Direct allylation of in situ generated aldehyde acyl anions by synergistic NHC and palladium catalysis

Article abstract of DOI:10.1002/anie.201400623

The direct regioselective allylation of in situ generated aldehyde acyl anions has been achieved by synergistic NHC and Pd catalysis. It provides an efficient access to valuable β,γ-unsaturated ketones under mild reaction conditions starting from easily accessible allylic carbonates and aldehydes without any preactivation. The synergistic catalysis method demonstrated herein adds a new dimension to the area of metal-mediated C allylation. Efficient access to β,γ-unsaturated ketones is achieved through synergistic NHC and Pd catalysis. The direct, regioselective allylation of in situ generated aldehyde acyl anions starts from easily accessible allylic carbonates and aldehydes without any preactivation and proceeds under mild reaction conditions. This synergistic catalysis method adds a new dimension to metal-mediated C allylations.

Full text of DOI:10.1002/anie.201400623

Angewandte
Chemie
DOI: 10.1002/anie.201400623
Synthetic Methods
Direct Allylation of In Situ Generated Aldehyde Acyl Anions by
Synergistic NHC and Palladium Catalysis**
Milind M. Ahire and Santosh B. Mhaske*
Abstract: The direct regioselective allylation of in situ gener-
ated aldehyde acyl anions has been achieved by synergistic
NHC and Pd catalysis. It provides an efficient access to
valuable b,g-unsaturated ketones under mild reaction condi-
tions starting from easily accessible allylic carbonates and
aldehydes without any preactivation. The synergistic catalysis
method demonstrated herein adds a new dimension to the area
of metal-mediated C allylation.
T
he development of efficient organo-metal-catalyzed syn-
thetic processes involving synergistic catalysis is much
desired. However, this task is challenging because it requires
the discovery of a perfect balance between the reactivity of
the catalysts with the substrates, the compatibility of the
catalysts, and the reaction kinetics.[1] In continuation of our
research interest in developing novel synthetic methodolo-
gies, we envisaged that such a multicatalytic system would be
highly useful for the direct allylation of in situ generated
aldehyde acyl anions. Seminal reports[2] demonstrated
organo–metal cooperative catalysis for allylation reactions,
but the functionalities that can be directly introduced to the
allylic system are still limited[3] to phenols, amines, thiols,
enolates, activated methylene groups, and benzoins.[4] To the
best of our knowledge, aldehydes have never been shown to
react directly as nucleophiles with p-allylpalladium com-
plexes under such conditions because of their electrophilic
nature.[5]
Scheme 1. Previously reported methods for the Pd-mediated allylation
of acyl anions. Cp=cyclopentadienyl.
synthesis of fine chemicals and complex structures.[5,8,10] In
view of their importance and the contemporary interest, many
methods for their synthesis have been reported recently,
starting from various other substrates.[9–11]
We envisioned (Scheme 2) that after umpolung, which is
achieved in situ by a catalytic amount of an N-heterocyclic
carbene (NHC), the aldehyde would react as a nucleophile
Pd-mediated allylations of acylzirconocene chloride,[6]
acylchromate complexes,[7] acylsilanes[5] and acylstannanes[8]
have been reported (Scheme 1), but they rely on the
preactivation of the acyl species using stoichiometric amounts
of the reagent in a separate step. Some of these reactions also
suffer from low regioselectivity,[7] requirement of heating (50–
1008C) of the reaction mixture,[5,6,8] cis/trans isomerization[7]
of the double bond, and its prototropic rearrangement to the
corresponding a,b-unsaturated ketone.[6] The development of
a straightforward, catalytic, and milder process would directly
provide an efficient access to b,g-unsaturated ketones, which
are frequently observed in natural products and biologically
active compounds.[5,8,9] They have been used also for the
Scheme 2. Proposed synergistic NHC and Pd catalysis.
with the electrophilic p-allylpalladium complex to furnish the
desired C-allylated product, the b,g-unsaturated ketone.
