A general Pd-catalyzed α- And γ-benzylation of aldehydes for the formation of quaternary centers

Article abstract of DOI:10.1039/c5ob00702j

A palladium-catalyzed benzylation of α-branched aldehydes has been developed using benzyl methyl carbonates. The method gives access to congested quaternary centers in the vicinity of one of the most sensitive carbonyl functionalities and displays unprecedented generality with respect to both coupling partners. Evidence for the direct involvement of a Pd-η³-benzyl intermediate is provided. Extension of this strategy to the γ-benzylation of α,β-unsaturated aldehydes is further demonstrated.

Full text of DOI:10.1039/c5ob00702j

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A general Pd−catalyzed − and −benzylation of
aldehydes for the formation of quaternary centers
Cite this: DOI: 10.1039/x0xx00000x
I. Franzoni,a L. Guénéeb and C. Mazet*a
A palladium-catalyzed benzylation of
methyl carbonates. The method gives access to congested quaternary centers in the vicinity of
one of the most sensitive carbonyl functionalities and displays unprecedented generality with
−branched aldehydes has been developed using benzyl
Received 00th January 2012,
Accepted 00th January 2012
DOI: 10.1039/x0xx00000x
respect to both coupling partners. Evidences for the direct involvement of a Pd-
intermediate are provided Extension of this strategy to the −benzylation of −unsaturated
aldehydes is further demonstrated.

3-benzyl
.

www.rsc.org/
though some of these approaches were very innovative, they
imposed severe restrictions in the diversity of nucleophilic
and/or electrophilic partners that could be coupled together.
Importantly, none of the existing protocols is applicable to the
coupling of both linear and branched aldehydes, with
indifferently electron-rich and electron-poor benzyl precursors.
Except from the work of List and co-workers and one isolated
example from Melchiorre and co-workers, access to quaternary
centers remains problematic and no examples using
−alkyl−alkyl aldehydes have been reported to date.10
Introduction
The alpha benzylation of aldehydes is a reaction of great
synthetic value which enables the direct construction of
C(sp3)−C(sp3) bonds and formally provides access to
homobenzylic (stereo)centers which are highly prevalent in
natural products and medicinally relevant compounds.1 The
aldehyde oxidation state constitutes a pivotal platform for
synthetic chemists which − in contrast − to other carbonyl
functionalities
limits
oxidation
state
manipulations.
Nonetheless, its exalted reactivity renders −functionalization
particularly challenging. For instance, enolate-based
approaches have not reached the same level of generality than
the −alkylation of the related ketones. In addition, over-
alkylation or O-alkylation might become competing processes
for traditional base-mediated approaches with benzyl halides.
Cannizzaro and Tishchenko disproportionations or self-aldol
condensation are also likely to occur under basic conditions.2
With the recent explosion of organocatalytic methods,
significant progress has been made in the −benzylation of
aldehydes.3 Amongst notable examples, Melchiorre, Cozzi and
Jacobsen have independently described protocols employing
linear aldehydes with stabilized benzylic carbocations.4-6
MacMillan and Melchiorre reported mechanistically distinct
photocatalytic systems for the enantioselective −benzylation
of aldehydes using strongly electron-deficient arenes and
heteroarenes.7,8 Finally, List and co-workers have identified
conditions enabling the use of benzyl bromides for the
−benzylation of −arylated aldehydes.9 All these methods
provide access to −chiral −benzylated aldehydes with often
high enantioselectivities but this is unfortunately achieved at
the expense of the generality of the reaction. Indeed, even
To address these limitations, we first considered developing
a general Pd−catalyzed benzylation of aldehydes with the
anticipation that on
a
longer-term perspective, an
enantioselective variant of this process could be conceived.
