Deacylative allylation of nitroalkanes: Unsymmetric bisallylation by a three-component coupling

Article abstract of DOI:10.1002/anie.201006273

Use it and lose it! Allylic alcohols were used directly for the synthesis of diallylated nitroalkanes in a three-component coupling based on the strategy of deacylative allylation for the in situ generation of a nucleophile and an allyl electrophile (see

Full text of DOI:10.1002/anie.201006273

Communications
DOI: 10.1002/anie.201006273
Synthetic Methods
Deacylative Allylation of Nitroalkanes: Unsymmetric Bisallylation by a
Three-Component Coupling**
Alexander J. Grenning and Jon A. Tunge*
Catalytic Tsuji–Trost allylation has become a ubiquitous
method for the allylation of active methylene compounds.[1]
Although monoallylation products are typically formed, the
bisallylation of malonates and related ketone enolates leads
to 1,6-dienes.[2] Given the utility of these 1,6-heptadienes in
metal-catalyzed cycloisomerization reactions,[3] it would be
beneficial if less stabilized carbon nucleophiles could be
bisallylated in a controlled manner. Unfortunately, the one-
pot bisallylation of other carbon nucleophiles is not well
documented and usually requires harsh reaction conditions.[4]
Moreover, the addition of two different allyl electrophiles to
form unsymmetrical 1,6-dienes in a one-pot operation is
exceedingly rare.[5] Herein, we describe the development of
an unsymmetric bisallylation of carbon nucleophiles and
introduce catalytic deacylative allylation as a new strategy for
the tandem in situ generation and coupling of nucleophiles
with allyl electrophiles [Eq. (1); EWG = electron-withdraw-
ing group].[1]
atives.[9,10] Indeed, Tsuji–Trost reactions proceeded with
deacylation in the presence of methanol and a base to
selectively afford the monoallylated nitroalkanes [Eq. (2)].
Similar treatment of cyclic nitroketones provided clean
monoallylated products containing
a
pendent ester
[Eq. (3)]. Thus, the clean one-pot monoallylation of nitro-
alkanes is possible by a deacylative Tsuji–Trost reaction.[8,11]
As in most other deacylative (retro-Claisen) reactions,[12]
in our monoallylation reactions the acyl group is simply used
as an activating group that can be readily removed. However,
we hypothesized that an allylic alcohol could deacylate the
intermediate a-nitroketone to simultaneously generate a
nitronate anion and an allylic acetate electrophile [Eq. (1)].
Such a process would enable a selective three-component
bisallylation with nitroacetones, an allylic acetate or carbon-
ate, and an allylic alcohol (Scheme 1). Because allylic alcohols
are relatively nonreactive toward palladium catalysts, the
nitroacetone was expected to undergo rapid, selective Tsuji–
Trost allylation with the allylic acetate. The resulting nitro-
ketone would be able to undergo further allylation only
through a deacylative allylation process. Ultimately, it was
We began our pursuit of a three-component catalytic
bisallylation reaction with the investigation of the deacylative
allylation of nitroalkanes. The palladium-catalyzed allylation
of nitroalkanes is a well-known, albeit nontrivial, process.[6,7]
For example, as the monoallylation of nitromethane and
primary nitroalkanes is complicated by competing bisallyla-
tion, excess nitroalkane is often required for successful
monoallylation.[6] It was expected that we could take advant-
age of the ease of Tsuji–Trost allylation of highly stabilized
nitroacetone nucleophiles to form allylated nitroketones
[Eq. (2); Boc = tert-butoxycarbonyl].[8] Ballini and co-work-
ers, and others, have shown that simple nitroalkanes can be
generated by the deacylation of related nitroacetone deriv-
[*] A. J. Grenning, J. A. Tunge
Department of Chemistry, University of Kansas
1251 Wescoe Hall Drive, Lawrence, KS 66045-7582 (USA)
Fax: (+1)785-864-5396
E-mail: tunge@ku.edu
Homepage: http://www.tunge.ku.edu
[**] This research was supported by the National Institute of General
Medical Sciences (NIGMS 1R01M079644).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201006273.
Scheme 1. Proposed bisallylation through deacylative allylation.
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anticipated that these kinetically distinct steps could be
combined to afford a three-component unsymmetric bisallyl-
ation reaction.
rise to a complex mixture of allylated products. Thus,
deacylative allylation provides a unique avenue to unsym-
metrically substituted 1,6-dienes.
The proposed coupling hinged on the hypothesis that an
allylic alcohol could deacylate an a-nitroketone to generate
an allylic acetate and a nitronate anion in situ. To begin, we
synthesized a model allylated nitroacetone by a Tsuji–Trost
allylation and examined its reactivity under a variety of
reaction conditions. We were pleased to find that
various primary allylic alcohol derivatives participated in
[Pd(PPh3)4]-catalyzed deacylative allylation when 1 equiva-
lent of the base Cs2CO3 was added (Table 1). The allylation
Since the allylic carbonate provided 2c in higher yield
than the allylic acetate [Eq. (4)], subsequent exploration of
the reaction scope focused on the coupling of allylic
carbonate derivatives (Scheme 2).[14] A comparison of 2c
(derived from allyl alcohol) and 2c’ (derived from cinnamyl
alcohol) suggests that the allylic carbonate and alcohol
partners can be reversed with little or no change in yield.
With regard to the nitroketone substrate, a-phenyl and
a-alkyl ketones were viable coupling partners. Notably, an
a substituent with a base-sensitive methyl ester moiety
survived the reaction conditions, and the functionalized
products 2i–k were formed. The fact that the methyl ester
remains intact shows that acyl substitution of nitroacetones by
Table 1: Scope of the deacylative allylation.[a]
Entry
Allylic alcohol
Product
Yield [%]
1
2a
2b
2c
87
2
79[b]
89[b]
3[c]
4
5
6
2d
2e
2b
92
79[d]
25[b]
[a] Reaction conditions: [Pd(PPh3)4] (2.5 mol%), allylic alcohol
(1.2 equiv), Cs2CO3 (1 equiv), CH2Cl2/ClCH2CH2Cl (1:1), 808C, 12 h.
[b] Linear/branched >19:1. [c] The reaction was carried out with
10 mol% of [Pd(PPh3)4]. [d] E/Z 5.6:1, linear/branched 3.8:1.
proceeded well with 2-hexenol as well as with cinnamyl