However, as a result of the high affinity of NHCs toward
metal catalysts, their parallel functioning is challenging to put
into practice,[1,4,12] hence very few examples that demonstrate
their compatibility were reported (Scheme 3).[4,13–16] Only
Scheidt and co-workers[15] (Scheme 3) reported an example of
NHC–Mg (Lewis acid) cooperative catalysis, which was
further explored for other transformations.[1d] Interestingly,
an example of NHC–transition metal synergistic catalysis, in
which two catalytic species synergistically work together in
[*] M. M. Ahire, Dr. S. B. Mhaske
Division of Organic Chemistry, CSIR-National Chemical Laboratory
Pune 411 008 (India)
E-mail: sb.mhaske@ncl.res.in
À
the same elemental step to form a new C C bond, particularly
[**] This work was supported by DST, CSIR-ORIGIN, CSIR-OSDD New
Delhi, and CSIR-NCL (start-up grant). M.M.A. thanks CSIR-New
Delhi for a research fellowship. NHC=N-heterocyclic carbene.
between two substrates that completely lack reactivity in the
absence of either catalyst, has not been reported to date.
Based on all the above considerations, we endeavored to
find suitable conditions for the proposed transformation
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201400623.
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Figure 1. Screening of various allyl substrates.
Hence, our initial choice, cinnamyl ethyl carbonate (1),
proved to be appropriate.
In our search for an appropriate base, we screened organic
and inorganic bases such as DBU, DABCO, TMEDA,
DMAP, DIPEA, Et3N, pyridine, 1,1,3,3-tetramethyl guani-
dine, pyrrolidine, diisopropylamine, NaHMDS, NaNH2,
NaOAc, tBuOK, K3PO4, K2CO3, Cs2CO3, and Ag2CO3, and
their combinations at different molar ratios. Though K2CO3,
TMEDA, and DABCO worked well, the substrate scope was
very limited. For example, K2CO3 provided good to moderate
yields when carbonate 1 was treated with an aromatic
aldehyde that bears electron-withdrawing groups, but there
was no reaction with an aromatic aldehyde bearing electron-
donating groups. Finally, a random selection through trial and
error resulted in 1-methylpiperazine as the optimal base. 1-
methylpiperazine worked well with all types of substrates
substituted either on the allyl carbonate or aldehyde,
plausibly because of its optimal basicity under homogenous
conditions.
Scheme 3. Early examples of NHC and metal catalyst compatibility.
EWG=electron-withdrawing group, Ms=methanesulfonyl, PHOX=2-
[2-(diphenylphosphino)phenyl]-4-isopropyl-4,5-dihydrooxazole, Tf=tri-
fluoromethanesulfonyl, Ts=toluene-p-sulfonyl, bpy=2,2’-bipyridyl.
(Scheme 2). The first attempt to validate the proof-of-
principle was the reaction of allyl carbonate 1 and aldehyde
2 using NHC precatalyst 3 and [Pd(PPh3)4] in the presence of
1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) as the base in THF
at room temperature. The reaction was vigorous and resulted
in a complex mixture of products. The desired product 4 was
obtained in 14% yield (Scheme 4).
The effect of various NHCs and their molar ratios on the
yield was also studied. Four different types of NHC precata-
lysts were screened (Figure 2). The Glorius NHC precatalyst
10[17] provided better yields with minimum side reactions
under mild reaction conditions. This result could be due to the
effective tolerance between Pd0 and NHC 10.[4]
Scheme 4. The first reaction attempted.
Encouraged by this result we began to optimize the
reaction conditions. To overcome all the drawbacks associ-
ated with the development of this synergistic catalysis and to
develop a general methodology, we undertook an extensive
screening of suitable substrates, Pd catalysts, NHCs, organic/
inorganic bases, additives, their molar ratios, the ideal
temperature, the addition sequence, reaction solvents, and
solvent combinations. Initially, we focused our attention on
the search for an appropriate allyl source and thus screened
five different allyl compounds (Figure 1). The reaction did not
work at all with cinnamyl acetate (5). Cinnamyl bromide (6)
and cinnamyl chloride (7) provided the expected product in
very poor yields. With cinnamyl phenyl carbonate (8),
a complex mixture of products along with a phenoxide-
allylated side product was formed. The leaving funcionality of
allyl substrates seems to have an important role, indicating the
need for a more reactive ethyl carbonate leaving group.
Figure 2. Assessment of various N-heterocyclic carbene precatalysts.
Pd catalysts such as [Pd(PPh3)4], [Pd(dba)2], [PdCl2-
(PPh3)2], [Pd2(dba)3], [Pd(dppf)Cl2]·CH2Cl2, Pd(OAc)2, Pd-
(OAc)2·tBuXPhos, Pd(OAc)2·BINAP, and PdCl2·tBuXPhos
were also screened. Out of these nine Pd catalysts evaluated,
[Pd(PPh3)4] was identified as the best for the present trans-
formation. The molar ratio 1:3 of Pd catalyst to NHC provides
better yields compared to the molar ratio 1:1. The effect of
various additives, such as FeCl3, LiCl, AcOH, neocuproine,
MeOH, phenol, and tBuOH was also studied. We did not
observe significant improvement in the yield with any of these
additives. The effect of the solvent was equally prominent as
that of the base. We screened various solvents, such as MeCN,
THF, 1,4-dioxane, DMF, NMP, CH2Cl2, DME, toluene,
tBuOH, and DCE, and several combinations of them (v/v).