Although conceptually closely related to the well-established
Pd−catalyzed allylic alkylation of carbonyl compounds, this
approach has not reached the same levels of mechanistic
understanding and synthetic developments.11 One of the reasons
often invoked is the difficulty associated with generating the
postulated −benzyl−palladium intermediate which requires
dearomatization of the electrophilic component. Elaborating on
studies by Fiaud and co-workers, the Rawal and Trost groups
independently reported the efficient benzylation of indoles,
oxindoles and azlactones.12-14 These robust cyclic nucleophiles
were coupled using benzyl carbonates and allowed for
quaternary centers to be installed. Concomitantly, Tunge has
described the Pd-catalyzed benzylation of enamines generated
in situ from ketones and aldehydes.15 Despite the good yields
obtained, the excess of pyrrolidine and carbonyl compounds
limits the practicality of the method while the use of
coumarinyl-methyl-acetates as benzyl surrogates severely
restricts the scope of the reaction. Noticeably, high
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enantioinductions were reported in the studies by Trost and
Traces of product 3aa were detected when using 4-
Czabaniuk who relied on the well-defined geometry of the methoxybenzyl trifluoroacetate 2a-2 with concomitant
cyclic enolates generated in situ from the corresponding formation of nominal amounts of 4-methoxybenzyl isobutyrate
oxindoles and azlactones. At the outset of our investigations, 4aa and 4-methoxybenzaldehyde 5a (entry 2). Variation of the
we were cognizant of the fact that working with linear phosphine ligand or of the solvent only led to poor conversions
aldehydes would constitute a major challenge in the control of and an increase into the product of formal oxidative
the enolate geometry and hence on the development of an esterification 4aa (entries 3-7). However, when 4-
enantioselective variant of a metal-catalyzed −benzylation methoxybenzyl methyl carbonate 2a-3 was used, a significant
process. Therefore, as a first step in this direction, we decided gain in reactivity was observed and 3aa, the product of
to first develop
Pd−catalyzed benzylation of aldehydes.
a
non-asymmetric but very general −benzylation, was detected as the major component (entry 8).
Evaluation of other bases and solvents from this positive hit
We report herein the development of a Pd−catalyzed proved detrimental as catalytic activity was completely lost
benzylation of −branched alkyl/alkyl and aryl/alkyl aldehydes (entries 9-12). With the less volatile aldehyde 2-methylpentanal
using electron-rich and electron-deficient benzyl carbonates to 1b, the reaction temperature could be raised to 100 °C and the
build congested −quaternary centers. Successful extension of reaction time decreased to 4 h. Final adjustment of the
this methodology to the −benzylation of −unsaturated stoichiometry in aldehyde (2 equiv.) afforded 3ba in 69% yield
aldehydes and preliminary mechanistic data are also presented.
after purification by chromatography (entry 13-14).
Table 2 Scope of −alkyl/−alkyl aldehydesa
Results and discussion
Our initial optimizations were performed with a challenging
−alkyl/−alkyl aldehyde (2-methylbutanal 1a) and 4-
methoxybenzyl acetate 2a-1 as a precursor of the electrophilic
component. A first test conducted with Pd(OAc)2, rac-binap
and Cs2CO3 as base in DMF resulted in no reaction (Table 1,
entry 1).
Table 1 Selected optimizations
Conv.
Entry
1
2
Ligand
Base
Solv.
3 : 4 : 5
(%)a
1
1a 2a-1 rac-binap Cs2CO3
1a 2a-2 rac-binap Cs2CO3
DMF
DMF
DMF
DMF
THF
Tol.
<5
18
16
27
58
62
−
2
3 : 2 : 1
0 : 1 : 2
0 : 5 : 1
1 : 9 : 1
1 : 10 : 1
2 : 2 : 1
11 : 1 : 1
−
3
1a 2a-2 t-Bu3P b
1a 2a-2 Ph3P b
Cs2CO3
Cs2CO3
4
5
1a 2a-2 rac-binap Cs2CO3
1a 2a-2 rac-binap Cs2CO3
1a 2a-2 rac-binap Cs2CO3
1a 2a-3 rac-binap Cs2CO3
6
7
DMA 20
DMF 69(55)
8
9
1a 2a-3 rac-binap i-Pr2NEt DMF
<5
10
11
12
13
14
1a 2a-3 rac-binap NaOAc
1a 2a-3 rac-binap Cs2CO3
1a 2a-3 rac-binap Cs2CO3
1b 2a-3 rac-binap Cs2CO3
1b 2a-3 rac-binap Cs2CO3
DMF
THF
Tol.
<5
−
<5
−
a Yield of isolated pure benzylated product for reactions conducted on 0.3-0.4
mmol scales. b 80 °C. c 16 h.
<5
62(58)c
80(69) c,d 48 : 1 : −
−
DMF
DMF
41 : 1 : 3
The scope of the reaction using −alkyl/−alkyl aldehydes
was explored next (Table 2). For example, 2-methylpentanal
1a, 2-methylpentanal 1b, cyclohexane-carboxaldehyde 1c and
2-methylhexanal 1d could be coupled efficiently with electron-
a
Formation of products measured by 1H NMR with an internal standard.
b
Reactions on 0.4-0.5 mmol scales. Isolated yield in parenthesis. With 10
mol% of ligand. c 100 °C, 4 h. d 2.0 equivalents of 1b.
