Conjugate reduction of α,β-unsaturated carbonyl compounds promoted by nickel nanoparticles

Article abstract of DOI:10.1055/s-2006-951494

The system composed of nickel(II) chloride, lithium metal, a catalytic polymer-supported arene, and ethanol, has been efficiently applied to the conjugate reduction of a variety of α,β-unsaturated carbonyl compounds (ketones and carboxylic acid derivatives) under very mild reaction conditions. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-951494

LETTER
3017
Conjugate Reduction of a,b-Unsaturated Carbonyl Compounds Promoted by
Nickel Nanoparticles
C
onjugate Re
d
r
uction
o
a
f
a
,
b
-Unsa
n
turated Carbo
c
nyl Com
p
i
Departamento de Química Orgánica, Facultad de Ciencias and Instituto de Química Orgánica (ISO), Universidad de Alicante, Apdo 99,
03080 Alicante, Spain
Fax +34(965)903549; E-mail: yus@ua.es
Received 27 March 2006
Dedicated to Professor Richard Heck for his pivotal contribution to the transition-metal-catalyzed reactions
mer(cat.),13 NiCl2·2H2O/Li/DTBB(cat.),13 NiCl2/Li/
Abstract: The system composed of nickel(II) chloride, lithium
DTBB(cat.)/EtOH, or NiCl2/Li/copolymer(cat.)/EtOH,
metal, a catalytic polymer-supported arene, and ethanol, has been
efficiently applied to the conjugate reduction of a variety of a,b-un-
also generate nanosized metallic nickel14 with demon-
strated or potential applicability in organic chemistry.
Very recently, we have discovered that the introduction of
an alcohol (EtOH or i-PrOH) as a source of hydrogen in
the reducing system [i.e., NiCl2/Li/DTBB(cat.)/ROH] is a
very convenient method for the highly stereoselective cis
semi-hydrogenation of internal alkynes (Scheme 1) and
the semi-hydrogenation of terminal alkynes under mild
reaction conditions.15
saturated carbonyl compounds (ketones and carboxylic acid deriva-
tives) under very mild reaction conditions.
Key words: conjugate reduction, ketones, carboxylic acid deriva-
tives, nickel, nanoparticles
The conjugate reduction of a,b-unsaturated carbonyl
compounds is an important functional group transforma-
tion in organic synthesis.1,2 Most of the attention has been
devoted, however, to the chemoselective reduction of a,b-
unsaturated ketones.2,3 Some general methods for the par-
tial reduction of enones include electron-transfer reduc-
tion, catalytic and transfer hydrogenation, metal hydrides
or biochemical reductions.2 Among them, copper(I) hy-
dride mediated reductions have shown to be very effective
for this purpose and have been widely studied.4 Nickel-
based reducing agents, such as the complex reducing
NiCl2/Li/DTBB(cat.)/EtOH
R1
R2
R1
R2
THF, r.t.
Scheme 1
We want herein to introduce a variant of the above-men-
tioned reducing system and its application to the selective
conjugate reduction of a variety of a,b-unsaturated com-
pounds. In this case, a polymer-supported arene,12b,16 pre-
pared by radical copolymerisation of 4-vinylbiphenyl and
divinylbenzene (mixture of regioisomers),16b was utilised
as an electron carrier instead of DTBB. As a result, easier
workup was achieved, since the arene is removed by sim-
ple filtration, and cleaner reaction crudes were obtained in
all cases.