alcohol to provide the linear allylation products 2b and 2c,
respectively (Table 1, entries 2 and 3). However, the coupling
of cinnamyl alcohol required a higher palladium-catalyst
loading of 10 mol% for the reaction to proceed in high yield.
The higher catalyst concentration promotes the desired C-
allylation of the intermediate nitronate at the expense of
problematic vinylogous Hass–Bender oxidation of cinnamyl
acetate to cinnamaldehyde.[7b,13] When crotyl alcohol was the
coupling partner, a decrease in selectively for the linear over
the branched allylation product was observed (3.8:1; Table 1,
entry 5). A similar drop in regioselectivity was noted in the
decarboxylative allylation of nitroacetates with crotyl alcohol
derivatives.[7b] The deacylative allylation appears to have a
steric limitation; whereas the primary alcohol derivatives
provided the products in good to excellent yields, a secondary
allylic alcohol provided the desired product in poor yield
(Table 1, entry 6).
Having demonstrated the requisite deacylative allylation,
we turned our attention to the three-component bisallylation
of an a-nitroketone. Indeed, the treatment of a-methylni-
troacetone with an allylic carbonate (or acetate) and allyl
alcohol selectively produced the desired nitro-substituted
1,6-diene 2c in high yield [Eq. (4)]. Importantly, attempts to
synthesize the same product directly from nitroethane gave
Scheme 2. Three-component unsymmetric bisallylation. [a] [Pd(PPh3)4]
(2.5 mol%), allylic carbonate (1 equiv), allylic alcohol (1.2 equiv),
Cs2CO3 (1 equiv), CH2Cl2/DCE (1:1), 808C, overnight. [b] The reaction
was carried out with 10 mol% of [Pd(PPh3)4]. Bn=benzyl.
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Communications
allylic alcohols is more facile than acyl substitution of esters.
decarboxylative coupling. The allylation reactions in
Scheme 3 suggest that deacylative allylation may enable
similar reactions to take place in an intermolecular fashion.
Finally, ketone substrates that participate in deacylative
allylation also undergo selective three-component coupling
to form unsymmetrical heptadienes [Eq. (7)].
Lastly, the reaction of a cyclic a-nitroketone provided the
ring-opened product with a pendent carboxylic acid [Eq. (5)].
The carboxylic acid was obtained in good yield; however, it
was necessary to convert it into the methyl ester to effect
complete purification.
Whereas secondary nitroketones were required for the
bisallylation reactions described above, trisallylation of a
primary nitroketone was also possible with 2 equivalents of an
allylic carbonate and 1.3 equivalents of allyl alcohol [Eq. (6)].
Thus, deacylative allylation enabled the selective synthesis of
2m from four reactant molecules through the formation of
In closing, we have developed deacylative allylation as a
synthetic strategy for the direct use of inexpensive, readily
available allylic alcohols in electrophilic allylation reactions.
Not only does deacylative allylation enable the selective
monoallylation of nitronates, but it can also be used in tandem
with the Tsuji–Trost allylation of stabilized nitronates to
enable the controlled synthesis of unsymmetrical 1,6-dienes
through a three-component coupling. Precise control of the
kinetics of the coupling processes obviates many possible side
reactions (e.g. homoallylation, allylation of alkoxide inter-
mediates) and leads to a highly selective bisallylation. Similar
strategies are expected to facilitate the selective multicompo-
nent allylation of a wide variety of acyl pronucleophiles with
allylic alcohols.
À
three new C C bonds in 81% yield.
Besides the deacylative allylation of nitroketones, pre-
liminary studies suggest that deacylative allylation will also
enable the intermolecular allylation of activated ketones
(Scheme 3). We and others have previously developed
Experimental Section
Representative deacylative allylation procedure: In a glove box under
an argon atmosphere, [Pd(PPh3)4] (14 mg, 0.0125 mmol) and Cs2CO3
(165 mg, 0.5 mmol) were placed in a flame-dried pressure vial
equipped with a septum. Anhydrous DCE (1 mL) was added, and
the vial was sealed. The vial was removed from the glove box, a
solution of a-allyl-a-methylnitroacetone (47 mg, 0.3 mmol) and allyl
alcohol (22 mg, 0.36 mmol) in dry CH2Cl2 (500 mL) was added with a
syringe, and the vessel from which this solution was transferred was
rinsed with CH2Cl2 (2 ꢀ 250 mL) to ensure complete transfer of the
substrates to the reaction mixture. The pressure vial was then
submerged in an oil bath at 808C, and the reaction mixture was stirred
at this temperature for 12 h. The reaction vessel was then cooled to
room temperature, and the resulting solution was diluted with 15%
Et2O/pentane (ca. 5 mL) and eluted through a silica plug with excess
15% Et2O/pentane (ca. 50–75 mL). After removal of the volatiles by
rotary evaporation, column chromatography (SiO2; 2–4% Et2O/
pentane) of the crude oil yielded pure 2a (40 mg, 87%) as a colorless
oil. 1H NMR (500 MHz, CDCl3): d = 5.65–5.55 (m, 2H), 5.12
(d, J=8.9 Hz, 2H), 5.09 (d, J = 16.3 Hz, 2H), 2.67 (dd, J = 14.2,
7.3 Hz, 2H), 2.48 (dd, J = 14.2, 7.3 Hz, 2H), 1.47 ppm (s, 3H);
13C NMR (126 MHz, CDCl3): d = 128.7, 118.4, 88.3, 41.2, 19.6 ppm;
MS: m/z 109.2 [MÀNO2]+, 46.0 [NO2]+.
decarboxylative allylations of ketones which proceed through
[1c–f]
À
the formation of ketone enolates by C C bond cleavage.
Although these reactions have significant utility, their use is
somewhat hampered by the need to incorporate the electro-
phile and nucleophile in the same molecular entity prior to
Representative bisallylation procedure: In a glove box under an
argon atmosphere, [Pd(PPh3)4] (14 mg, 0.0125 mmol) and Cs2CO3
(165 mg, 0.5 mmol) were placed in a flame-dried pressure vial
equipped with a septum. Anhydrous DCE (1 mL) was added, and
the was vial sealed. The vial was removed from the glove box, a
solution of a-methylnitroacetone (58 mg, 0.5 mmol) and tert-butyl
cinnamyl carbonate (124 mg, 0.5 mmol) in dry CH2Cl2 (500 mL) was
Scheme 3. Deacylative allylation of an acetyl acetone derivative.
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Angew. Chem. Int. Ed. 2011, 50, 1688 –1691