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neutral and various electron-rich para-, ortho- and meta-
When testing our optimized protocol for the −benzylation
substituted benzyl methyl carbonates (11 examples; 61% of −aryl/−alkyl aldehydes with 2-phenylpropanal 6a as a
average yield). In some cases, generation of the −benzylation representative substrate, it rapidly appeared that the reaction
product was accompanied by formation of the corresponding temperature could be decreased to 50 °C with a prolonged
benzaldehyde derivative, leading to a slight decrease in yield reaction time (16 h) while all other parameters were kept
upon purification. Electron-deficient benzyl methyl carbonates constant. The formation of ester and benzaldehyde derivatives
were also tolerated although the corresponding −benzylated was never observed for these cross-coupling reactions.
products were isolated in much lower yields (3bh: 32%, 3ci
:
Systematic evaluation of the electronic demand of the
30%). Remarkably, perfect site selectivity was obtained when electrophilic component indicated that aldehyde 6a is
2,6-dimethylhept-5-enal 1e was used as nucleophilic particularly well-suited for −benzylation and electron-rich,
component, affording 3ea in 45% yield and leaving the remote electron-neutral, electron-deficient and ortho-substituted benzyl
olefinic moiety unreacted.16
methyl carbonates were all tolerated (9 examples, 68% average
yield). Further variations of both coupling partners enabled all
Table 3 Scope of −aryl/−alkyl aldehydesa
possible electronic permutations between
−aryl/−alkyl aldehydes and a representative collection of
benzyl precursors (see for instance: 7ba (87%), 7cd (72%),
a variety of
6
2
7ch (80%), 7ii (79%)). Moreover, sterically demanding
substrates were also compatible with our method as aldehydes
with a secondary alkyl substituent or an ortho-substituted aryl
moiety were cross-coupled efficiently (7da (62%), 7dg (66%),
7ej (80%), 7hk (72%), 7ib (92%)). Scaling up of this robust
process to a gram scale was also demonstrated (7aa, 82%, 1.04
g).
When a particularly cumbersome substrate such as methyl
2,4,6-trimethylbenzyl carbonate 2l was employed for the
−benzylation of 6a, the reaction still proceeded and a mixture
of 3 isomeric products was obtained (7al, 35% combined
yield). Similarly, when the furanyl-benzyl methyl carbonate 2m
was subjected to the optimized reaction conditions, an
unexpected regio-isomeric compound (7am) was isolated as the
sole cross-coupling product (Fig. 1).17 Although the yields of
these reactions are not in the practical range, the nature and
distribution of products support the existence of transient
Pd−−benzyl intermediates which equilibrate prior to
nucleophilic attack and reductive elimination.
Fig. 1
Benzylation of 6a with methyl 2,4,6-trimethylbenzyl carbonate 2l (a)
and furan-2-ylmethyl methyl carbonate 2m (b).
Cationic benzyl-palladium complexes have been
spectroscopically and structurally characterized only
sporadically.18,19 Moreover, their role as competent catalytic
a Yield of isolated product for reactions conducted on a 0.3 mmol scale. b 100
°C. c 4 h. d 80 °C.
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entities has been demonstrated in only one case when experiments for the coupling of 6a with 2f using either the
Nettekoven and Hartwig secured that a 3-arylethylpalladium Pd(OAc)2)/binap combination or 10 respectively displayed
complex was a viable intermediate in the Markovnikov comparable reactivity. In the former case, 7af was isolated in
hydroamination of styrenyl derivatives.19 In the specific context 62% yield, while in the latter it was obtained in 57% yield.
of catalytic −benzylations of carbonyl compounds, Monitoring of the in situ coupling reaction by 31P NMR also
Pd−−benzyl complexes have been generally invoked but never revealed the presence of two characteristic doublets that are
truly identified as potential intermediates. To remediate to this consistent with the transient formation of 10 during catalysis
situation, we therefore carried out experiments of supporting (See ESI for details).21 Collectively, these data strongly support
organometallic chemistry at the stoichiometric and catalytic the viability of 10 as a catalytically competent intermediate in
levels. Complex
9 was obtained as an air-stable yellow powder the −benzylation of −branched aldehydes. In these
by reacting [(cod)PdCl2] with one equivalent of freshly experiments, all products were obtained in racemic form when
prepared (2-methylbenzyl)magnesium chloride at low (R)-binap was used as ligand. As anticipated, a major difficulty
temperature. Subsequent treatment of
9 with 1.0 equivalent of in rendering this Pd-catalyzed −benzylation of aldehydes
(R)-binap in dichloromethane followed by ion metathesis with enantioselective will certainly be to control the geometry of the
1.0 equivalent of AgOTf delivered a yellow solid of general enolates with in situ deprotonation of the aldehydes.