6
agent NiCRA,5 ultrasonically activated Zn–NiCl2 or
Raney nickel,7 have also found application in this trans-
formation. In a more recent study, nickel boride,8 generat-
ed in situ from NiCl2·6H2O and NaBH4 in methanol–
water, chemoselectively reduced a variety of a,b-unsatur-
ated carbonyl compounds.9 However, the large amounts
of NiCl2·6H2O used (and also of NaBH4, 1:5–1:30 sub-
strate/Ni molar ratio, i.e. 1.19 g to 7.31 g of nickel salt per The role of the different components of the reducing sys-
mmol of substrate) clearly curtail the application of this tem mentioned above is as follows: (a) nickel(II) chloride
methodology. At any rate, the 1,4-selective reduction of is the source of Ni(0) nanoparticles, (b) lithium has got a
carboxylic acid derivatives has not been developed as double role, the reduction of Ni(II) to Ni(0) and the in situ
much as that of ketones and aldehydes.8,10
generation of molecular hydrogen by reaction with etha-
nol, (c) the polymer-supported arene is used in catalytic
amounts and acts as an electron carrier from lithium to
nickel(II) chloride, and (d) ethanol is the source of hydro-
gen. One of the main advantages of this methodology is
that the handling of external molecular hydrogen is avoid-
ed since it is generated in situ in the reaction flask. In this
letter, this reducing system has been successfully applied
to the selective 1,4-reduction of a variety of unsaturated
ketones and carboxylic acid derivatives in tetrahydrofuran
at 0 °C or room temperature (Scheme 2).17,18
On the other hand, we have recently reported the fast syn-
thesis of nickel(0) nanoparticles with diameters of 2.5 1.5
nm by reduction of anhydrous nickel(II) chloride with
lithium powder and a catalytic amount of DTBB (4,4¢-di-
tert-butylbiphenyl) in tetrahydrofuran at room tempera-
ture.11 The high reactivity of these nanoparticles was dem-
onstrated in the catalytic hydrogenation of a variety of
organic compounds.12,13 Moreover, similar reduction sys-
tems to NiCl2/Li/DTBB(cat.) such as NiCl2/Li/copoly-
Concerning the reduction of acyclic a,b-unsaturated ke-
tones, chalcone was mildly reduced in very high isolated
yield (Table 1, entry 1). By adding 1.8 mmol excess of
both lithium metal and ethanol, phorone was transformed
SYNLETT 2006, No. 18, pp 3017–3020
Advanced online publication: 25.10.2006
DOI: 10.1055/s-2006-951494; Art ID: S04706ST
© Georg Thieme Verlag Stuttgart · New York
0
3
.1
1
.2
0
0
6

3018
F. Alonso et al.
LETTER
O
O
that of an enone because of the greater reactivity of the al-
dehyde functionality. At present, we are trying to optimise
the reaction conditions in order to broaden the substrate
scope of this methodology.
NiCl2/Li/copolymer(cat.)/EtOH
THF, 0 °C or r.t.
R1
R2
R1
R2
R1 = alkyl, cycloalkyl, aryl
R2 = alkyl, OEt, OH, NH2
72–98%
In conclusion, we have described a new reducing system,
based on the in situ generation of nickel(0) nanoparticles
and molecular hydrogen, which has been successfully ap-
plied to the selective conjugate reduction of a,b-unsatur-
ated ketones and carboxylic acid derivatives. Good to
excellent yields of the products were obtained under very
mild reaction conditions.
Scheme 2
into diisobutylketone as a result of the effective reduction
of the two carbon–carbon double bonds (Table 1, entry 2).
The 1,4-reduction was also selective for ketones contain-
ing an additional endocyclic carbon–carbon double bond,
either an isolated or a conjugated one. Thus, both a- and
b-ionone were reduced to the expected products in good
yields and without any double bond isomerisation
(Table 1, entries 3 and 4).
Acknowledgment
This work was generously supported by the Spanish Ministerio de
Educación y Ciencia (MEC; grant no. CTQ2004-01261) and the
Generalitat Valenciana (GV; grants no. GRUPOS03/135 and
GV05/005). I. O. thanks the Basque Country Government for a
Monocyclic and bicyclic unsaturated ketones, such as iso-
phorone and (1S)-verbenone, respectively, were also re- postdoctoral fellowship.
duced in high isolated yields at room temperature and in
shorter reaction times in comparison with the acyclic ke-
tones (Table 1, entries 5 and 6). The exocyclic conjugated
References and Notes
(1) For a monograph, see: Hudlický, M. Reductions in Organic
carbon–carbon double bond of (R)-(+)-pulegone, even
though tetrasubstituted, was reduced with a high yield to
give a cis/trans (75:25) diastereomeric mixture of (+)-iso-
menthone and (–)-menthone, respectively (Table 1, entry
7). More challenging was the reduction of (R)-(–)-car-
vone, which contains a conjugated trisubstituted carbon–
carbon double and an isolated methylidene group
(Table 1, entry 8). In this case, the reduction showed to be
regioselective, the conjugate reduction being more
favoured furnishing a cis/trans (83:17) diastereomeric
mixture of (+)-isodihydrocarvone and (+)-dihydrocar-
vone, respectively, in 82% yield. Nonetheless, in this case
a 18% yield of the overreduced ketone p-menthan-2-one
was observed.