added with a syringe, and the vessel from which this solution was
transferred was rinsed with CH2Cl2 (2 ꢀ 250 mL) to ensure complete
transfer of the substrates to the reaction mixture. Allyl alcohol
(36 mg, 0.6 mmol) was then added with a syringe, the pressure vial
was submerged in an oil bath at 808C, and the reaction mixture was
stirred overnight. The reaction vessel was then cooled to room
temperature, and the resulting solution was diluted with 15% EtOAc/
hexanes (ca. 5 mL) and eluted through a silica plug with excess 15%
EtOAc/hexanes (ca. 50–75 mL). After removal of the volatiles by
rotary evaporation, column chromatography (SiO2; 2% EtOAc/
hexanes) of the crude oil yielded pure 2c (103 mg, 89%) as a colorless
oil. 1H NMR (500 MHz, CDCl3): d = 7.28–7.22 (m, 4H), 7.19–7.15
(m, 1H), 6.41 (d, J = 15.7 Hz, 1H), 5.96 (dt, J = 15.3, 7.5 Hz, 1H), 5.63
(m, 1H), 5.14 (d, J = 9.2 Hz, 1H), 5.11 (d, J = 16.4 Hz, 1H), 2.83 (ddd,
J = 14.2, 7.3, 1.3 Hz, 1H), 2.72 (dd, J = 14.2, 7.3 Hz, 1H), 2.63 (ddd,
J = 14.2, 7.7, 1.3 Hz, 1H), 2.52 (dd, J = 14.2, 7.7 Hz, 1H), 1.51 ppm
(s, 3H); 13C NMR (126 MHz, CDCl3): d = 136.6, 135.4, 130.8, 128.6,
127.8, 126.3, 122.1, 120.7, 90.9, 43.5, 42.6, 22.1 ppm; MS: m/z 231.2
[M]+, 185.2 [MÀNO2]+, 46.0 [NO2]+.
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1
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Received: October 6, 2010
Published online: December 29, 2010
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Keywords: allylation · deacylation · 1,6-dienes ·
multicomponent reactions · nitroalkanes
.
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