formula [(R)-(binap)Pd(2-methylbenzyl)]OTf 10 (Fig. 2). The
solution structure of 10 revealed the existence of two isomeric
species in rapid equilibrium at room temperature in CD2Cl2 but
a single species was observed in DMF-d7. Although complete
structural assignment was not possible, all spectra were
consistent with a 3-coordination of the benzyl fragment.18
Single crystals of suitable quality for an X-ray diffraction study
were obtained and a CYLview representation of 10 is disclosed
on Fig. 2.20 The salient features of this distorted square planar
palladium complex are (i) the slightly longer P(1)−Pd bond
distance compared to P(2)−Pd (2.3484 vs 2.2633 Å) and (ii) the
much shorter Pd−C(1) bond distance than Pd−C(3) (2.124 vs
2.441 Å). This trend is similar to what has been observed for
the only other structurally characterized cationic Pd-3-benzyl-
Fig. 3
catalytic conditions.
Stoichiometric and catalytic experiments with complex 10 and ex situ
complex supported by a chelating bisphosphine ligand.
Table 4 −benzylation of aldehydesa
a On a 0.3 mmol scale with 2 equiv. of aldehyde.
Interestingly, without any variation of the optimized conditions,
we found that the protocol developed for the −benzylation of
aldehydes can be directly translated to the remote
−benzylation of −substituted −unsaturated aldehydes
(Table 4). Linear aldehydes with −alkyl, −benzyl or −aryl
substituents and a cyclic aldehyde were all benzylated with
perfect site selectivity at the −position using 3,4-
dimethoxybenzyl methyl carbonate 2n (57-72% yield).
Although all linear substrates were geometrically pure,
substantial olefin isomerization was systematically noted. This
Fig. 2
Synthesis and structural characterization of [(R)-(binap)Pd-3-(2-
methylbenzyl)]OTf 10. Representative bond lengths (Å) and angles (°): P(1)-Pd =
2.3484(2), P(2)-Pd = 2.2633(2), Pd-C(1) = 2.124(7), Pd-C(2) = 2.274(7), Pd-C(3) =
2.441(7), P(1)-Pd-P(2) = 95.77(6).
To evaluate whether complex 10 could be a viable
intermediate in the −benzylation of −branched aldehydes, it
was engaged in a stoichiometric cross-coupling reaction using
6a as nucleophile (Fig. 3). The corresponding product 7af was
obtained in 84% yield. Control in situ and ex situ catalytic
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contrasts with the results of the related −arylation of
−unsaturated aldehydes recently reported from our
laboratory.22
5
(a) P. G. Cozzi, F. Benfatti and L. Zoli, Angew Chem. Int. Ed.,
2009, 48, 1313; (b) F. Benfatti, M. G. Capdevila, L. Zoli, E.
Benedetto and P. G. Cozzi, Chem. Commun., 2009, 5919; (c)
F. Benfatti, E. Benedetto, and P. G. Cozzi, Chem. Asian J.,
Conclusions
2010, 5, 2047.
6
7
8
A. R. Brown, W.-H. Kuo, and E. N. Jacobsen, J. Am. Chem.
Soc., 2010, 132, 9286.
In conclusion, we have developed a general protocol for the −
and −benzylations of branched aldehydes using benzyl methyl
carbonates to construct quaternary centers. The reaction is
tolerant to a wide variety of electronically and sterically distinct
electrophilic and nucleophilic coupling partners. We have
identified and structurally characterized a cationic 3-benzyl
palladium complex that was demonstrated to be a chemically
competent intermediate in the cross-coupling reaction. Current
studies are aimed at developing an enantioselective version of
this challenging process.
H.-W. Shih, M. N. Vander Wal, R. L. Grange and D. W. C.
MacMillan, J. Am. Chem. Soc., 2010, 132, 13600.
(a) E. Arceo, I. D. Jurberg, A. Álvarez-Fernández and P.
Melchiorre, Nat. Chem., 2013,
Bahamonde, G. Bergonzini and P. Melchiorre, Chem. Sci.,
2014, , 2438.
