Synthesis of Substituted Benzaldehydes via a Two-Step, One-Pot Reduction/Cross-Coupling Procedure

Article abstract of DOI:10.1021/acs.orglett.9b01274

The synthesis of functionalized (benz)aldehydes, via a two-step, one-pot procedure, is presented. The method employs a stable aluminum hemiaminal as a tetrahedral intermediate, protecting a latent aldehyde, making it suitable for subsequent cross-coupling with (strong nucleophilic) organometallic reagents, leading to a variety of alkyl and aryl substituted benzaldehydes. This very fast methodology also facilitates the effective synthesis of a ¹¹C radiolabeled aldehyde. Aluminum-ate complexes enable transmetalation of alkyl fragments onto palladium and subsequent cross-coupling.

Full text of DOI:10.1021/acs.orglett.9b01274

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Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Synthesis of Substituted Benzaldehydes via a Two-Step, One-Pot
Reduction/Cross-Coupling Procedure
Dorus Heijnen,†,§ Hugo Helbert,†,‡,§ Gert Luurtsema,‡ Philip H. Elsinga,‡ and Ben L. Feringa*,†
†Stratingh Institute for Chemistry, University of Groningen, Nijenborgh 4, 9747 AG Groningen, The Netherlands
‡Department of Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center Groningen
Hanzeplein 1, 9713 GZ Groningen, The Netherlands
S
* Supporting Information
ABSTRACT: The synthesis of functionalized (benz)aldehydes, via a
two-step, one-pot procedure, is presented. The method employs a stable
aluminum hemiaminal as a tetrahedral intermediate, protecting a latent
aldehyde, making it suitable for subsequent cross-coupling with (strong
nucleophilic) organometallic reagents, leading to a variety of alkyl and
aryl substituted benzaldehydes. This very fast methodology also
facilitates the effective synthesis of a 11C radiolabeled aldehyde.
Aluminum−ate complexes enable transmetalation of alkyl fragments onto palladium and subsequent cross-coupling.
Scheme 1. One-Pot Cross-Coupling Procedures with
Weinreb Amides to Ketones6 and Aldehydes
he synthesis of small, highly functionalized molecules lies
Tat the basis of many areas of chemistry, ranging from drug
design to (hetero)cyclic materials for photovoltaics and ligands
for catalytic applications.1 Transition metal catalyzed cross-
coupling methods for derivatization of these compounds,
despite their great versatility, frequently rely on rather
expensive coupling partners with reduced reactivity requiring
higher temperatures and long reaction times. When using
highly reactive reagents, traditional protecting group strategies
are generally applied.2 Facing environmental awareness,
catalytic methods with lighter reagents that produce less
waste and of lower toxicity should be favored according to the
principles of green chemistry.3 The application of cheaper and
more reactive organometallic reagents as coupling partners in
combination with carbonyl functional groups has some
precedence, but still remains a major synthetic challenge.4
The reactive aldehyde functionality in particular is prone to
side reactions with organometallic reagents. On the other hand
it is this high reactivity with a range of reagents that make
aldehydes such privileged building blocks in organic synthesis,
and therefore alternative methodology allowing general and
facile synthesis of substituted (benz)aldehydes remains a
highly desirable goal. In order to prevent the fast 1,2-addition
of an organometallic nucleophile to the aldehyde (Scheme 1a),
or over-addition to a synthetic precursor, Weinreb amides 1
have proven themselves to be valuable precursors to aldehydes
2. By addition of an organometallic compound to 1, a stable
tetrahedral intermediate 4 (Scheme 1b) is created in situ,
which is not susceptible to further nucleophilic attack.5 We
discovered that these metal chelated intermediates, represent-
ing a protected/latent carbonyl functional group, are stable
toward organolithium cross-coupling conditions. As a con-
sequence, a method for the synthesis of cross-coupled ketones,
with organolithium reagents and bromo-substituted Weinreb
amides as the coupling partners via reaction intermediate 4,
was developed (Scheme 1b).6
Adding to the well-known transformations of Weinreb
amides, this method provides an easy approach to cross-
coupled carbonyl compounds, and we envisioned that
reduction with a (aluminum-) hydride source would yield a
hemiaminal with similar stability, facilitating a procedure for
the cross-coupling of masked aldehydes. Various Weinreb
amides are easily prepared on a multigram scale from cheap,
commercially available benzoic acids, providing a viable
Received: April 11, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b01274
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Letter
synthetic pathway for the synthesis of aldehyde building
blocks.
