, D. Seebach, Helv. Chim. Acta 2002, 85, 963–
978; b) H. Roder, G. Helmchen, E.-M. Peters, K. Peters,
H.-G. Schnering, Angew. Chem. Int. Ed. Eng. 1984, 23,
898–899.
[5] a) S. Okamoto, X. Teng, S. Fujii, Y. Takayama, F. Sato, J.
Am. Chem. Soc. 2001, 123, 3462–3471; b) T. Hanazawa,
S. Okamoto, F. Sato, Org. Lett. 2000, 2, 2369–2371;
c) X. Teng, Y. Takayama, S. Okamoto, F. Sato, J. Am.
Chem. Soc. 1999, 121, 11916–11917.
[6] M. Lombardo, S. Licciulli, C. Trombini, Pure Appl.
Chem. 2004, 76, 657–669; M. Lombardo, K. Gianotti,
S. Licciulli, C. Trombini, Tetrahedron 2004, 60, 11725–
11732.
[7] M. Lombardo, S. Morganti, S. Licciulli, C. Trombini, Syn-
lett 2003, 43–46.
4,5-cis-2,2-Dimethyl-4-phenyl-3-tosyl-5-
vinyloxazolidine (15)
[8] Chromium is listed by the US EPA as one of 129 priority
pollutants. Chromium is considered one of the 14 most
noxious heavy metals. Chromium is also listed among
the 25 hazardous substances thought to pose the most
significant potential threat to human health. EPA, Office
of Water, Water Quality Standards Database: http://oas-
pub.epa.gov/wqsdatabase/wqsi epa criteria.rep para-
meter.
Aminol 14 (0.05 g, 0.12 mmol) was dissolved in MeOH/H2O
(1 mL, 4:1 v/v), K2CO3 (0.50 g, 0.36 mmol) was added and
the reaction mixture was stirred at room temperature over-
night. MeOH was removed at reduced pressure and the aque-
ous layer was extracted with ether. The combined organic lay-
ers were dried (Na2SO4) and evaporated under reduced pres-
sure. The crude mixture was dissolved into freshly distilled
2,2-dimethoxypropane (1 mL) and a catalytic amount of p-tol-
uenesulfonic acid was added. The reaction mixture was stirred
at room temperature overnight, filtered (Celiteꢁ) and the or-
ganic layer was evaporated under reduced pressure. Purifica-
tion by flash-chromatography on SiO2 (cyclohexane/ethyl ace-
tate, 9:1) afforded 15; yield: 0.02 g (0.06 mmol, 50%).
´
[9] S. Seka, O. Buriez, J. Perichon, Chem. Eur. J. 2003, 9,
3597–3603.
´
[10] M. Amatore, C. Gosmini, J. Perichon, Eur. J. Org. Chem.
´
2005, 989–992; C. Gosmini, J. Perichon, Org. Biomol.
Chem. 2005, 3, 216–217, and references cited therein.
´
[11] P. Gomes, C. Gosmini, J. Perichon, Synthesis 2003, 1909–
´
1915; P. Gomes, C. Gosmini, J. Perichon, Lett. Org.
Synth. 2004, 1, 105–108.
Acknowledgements
[12] Cheaper CoCl2 or Co(Ac)2 are not useful under these
conditions in acetonitrile. While reduction of CoCl2 by
means of unactivated commercial Zn(0) in acetonitrile
is very sluggish, the acetate does not undergo reduction
at all.
This work was supported by M. I. U. R. (Rome) grants (PRIN
project “Stereoselezione nella sintesi organica” and FIRB proj-
ect “Progettazione, preparazione e valutazione biologica e
farmacologica di nuove molecole organiche quali potenziali
farmaci innovativi”) and by the University of Bologna (Funds
for selected research topics).
´
´
[13] O. Buriez, E. Labbe, J. Perichon, J. Electroanal. Chem.
2003, 543, 143–151.
[14] The h3 structure was arbitrarily assigned to complexes 10
and 11 not on the basis of experimental evidence but
purely on analogy to what was proposed in ref.[11]
[15] An experiment planned to verify the possible interaction
of zinc metal with allylidene dipivalate in acetonitrile,
gave unambiguous evidence of a complete lack of reac-
tivity.
[16] Spectroscopic data are in perfect agreement to those re-
ported by X. Verdaguer, M. C. Hansen, S. C. Berk, S. L.
Buchwald, J. Org. Chem. 1997, 62, 8522–8528.
[17] Spectroscopic data are in perfect agreement to those re-
ported by J. Cossy, F. Bargiggia, S. BouzBouz, Org. Lett.
2003, 5, 459–462.
References and Notes
[1] J. C. Stowell, Chem. Rev. 1984, 84, 409–435.
[2] H. Ahlbrecht, U. Beyer, Synthesis 1999, 365–390.
[3] a) F. A. Luzzio, R. W. Fitch, J. Org. Chem. 1999, 64,
5485–5493; b) M. García-Valverde, R. Pedrosa, M. Vice-
nte, Tetrahedron: Asymmetry 1995, 6, 1787–1794; c) M.
Kawashima, T. Fujisawa, Bull. Chem. Soc. Jpn. 1988,
61, 3377–3379; d) J. Barluenga, J. R. Fernandez, C. Rub-
iers, M. Yus, J. Chem. Soc. Perkin Trans. 1 1988, 3113–
3117; e) T. Mandai, T. Moriyama, K. Tsujimoto, M. Ka-
wada, J. Otera, Tetrahedron Lett. 1986, 27, 603–606;
f) H. J. J. Loozen, J. Org. Chem. 1975, 40, 520–521.
[18] L. C. Vishwakarma, O. D. Stringer, F. A. Davis, Org.
Synth. 1988, 66, 203–210.
2018
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Adv. Synth. Catal. 2005, 347, 2015 – 2018