5, 750; (b) E. Arceo, A.
5
9
B. List, I. Čorić, O. O. Grygorenko, P. S. J. Kaib, I. Komarov,
A. Lee, M. Leutzsch, S. C. Pan, A. V. Tymtsunik, and M. Van
Gemmeren, Angew. Chem. Int. Ed., 2014, 53, 282.
10 For recent reviews on the construction of quaternary centers,
see: (a) Quaternary Stereocentres: Challenges and Solutions
for Organic Synthesis, J. Christoffers and A. Baro eds, Wiley-
Acknowledgements
This work was supported by the University of Geneva and the
Swiss National Foundation (Project PP00P2_133482). Johnson-
Matthey is gratefully acknowledged for a gift of palladium
precursors.
VCH: Weinheim, 2005; (b) K. Fuji, Chem. Rev., 1993, 93
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2037; (c) A. B. Dounay, L. E. Overman, Chem. Rev., 2003,
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Notes and references
11 (a) J. D. Weaver, A. Recio III, A. J. Grenning and J. Tunge,
Chem. Rev., 2011, 111, 1846; (b) B. M. Trost and L. C.
Czabaniuk, Angew. Chem. Int. Ed., 2014, 53, 2826.
a University of Geneva, Department of Organic Chemistry, 30 quai Ernest
Ansermet, 1211 Geneva-4, Switzerland.
b
University of Geneva, Laboratoire de Cristallographie, 24 quai Ernest
12 (a) J.-Y. Legros and J.-C. Fiaud, Tetrahedron Lett., 1992, 33
2509; (b) J.-Y. Legros, M. Toffano and J.-C. Fiaud,
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†
Electronic Supplementary Information (ESI) available: Synthetic
6
procedures and characterizations of all compounds including copies of
1H, 31P{1H}, and 13C{1H} NMR spectra. CCDC 1054603 contains the
supplementary crystallographic data for this paper (compound 10).
,
1183; (d) M. Assié, A. Meddour, J.-C. Fiaud and J.-Y. Legros,
Tetrahedron: Asymmetry, 2010, 21, 1701.
[C52H41P2Pd](CF3SO3)(CH2Cl2),
M
=
1068.18, monoclinic,
a
=
13 (a) Y. Zhu and V. H. Rawal, J. Am. Chem. Soc., 2012, 134
,
10.9070(3), b = 20.1115(5), c = 11.0941(3) Å, β = 99.508(3)°, V =
2400.12(11) Å3, T = 180K, space group P21 (no.4), Z = 2, 17699
reflections measured, 9439 unique (Rint = 0.0252), which were used in
all calculations. Final R1 = 0.0630 and wR2 = 0.1652 (all data). These
data can be obtained free of charge from The Cambridge Crystallographic
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Data
Centre
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2
3
For an excellent review, see: D. M. Hodgson and A. Charlton,
Tetrahedron, 2014, 70, 2207.
16 For examples of benzylative Heck cross-coupling reactions,
see: (a) R. F. Heck and J. P. Nolley Jr., J. Org. Chem., 1972,
37, 2320; (b) G.-Z. Wu, F. Lamaty and E.-I. Negishi, J. Org.
Chem., 1989, 54, 2507; (c) H. Narahashi, A. Yamamoto and I.
Shimizu, Chem. Lett., 2004, 33, 348; (d) Z. Yang and J. Zhou,
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
−functionalization of aldehydes, see: (a) D. W. C.
MacMillan, Nature, 2008, 455, 304; (b) A.-N. Alba, M.
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1
17 For a related observation, see; S. Zhang, X. Yu, X. Feng, Y.
Yamamoto and M. Bao, Chem. Commun., 2015, 51, 3842.
18 For structurally characterized cationic Pd-benzyl complexes,
see: (a) G. Gatti, J. A. López, C. Mealli and A. Musco, J.
4
4
R. R. Shaikh, A. Mazzanti, M. Petrini, G. Bartoli and P.
Melchiorre, Angew. Chem. Int. Ed., 2008, 47, 8707.
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(http://www.cylview.org).
21 The 2 characteristic doublets for 10 in 31P{1H} resonate at 21.3
and 33.4 ppm in DMF-d7. We believe the slight chemical shift
difference observed when monitoring the reaction is likely due
to the nature of the counter-ion (methoxide vs triflate) and
dilution effect.
22 I. Franzoni, L. Guénée and C. Mazet, Chem. Sci., 2013, 4,
2619.
6 | J. Name., 2012, 00, 1-3
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