Scheme 2. Scope of the One-Pot Reduction/Cross-Coupling
Strategy for Substituted Benzaldehydes
a
As the reductant of the Weinreb amide, diisobutylaluminum
hydride (DIBAL-H), was chosen, initial screening with Pd-
complexes based on carbene and phosphine ligands showed
the latter to be the more reactive and selective catalyst for the
cross-coupling of aryl bromides with organolithium reagents. A
significant acceleration of the reaction was observed upon
preoxidation of the Pd-phosphine catalyst by means of
molecular oxygen, while preserving excellent conversion and
selectivity toward the desired aldehyde (Table 1). A similar
a
Table 1. Reaction Optimization
b
entry
catalyst
“H”/solvent
yield
1
2
3
4
5
6
Pd(PtBu3)2
DIBAL-H (1 equiv)/toluene
DIBAL-H (1 equiv)/toluene
DIBAL-H (1 equiv)/THF
DIBAL-H (1 equiv)/toluene
DIBAL-H (1 equiv)/toluene
Red-Al (1 equiv)/toluene
85
87
c
Pd(PtBu3)2
Pd(PtBu3)2
40
92
c
Ox. Pd(PtBu3)2
Ox. Pd(PtBu3)2
Ox. Pd(PtBu3)2
cd
,
90
e
30
a
Reaction conditions: Weinreb amide (0.3 mmol) in toluene (2 mL)
at 0 °C, hydride source added dropwise over 5 min. Catalyst added as
a 10 mg/mL solution. Phenyllithium added over 1 h by means of a
b
syringe pump. Reaction was quenched with sat. aq NH4Cl. Yield
c
determined by GC/MS analysis of the organic phase. DIBAL-H
d
added over 1 min. The organolithium reagent was added over 5 min.
Sodium bis(2-methoxyethoxy)aluminum hydride.
a
e
Reaction conditions: Weinreb amide (0.5 mmol) in toluene (2 mL)
at 0 °C, DIBAL-H added dropwise over 5 min. Pre-oxidized catalyst
(5 mol %) added as a 10 mg/mL solution. Organolithium reagent
added over 10 min by means of a syringe pump. Reaction was
quenched with sat. aq NH4Cl. Yields refer to isolated yields after
column chromatography. Lower yield due to volatile product. Yield
corrected for minor isobutylbenzaldehyde impurities. Performed on
effect was observed in our previous work and was attributed to
the in situ formation of Pd nanoparticles as the active catalyst
resulting in an increase in reactivity.7 By switching the
reductant to Red-Al, the conversion toward the aldehyde
remained quantitative, but selectivity in the subsequent
coupling reaction dropped due to competing dehalogenation
of the aryl bromide. The lithium halogen exchange that leads
to the formation of benzaldehyde is expected to be accelerated
by the chelating effect of the ether moieties in the Red-Al.8
Having the optimal conditions for the reduction/aryl cross-
coupling (fast 1 min DIBAL-H addition at 0 °C in toluene, and
Ar−Li addition at rt, Table 1, entry 5) in hand, we employed
various organolithium reagents (Scheme 2), including phenyl-
lithium, as well as (functionalized) aryllithium reagents to
provide 5, 6, and 7, respectively. The coupling of a lithiated
enol ether derivative and lithiated heterocycles that are
commercially available, or easily prepared via direct deproto-
nation, led to products 8, 9, and 10, respectively. The direct
deprotonation and coupling of ferrocene yielded aldehyde 11,
providing an easy synthetic route toward functionalized
ferrocenes, compared to current methods.9
b
c
d
1 mmol scale.
procedure. Interestingly the coupling of cyclopropyl lithium
yielded benzaldehyde 15 providing a valuable method for the
incorporation of this motif in medicinally relevant com-
pounds.10 Unfortunately, the relatively light and volatile
aldehydes showed significant loss in yield upon purification
(GC-MS conversion for those compounds are given in the
Supporting Information). The Weinreb amide used in this
transformation was also varied (Scheme 3), and the less
volatile naphthyl-analogue 16 proved to be less prone to
evaporation and was isolated in 63% yield. It was found that
meta-bromo substituted Weinreb amides were also reactive
under the standard reaction conditions and provided aldehydes
17 and 18 in good yield, the latter being obtained after a
double cross-coupling reaction starting from the 3,5-dibromo-
N-methoxy-N-methylbenzamide. Methoxy substituted alde-
hydes could also be synthesized illustrated by the preparation
of compound 19. 2,5-Dimethyl substituted Weinreb amide was
also subjected to reduction followed by a cross-coupling
reaction but afforded compound 20 in low yield. The decrease
Expanding the scope of the organolithium coupling partner
to alkyl fragments, we were able to isolate the methyl, ethyl,
and trimethylsilylmethylene substituted benzaldehydes 12, 13,
and 14 with little to no alteration to the previously optimized
B
DOI: 10.1021/acs.orglett.9b01274
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Letter
a
new PET-tracers, vital for mapping of processes and biological
targets in the human body.