Chemistry, 2nd ed.; ACS: Washington D.C., 1996.
(2) Keinan, E.; Greespoon, N. In Comprehensive Organic
Synthesis, Vol. 8; Trost, B. M.; Fleming, I., Eds.; Pergamon
Press: Oxford, 1991, Chap 3.5.
(3) (a) Hudlický, M. Reductions in Organic Chemistry, 2nd ed.;
ACS: Washington D.C., 1996, 138. (b) Hudlický, M.
Reductions in Organic Chemistry, 2nd ed.; ACS:
Washington D.C., 1996, 164. (c) For a recent example, see
for instance: Doi, T.; Fukuyama, T.; Horiguchi, J.; Okamura,
T.; Ryu, I. Synlett 2006, 721.
(4) Lipshutz, B. H. In Modern Organocopper Chemistry; Kraus,
N., Ed.; Wiley-VCH: Weinheim, 2002, Chap 5.
(5) Fort, Y.; Vanderesse, R.; Caubère, P. Tetrahedron Lett.
1986, 27, 5487.
(6) Petrier, C.; Luche, J.-L. Tetrahedron Lett. 1987, 28, 2347.
(7) (a) Barrero, A. F.; Alvarez-Manzaneda, E. J.; Chahboun, R.;
Meneses, R. Synlett 1999, 1663. (b) Wang, H.; Lian, H.;
Chen, J.; Pan, Y.; Shi, Y. Synth. Commun. 1999, 29, 129.
(8) Choi, J.; Yoon, N. M. Synthesis 1996, 597.
(9) (a) Khurana, J. M.; Sharma, P. Bull. Chem. Soc. Jpn. 2004,
77, 549. (b) We thank the referee for suggesting us to stress
the nickel boride methodology.
(10) (a) Hudlický, M. Reductions in Organic Chemistry, 2nd ed.;
ACS: Washington D.C., 1996, 217. (b) Hudlický, M.
Reductions in Organic Chemistry, 2nd ed.; ACS:
Washington D.C., 1996, 241. (c) For a recent example on
the conjugate reduction of a,b-unsaturated nitriles, see: Kim,
D.; Park, B.-M.; Yun, J. Chem. Commun. 2005, 1755.
(11) Alonso, F.; Calvino, J. J.; Osante, I.; Yus, M. Chem. Lett.
2005, 34, 1262.
(12) (a) Alonso, F.; Yus, M. Adv. Synth. Catal. 2001, 343, 188.
(b) Alonso, F.; Candela, P.; Gómez, C.; Yus, M. Adv. Synth.
Catal. 2003, 345, 275.
(13) Alonso, F.; Yus, M. Chem. Soc. Rev. 2004, 33, 284.
(14) Alonso, F.; Osante, I.; Yus, M. submitted for publication.
(15) Alonso, F.; Osante, I.; Yus, M. Adv. Synth. Catal. 2006, 348,
305.
This methodology was also applied to the selective reduc-
tion of several a,b-unsaturated esters, which proceeded, in
general, faster than that of ketones. For instance, ethyl
trans-crotonate and ethyl cinnamate were reduced at room
temperature in only 1.5 hours and 3 hours, giving ethyl
butyrate and ethyl hydrocinnamate, respectively, in 98%
yield (Table 1, entries 9 and 10). Similarly, diethyl male-
ate was reduced to diethyl succinate in 5 hours and 92%
isolated yield (Table 1, entry 11).
Finally, we explored the possibility to extend this reduc-
ing system to other carboxylic acid derivatives. Both cin-
namic acid and cinnamamide were selectively reduced
under the same conditions giving high yields of hydrocin-
namic acid and hydrocinnamamide, respectively (Table 1,
entries 12 and 13). In these cases, the reactions proceeded
slower in comparison with the rest of the substrates stud-
ied in this letter.
It is noteworthy that the conjugate reduction of other a,b-
unsaturated compounds, such as aldehydes or nitriles, un-
der the conditions depicted in Scheme 1 was not so effec-
tive. Nonetheless, the conjugate reduction of the carbon–
carbon bond of a a,b-enal is inherently more difficult than
(16) (a) Gómez, C.; Ruiz, S.; Yus, M. Tetrahedron Lett. 1998, 39,
1397. (b) Gómez, C.; Ruiz, S.; Yus, M. Tetrahedron 1999,
55, 7017. (c) Candela, P.; Gómez, C.; Yus, M. Russ. J. Org.