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MeCN stood out as the most suitable solvent. All the above
parameters were tested at various molar ratios, different
addition sequences, and temperatures ranging from 08C to
608C. Decomposition of the formed product was observed at
higher temperatures.
is important to note that the careful choice of the allyl
substrate, the NHC/Pd catalyst, the base, and their molar
ratios and the solvent drastically changed the mode of
reaction from a tandem benzoin formation/a-allylation[4] to
novel aldehyde acyl anion allylation.
Optimized conditions for the developed reaction included
the addition of a solution of the aldehyde (1 equiv) and the
base 1-methylpiperazine (20 mol%) in acetonitrile to the
reaction mixture containing the allyl carbonate (2 equiv), the
NHC (10, 15 mol%), [Pd(PPh3)4] (5 mol%), and MgSO4 in
acetonitrile at 08C over a period of 10–15 minutes. The
reaction mixture was gradually allowed to warm up to room
temperature and stirring was continued until completion of
the reaction (by TLC). Purification by column chromatog-
raphy furnished the desired b,g-unsaturated ketone and the
excess of unreacted allyl carbonate could also be recovered. It
We next applied the newly developed “synergistic catal-
ysis” protocol to the synthesis of diverse b,g-unsaturated
ketones. The substrate scope of the developed method was
studied on several different allyl carbonates and aldehyde
substrates to establish the generality of the process (Table 1).
Cinnamyl ethyl carbonate (1) was treated with differently
substituted aromatic and aliphatic aldehydes to investigate
the effect of electronic factors (Table 1, entries 1–5). Elec-
tron-donating and electron-withdrawing substituents on the
aromatic aldehyde were tolerated at various positions. The
process was also compatible with an additional reactive
Table 1: Substrate scope.[a]
Entry Carbonate
1
Aldehyde
Product (t, Yield[b])
Entry Carbonate
10
Aldehyde
Product (t, Yield[b])
2[c]
11
12
3
4
13
5
6
14
15
7
8
9
16
17
[a] Reaction conditions: allyl carbonate (2 equiv), aldehyde (1 equiv), NHC 10 (15 mol%), [Pd(PPh3)4] (5 mol%), and 1-methylpiperazine (20 mol%).
[b] Yields of isolated products. [c] The reaction was quenched before it reached room temperature to avoid side reactions.
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aldehyde functionality (Table 1, entry 2). An aliphatic alde-
hyde also provided the expected product, but in low yield, and
interestingly, the a-allylated product[2b] was not observed
(Table 1, entry 5). The effect of an electron-withdrawing
substituent (Table 1, entry 6), halides (Table 1, entries 7, 16),
an alkyl substituent (Table 1, entry 8), and electron-donating
substituents (Table 1, entries 9–12) at various positions of the
aromatic ring of the allyl carbonates, as well as bicyclic
aromatic (Table 1, entry 13) and heteroaromatic (Table 1,
entry 14) ethyl carbonates were studied, and all of these
substrates reacted well.
excludes the possibility of a Pd–NHC complex being an
actual catalyst for this transformation, however, a thorough
investigation is necessary. A plausible reaction mechanism for
the synergistic catalysis protocol developed herein is depicted
in Figure 3. We believe that two catalytic cycles operate
A variety of aromatic aldehydes with electron-donating/
withdrawing, alkyl, halide, and alkyl halide substituents
(Table 1, entries 1–12, 14–17), and benzaldehyde (Table 1,
entry 13) were reacted smoothly under the developed proto-
col. Though we did not notice any particular reactivity
pattern, it appears that aromatic allyl carbonates and
aldehydes with electron-withdrawing substituents are better
substrates. In addition to the above-mentioned variations in
carbonate, we were interested in the effect of the substituent
at the alkene carbon atom of the allyl carbonate. Accordingly,
we selected two allyl carbonates (Table 1, entry 15 and 16)
with a methyl substituent on alkene carbon atom, and their
reactivity was comparable to those of the unsubstituted ones.