Scheme 3. Variation of the Weinreb Amide
Upon further expansion of the scope to other alkyllithium
reagents, we observed the competing coupling of an isobutyl
group, originating from the DIBAL-aminal intermediate. It is
known that, for cross-coupling reactions, mixed aryl/alkyl
aluminum species selectively transmetallate the sp2 center, and
only trialkyl-aluminum species transfer the sp3 center.13 We
expected the isobutyl to derive from the aluminum−ate
complex, which is formed after addition of the alkyllithium
reagent.
Table 2 shows the selectivity toward cross-coupling of
isobutyl versus that of the added alkyl fragment. Tetrahedral
Table 2. Scrambling of Alkyl Fragments upon Alkyllithium
Addition and Cross-Coupling
a
Starting from the corresponding dibromo compounds. Cross-
coupling step performed using 3 equiv of PhLi.
in yield was anticipated to be a consequence of the lower
stability of the aluminum intermediate, induced by the
additional steric bulk from the two ortho-methyl substituents.
We have previously successfully incorporated the short-lived
11C isotope (t1/2 = 20.3 min) for Positron Emission
Tomography (PET) by means of a palladium catalyzed
cross-coupling of methyl-lithium with aryl bromides. In
expanding the scope of the organolithium cross-coupling, the
rapid formation of radiolabeled aldehydes remains a syntheti-
cally challenging, but highly desirable, goal.11 Due to the
limited amount of methods available for the preparation or
functionalization of radiolabeled aldehydes, we set out to
design a method for the incorporation of 11C in (substituted)
benzaldehydes for future PET tracer development. By
employing the above-described general reduction/cross-cou-
pling strategy, we aimed to synthesize compound
[methyl-11C]16 as a model substrate. With our previously
described method for making [11C]methyllithium from
[11C]methyl iodide by means of an in situ lithium halogen
exchange with n-BuLi, the one-pot procedure described above
yields the isolated target molecule [methyl-11C]16 in a 23%
decay corrected yield with a radiochemical purity of >99% and
a reaction time of only 4 min (Scheme 4).
a
entry
R−Li
nBuLi
nBuLi
nBuLi
iPr−Li
iPr−Li
tBu−Li
tBu−Li
temp (°C)
selectivity 21a/21b
b
1
2
3
4
5
6
7
23
0
95−60 /5−40
65/35
85/15
68/32
61/39
45
23
0
cd
,
23
0
<1/99
<1/99
cd
,
a
b
As determined by GC/MS analysis. Selectivity varied under
identical reaction conditions. Varying amounts of homocoupling
(bis-benzaldehyde) were also observed. Reversed selectivity: only
c
d
the isobutyl coupled benzaldehyde observed.
intermediate 1-th is formed upon DIBAL-H addition and is the
precursor to the anionic aluminum-ate complex 1-ate upon
alkyllithium addition. For both n-butyl- (entries 1−3) and
isopropyl-lithium (entries 4 and 5), varying selectivity for the
alkyl substituted benzaldehyde was found, regardless of
addition speed or reaction temperature. We were unable to
find reaction conditions that gave satisfactory selectivity toward
the desired product. In order to force the selectivity toward
isobutyl (originating from the DIBAL-H fragment) coupling,
the reluctant coupling partner t-BuLi was added, which indeed
showed full selectivity in the alkyl transfer toward the isobutyl
coupled benzaldehyde 21b (entries 6, 7). Similar to our
previous findings on homocoupling reactions of aryl bromides,
the lithium halogen exchange is a prominent reaction pathway,
and thus a significant amount of 4,4′-bisbenzaldehyde was
observed.
To the best of our knowledge, this is one of the few
examples of the formation of radiolabeled (substituted)
benzaldehydes. Radiolabeled aldehydes used as such or
followed by rapid transformation,12 taking advantage of its
high reactivity, could play an important role in the synthesis of
Scheme 4. Synthesis of Radiolabeled [11C]6-Methyl-2-
naphthaldehyde
In order to check for the formation of free isobutyllithium
(displacement of the alkyl fragment by n-butyllithium), a range
1
of starting materials and mixtures were subjected to H NMR
C
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Letter
analysis (Figure 1). The CH2 fragment of the isobutyl in
DIBAL-H (spectrum 1) is clearly visible at 0.44 ppm and is
Scheme 5. One-Pot Preparation of Secondary Alcohols via
DIBAL-H Reduction/Cross-Coupling Reaction
yields a substituted benzylic aluminum alkoxide that can be
further functionalized. Addition of tert-butyllithium is
hypothesized to generate 26, a similar ate complex as shown
in the previous section. Selective isobutyl transmetalation from
aluminum to palladium and consecutive cross-coupling readily
give access to industrially relevant alcohol 25, a precursor to
anti-inflammatory agent Ibuprofen, in 43% yield (Scheme 6).15
Figure 1. 1H NMR studies of DIBAL-H reduction of Weinreb amides.