Chem. 2004, 40, 795.
Synlett 2006, No. 18, 3017–3020 © Thieme Stuttgart · New York

LETTER
Conjugate Reduction of a,b-Unsaturated Carbonyl Compounds
3019
Table 1 Conjugate Reduction of a,b-Unsaturated Carbonyl Compounds
Entry
1
Substrate
Temp (°C)
0
Time (h)
12
Product
Yields (%)a
95b
O
O
Ph
Ph
Ph
Ph
2
3
r.t.c
0
12
12
91
O
O
72b
O
O
4
5
0
12
5
75b
92b
O
O
r.t.
O
O
O
O
6
7
r.t.
4
8
92
0
91d
O
O
O
O
8
0
16
82e,f
9
10
11
r.t.
r.t.
r.t.
1.5
3
98e
98
O
O
OEt
OEt
O
O
Ph
OEt
Ph
O
OEt
5
92
O
OEt
OEt
OEt
OEt
O
O
12
13
r.t.
r.t.
24
24
92
O
O
O
O
Ph
Ph
OH
Ph
Ph
OH
93g
NH2
NH2
a Isolated yield from the reaction crude, unless otherwise stated.
b Isolated yield after column chromatography (flash silica gel, hexane–EtOAc).
c Following the general procedure (ref.13) but using Li (42 mg, 6 mmol) and EtOH (0.23 mL, 4 mmol).
d Obtained as a cis/trans (75:25) diastereomeric mixture.
e GLC yield.
f Obtained as a cis/trans (83:17) diastereomeric mixture.
g Isolated yield after recrystallisation in Et2O.
Synlett 2006, No. 18, 3017–3020 © Thieme Stuttgart · New York

3020
F. Alonso et al.
LETTER
(17) The products 1,3-diphenylpropane-1-one, diisobutylketone,
3,3,5-trimethylcyclohexanone, (+)-dihydrocarvone, (–)-
menthone, (+)-isomenthone, ethyl butyrate, ethyl hydro-
cinnamate, ethyl succinate, and hydrocinnamic acid, were
characterised by comparison of their chromatographic and
spectral data with those of the corresponding commercially
available pure samples. Dihydro-a-ionone,19 dihydro-b-
ionone,20, dihydroverbenone,21 (+)-isodihydrocarvone,22
p-menthan-2-one,22, and hydrocinnamamide,23 were
(1 mmol). The reaction course was monitored by GC–MS
until the complete disappearance of the starting material.
The resulting mixture was filtered through a pad containing
celite (upper layer) and silica gel (lower layer) in a 3:1 ratio,
dried over anhyd Na2SO4, and the solvent was evaporated
under vacuum (15 Torr). Most of the reaction crudes did not
need any further purification, whereas in some cases
purification by column chromatography was applied (see
footnotes in Table 1).
characterised by comparison of their chromatographic and
spectral data with those described in the literature.
(19) Mori, K.; Puapoomchareon, P. Liebigs Ann. Chem. 1991,
1053.
(18) General Procedure for the Conjugate Reduction of a,b-
Unsaturated Carbonyl Compounds: Anhyd NiCl2 (130
mg, 1 mmol) was added to a suspension of Li powder (29.4
mg, 4.2 mmol) and the vinylbiphenyl–divinylbenzene
copolymer (52 mg, 0.05 mmol) in THF (2 mL) under an Ar
atmosphere. After 10 min, a black suspension was formed
indicating the generation of the nickel(0) nanoparticles. The
suspension was diluted with THF (18 mL) followed by the
addition of EtOH (0.13 mL, 2.2 mmol) and the substrate
(20) Herlem, D.; Kervagoret, J.; Yu, D.; Khuong-Huu, F.; Kende,
A. Tetrahedron 1993, 49, 607.
(21) Von Holleben, M. L. A.; Zucolotto, M.; Zini, C. A.; Oliveira,
E. R. Tetrahedron 1994, 50, 973.
(22) Savoia, D.; Tagliavini, E.; Trombini, C.; Umani-Ronchi, A.
J. Org. Chem. 1981, 46, 5344.
(23) Koltunov, K. Y.; Walspurger, S.; Sommer, J. Eur. J. Org.
Chem. 2004, 4039.
Synlett 2006, No. 18, 3017–3020 © Thieme Stuttgart · New York