In all the above-mentioned cases, only aromatic allyl carbo-
nates without any substituent at the a-carbon atom to the
alkene were used, hence we next studied the reactivity of an
aliphatic allyl carbonate with a substituent at the a-carbon
atom to the alkene. Cyclohexenyl ethyl carbonate (Table 1,
entry 17) was selected for this purpose and we were delighted
to find that it reacted quite fast with p-nitrobenzaldehyde (2)
to cleanly provide the expected product in excellent yield. We
did not observe the formation of the regioisomer, the double
bond cis-isomer, a,b-unsaturated ketone, or the tandem
benzoin formation/a-allylation[4] product in any example
(Table 1) under these reaction conditions. Overall, a variety
of functional groups were tolerated on both the substrates to
furnish the corresponding b,g-unsaturated ketones in moder-
ate to excellent yields (Table 1). All the entries mentioned in
Table 1 were performed on a scale of 0.1–0.3 mmol of the
corresponding aldehydes. The robustness of the developed
protocol was also studied at a higher scale on representative
examples. The reactions in entries 1, 4, 5, and 17 were
repeated on a 10 mmol scale to obtain the products in 60%,
43%, 21%, and 92% yield, respectively, which are compa-
rable with the yields obtained at the smaller scale. The time
required for the reactions was reduced substantially at
a higher scale, indicating further scope to reduce the
amount of catalysts.
Figure 3. A plausible reaction mechanism for the developed protocol.
simultaneously, wherein one cycle involves the deprotonation
of thiazolium precatalyst 10 by the base 1-methylpiperazine to
generate NHC (A), which reacts with aldehyde B to form
a Breslow intermediate (C). The other catalytic cycle
comprises the reaction of Pd catalyst A’ with allyl carbonate
B’ to form palladium allyl complex (C’). Both active
intermediates react with each other and the catalytic cycles
À
work synergistically to form a new C C bond to provide
product D. Finally, the NHC (A) and the Pd0 species (A’) are
regenerated for further catalytic cycles.
In conclusion, we developed an efficient catalytic system
for the C allylation involving NHC and Pd0 catalysts, which
work synergistically to provide value-added b,g-unsaturated
ketones from allylic carbonates and aldehydes as readily
available starting materials. A straightforward experimental
procedure, mild reaction conditions, high regioselectivity,
high functional-group tolerance, and moderate to excellent
yields without the requirement of aldehyde preactivation are
some of the important features of this organo–metal-cata-
2
3
À
lyzed C(sp ) C(sp ) bond-forming methodology. Currently,
we are exploring its potential to develop an enantioselective
direct allylation of aldehyde acyl anions by investigating
appropriate combinations of ligands and chiral NHC or
transition-metal catalysts to access enantiomerically pure
products with variable regioselectivity.
Received: January 20, 2014
Revised: April 2, 2014
Published online: && &&, &&&&
Several control experiments were performed to inves-
tigate the mechanistic aspects of the newly developed
catalytic transformation. In the absence of either NHC or
Pd catalyst, the reaction did not work at all. Moreover, when
the NHC precatalyst, base, and Pd catalyst were stirred
together in acetonitrile for 30 minutes followed by the
addition of the substrates, the expected product was formed
with a lower yield, probably indicating that the ligation of the
in situ formed NHC with the Pd catalyst might be facile in the
absence of both substrates. This outcome perhaps also
Keywords: aldehyde umpolung · C allylation ·
.
N-heterocyclic carbenes · palladium · synergistic catalysis
[1] Recent reviews on synergistic catalysis: a) C. S. Schindler, E. N.
Jacobsen, Science 2013, 340, 1052; b) Z. Du, Z. Shao, Chem. Soc.
4
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Rev. 2013, 42, 1337; c) A. E. Allen, D. W. C. MacMillan, Chem.
Sci. 2012, 3, 633; d) D. T. Cohen, K. A. Scheidt, Chem. Sci. 2012,
3, 53; e) N. T. Patil, V. S. Shinde, B. Gajula, Org. Biomol. Chem.
2012, 10, 211; f) N. T. Patil, Angew. Chem. 2011, 123, 1797;
Angew. Chem. Int. Ed. 2011, 50, 1759; g) C. Zhong, X. Shi, Eur. J.
Org. Chem. 2010, 2999.
[9] a) B. A. Trofimov, E. Y. Schmidt, N. V. Zorina, E. V. Ivanova,
I. A. Ushakov, J. Org. Chem. 2012, 77, 6880, and references
therein; b) B. M. Trost, H. Yang, O. R. Thiel, A. J. Frontier, C. S.