Conditions: Concentration of all reagents: 0.1 mmol in 0.5 mL of Tol-
d8. Reduction and n-BuLi addition performed at 0 °C.
Scheme 6. Twofold Use of DIBAL-H in the Reduction and
Cross-Coupling of 4-Bromoacetophenone
completely consumed upon addition to the Weinreb amide
starting material (spectrum 2). The large variety of signals
between 0 and 0.4 ppm can be explained by the generation of
unequal alkyl fragments on the aluminum center, in
combination with diastereotopic protons. Upon addition of
n-butyllithium, the CH2 fragment of the linear alkyl chains
becomes apparent at −0.17 ppm (spectrum 3). A similar trend
is visible when the trialkyl-aluminum complex (doublet at 0.38,
spectrum 4) is mixed with n-butyllithium (spectrum 5) where
an upfield shift is observed that leads to a signal at −0.32 ppm.
When this mixture is added to a stirred solution of Pd-catalyst
and 1-bromonaphthalene, a similar product distribution to that
of Table 2, entry 2 between n- and isobutyl coupled
naphthalene is observed. Finally, as a control, the pure sample
of both n-butyllithium (spectrum 6) and isobutyllithium
(spectrum 7) provided the reference for the hypothesis that
no observable free alkyllithium is present in sample 3 and 5.
This, together with literature precedence, supports the
hypothesis of the unselective alkyl transmetalation from
aluminum to palladium.14
The reduction/cross-coupling strategy could be further
expanded from Weinreb amides to ketones. Ketones such as
acetophenones are easily prepared via Friedel−Craft acetyla-
tion and make up an important class of chemical intermediates.
In a two-step procedure, the acidic proton of the benzylic
alcohol would consume a stoichiometric amount of organo-
lithium reagent. It is therefore determined that this group is
suitably protected as a metal alkoxide (for example an
aluminum alkoxide), which is conveniently formed upon
reduction of the carbonyl by means of DIBAL-H. The transfer
of the hydride leads to an aluminum alkoxide, suitable for
subsequent cross-coupling with an organolithium reagent.
Secondary alcohols 22, 23, and 24 were obtained following this
strategy, providing a viable route toward both cyclic and linear
structures (Scheme 5).
In conclusion, we have shown that the DIBAL-H reduction
of Weinreb amides yields a masked aldehyde in the form of a
stable aluminum aminal intermediate, providing a platform for
subsequent functionalization with nucleophilic cross-coupling
partners. The method not only provides an alternative route to
aldehydes but also is applicable to ketones, yielding secondary
alcohols, as showcased by the twofold use (reducing agent and
alkyl transfer agent) of DIBAL-H in the synthesis of an
1
Ibuprofen precursor. H NMR studies show the formation of
an aluminum−ate complex upon addition of primary and
secondary alkyllithium reagents, which is hypothesized to
transfer an alkyl fragment on to palladium, followed by cross-
coupling. These aluminum aminal intermediates might provide
attractive opportunities in other multistep one-pot procedures.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b01274.
General, experimental procedures, and characterization
of compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
■
The isobutyl transfer observed in previous examples led us
to attempt the twofold use of DIBAL-H in the reaction with 4-
bromoacetophenone. Reduction of the acetophenone moiety
*E-mail: b.l.feringa@rug.nl.
D
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ORCID
Letter
́
Placzek, M. S.; Hooker, J. M.; Gee, A. D.; Dolle, F.; Wilson, A. A.;
Vasdev, N. Chem. Soc. Rev. 2016, 45, 4708−4726.
Ben L. Feringa: 0000-0003-0588-8435
Author Contributions
§D.H. and H.H. contributed equally.
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported financially by the European Research
Council (Advanced Investigator Grant, No. 227897 to B.L.F.);
The Netherlands Organization for Scientific Research
(NWO−CW); funding from the Ministry of Education,
Culture, and Science (Gravitation program 024.001.035);
The Royal Netherlands Academy of Arts and Sciences
(KNAW); and NRSC-Catalysis, which are gratefully acknowl-
edged.
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