Brindle, J. Am. Chem. Soc. 2007, 129, 2206.
[10] S. Kang, T.-S. Jang, G. Keum, S. B. Kang, S.-Y. Han, Y. Kim, Org.
Lett. 2000, 2, 3615, and references therein.
[2] a) S. Mukherjee, B. List, J. Am. Chem. Soc. 2007, 129, 11336; b) I.
Ibrahem, A. Cꢀrdova, Angew. Chem. 2006, 118, 1986; Angew.
Chem. Int. Ed. 2006, 45, 1952; c) B. G. Jellerichs, J.-R. Kong,
M. J. Krische, J. Am. Chem. Soc. 2003, 125, 7758.
[3] For information on known nucleophiles used in the Tsuji–Trost
allylation, see: a) B. M. Trost, M. L. Crawley, Chem. Rev. 2003,
103, 2921; b) Handbook of Organopalladium Chemistry for
Organic Synthesis, Vol. 2 (Eds.: A. de Meijere, E.-i. Negishi),
Wiley, New York, 2002, chap. V, p. 1669; c) B. M. Trost, T. R.
Verhoeven in Comprehensive Organometallic Chemistry, Vol. 8
(Eds.: G. Wilkinson, F. G. A. Stone, E. W. Abel), Pergamon,
Oxford, 1982, p. 799.
[11] Selected recent publications on the synthesis of b,g-unsaturated
ketones: a) C. L. Moody, D. S. Pugh, R. J. K. Taylor, Tetrahedron
Lett. 2011, 52, 2511; b) B. A. Trofimov, E. Y. Schmidt, I. A.
Ushakov, N. V. Zorina, E. V. Skitalꢁtseva, N. I. Protsuk, A. I.
Mikhaleva, Chem. Eur. J. 2010, 16, 8516; c) M. Zhang, H. Jiang,
P. H. Dixneuf, Adv. Synth. Catal. 2009, 351, 1488; d) S. Omura, T.
Fukuyama, J. Horiguchi, Y. Murakami, I. Ryu, J. Am. Chem. Soc.
2008, 130, 14094; e) F. Shibahara, J. F. Bower, M. J. Krische, J.
Am. Chem. Soc. 2008, 130, 14120; Refs. [9] and [10].
[12] X. Bugaut, F. Glorius, Chem. Soc. Rev. 2012, 41, 3511.
[13] T. Nemoto, T. Fukuda, Y. Hamada, Tetrahedron Lett. 2006, 47,
4365.
[4] R. Lebeuf, K. Hirano, F. Glorius, Org. Lett. 2008, 10, 4243.
[5] Y. Obora, Y. Ogawa, Y. Imai, T. Kawamura, Y. Tsuji, J. Am.
Chem. Soc. 2001, 123, 10489.
[14] Z. Chen, X. Yua, J. Wu, Chem. Commun. 2010, 46, 6356.
[15] D. E. A. Raup, B. Cardinal-David, D. Holte, K. A. Scheidt, Nat.
Chem. 2010, 2, 766.
[6] Y. Hanzawa, N. Tabuchi, T. Taguchi, Tetrahedron Lett. 1998, 39,
6249.
[7] H. Sakurai, K. Tanabe, K. Narasaka, Chem. Lett. 1999, 309.
[8] Y. Obora, M. Nakanishi, M. Tokunaga, Y. Tsuji, J. Org. Chem.
2002, 67, 5835.
[16] D. A. DiRocco, T. Rovis, J. Am. Chem. Soc. 2012, 134, 8094.
[17] I. Piel, M. D. Pawelczyk, K. Hirano, R. Frçhlich, F. Glorius, Eur.
J. Org. Chem. 2011, 5475.
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Communications
Synthetic Methods
M. M. Ahire,
S. B. Mhaske*
&&&& — &&&&
Direct Allylation of In Situ Generated
Aldehyde Acyl Anions by Synergistic NHC
and Palladium Catalysis
Efficient access to b,g-unsaturated
hydes without any preactivation and
proceeds under mild reaction conditions.
This synergistic catalysis method adds
a new dimension to metal-mediated
C allylations.
ketones is achieved through synergistic
NHC and Pd catalysis. The direct, regio-
selective allylation of in situ generated
aldehyde acyl anions starts from easily
accessible allylic carbonates and alde-
6
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Angew. Chem. Int. Ed. 2014, 53, 1 – 6
These are not the final page numbers!