Fe-catalyzed regiodivergent [1,2]-shift of α-aryl aldehydes

Article abstract of DOI:10.1021/ja4068707

An Fe-catalyzed conversion of aldehydes to ketones via [1,2]-shift has been developed. This skeletal rearrangement shows a wide substrate scope and chemoselectivity profile while exhibiting an excellent [1,2]-aryl or [1,2]-alkyl shift selectivity that is easily switched by electronic effects.

Full text of DOI:10.1021/ja4068707

Communication
pubs.acs.org/JACS
Fe-Catalyzed Regiodivergent [1,2]-Shift of α‑Aryl Aldehydes
†
†
,‡
́
Alvaro Gutierrez-Bonet, Areli Flores-Gaspar, and Ruben Martin*
́
†Institute of Chemical Research of Catalonia (ICIQ), Av. Països Catalans 16, 43007 Tarragona, Spain
‡Catalan Institution for Research and Advanced Studies (ICREA), Passeig Lluïs Companys, 23, 08010, Barcelona, Spain
S
* Supporting Information
Scheme 1. Catalytic Pathways for α-Aryl Aldehydes
ABSTRACT: An Fe-catalyzed conversion of aldehydes to
ketones via [1,2]-shift has been developed. This skeletal
rearrangement shows a wide substrate scope and chemo-
selectivity profile while exhibiting an excellent [1,2]-aryl or
[1,2]-alkyl shift selectivity that is easily switched by
electronic effects.
arbonyl compounds rank among the most versatile
C
synthons in organic synthesis.1 Despite the robustness
of classical protocols for their synthesis,1 the search for
alternatives, particularly in a catalytic fashion, still represents a
formidable challenge.2 Among all available scenarios, the means
for catalytically interconverting carbonyl compounds with total
control of selectivity would be highly desirable, hence
increasing molecular complexity while following the principles
of both atom3 and step economy.4 Indeed, aldehydes are
known to undergo skeletal rearrangements en route to ketone
derivatives via [1,2]-shift.5,6 However, the need for stoichio-
metric amounts of highly reactive Brønsted5 or Lewis acids6
and the harsh reaction conditions required5b reduce the
potential application profile of these rather appealing events.7
In 2005, a remarkable contribution by Chatani showed that
GaCl3 nicely promoted the skeletal rearrangement of
aldehydes.8 Unfortunately, large amounts of GaCl3 were
required (typically 50−200 mol%), and low selectivities were
found for [1,2]-alkyl shifts.8
a
Table 1. Optimization of Reaction Conditions
The ability to prepare highly functionalized backbones
rationally, predictably, and in a catalytic fashion from a
common precursor is central in organic synthesis.9 Recently,
our research group described an intriguing ligand-controlled
selectivity in C−H functionalization reactions in which
benzocyclobutenones or styrenes were selectively prepared
from common α-aryl aldehyde precursors10 utilizing rather
electron-rich palladium complexes (Scheme 1, top pathways).11
We envisioned that orthogonal reactivity could be achieved via
[1,2]-shift using a more Lewis acidic catalyst (routes c and
d).12,13 Herein, we describe our investigations on the
regiodivergent catalytic skeletal rearrangement via [1,2]-shift
of α-aryl aldehydes using simple, abundant, and nontoxic iron
salts as catalysts (routes c and d).14 The method is
characterized by its wide scope, simplicity, and divergence in
product selectivity that can be easily switched by electronic
effects.
a
Conditions: 1a (0.5 mmol), Fe catalyst (5 mol%), solvent (2 mL),
b
ligand (if any, 5 mol%), 14 h. GC yield using dodecane as internal
standard. Isolated yield. With 4 Å MS. Conditions reported in ref 8
(50 mol% GaCl3), additionally obtaining 4aa in a 9% yield.
c
d
e
obtained when using Fe salts (5 mol%) at 80 °C. As expected,
both the counterion and the oxidation state of the iron salt
played critical roles for success, with FeBr3 providing excellent
results (entry 4).16,17 In line with known literature data
employing Lewis acids as catalysts,12 while coordinating
We initiated our investigation with 1a as the model substrate,
and the effects of several Lewis acids, solvents, and temper-
atures were systematically examined (Table 1).15 Among all
Lewis acids analyzed, we found that the best reactivity was
Received: July 5, 2013
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ja4068707 | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
a b
,
solvents gave no conversion to 4a (entries 10−12), the use of
xylene or dichloroethane (DCE) delivered the expected
product (entries 8 and 9). Similarly, the inclusion of
nitrogen-containing ligands had a deleterious effect on
reactivity (entries 13−15). It should be noted that the ring-
expansion product 4aa via [1,2]-alkyl shift was not obtained
using FeBr3 as the catalyst (entry 4). To put these results in
perspective, we found no reaction of 1a with GaCl3 (5 mol%)
and non-negligible amounts of 4aa under Chatani’s conditions
(50 mol% GaCl3, entry 16).8 We believe these results nicely
illustrate the excellent reactivity and selectivity of this new Fe-
catalyzed protocol.18
Table 3. Fe-Catalyzed [1,2]-Alkyl Shift
Encouraged by these findings, we turned our attention to
explore the preparative scope of this reaction (Table 2). As
a b
,
Table 2. Fe-Catalyzed [1,2]-Aryl Shift
a
b
As for Table 1, entry 4 (110 °C). Isolated yields, average of at least
c
d
e
f
two independent runs. T = 50 °C. 1.0 g scale. Z = p-CF3(C6H4). T
g
= 25 °C. 5:1 regioisomeric mixture of [1,2]-Bn vs [1,2]-Et migration.
h
FeBr3 (10 mol%).
aryl (5ae−5ai, 5ak) or heteroaryl motifs (5aa−5ad, 5aj, and
5am).18,24 Interestingly, not even traces of [1,2]-aryl shift were
detected in the crude reaction mixtures. These results are in
sharp contrast with a recent Fe-catalyzed [1,2]-shift of aryl
azides that selectively transfers electron-rich aromatic motifs in
the presence of alkyl residues.25 Importantly, the preparation of
5ad could be easily scaled up without affecting the yield. As
shown for 5aa and 5ab, the [1,2]-alkyl shift operated at lower
temperatures than those used in Table 2, even room
temperature (5ae and 5ag).26 Equally interesting is the fact
that alkenes (5af) and alkynes (5ae) were easily accommodated
as well. Surprisingly, an unprotected phenol is well tolerated
(5ag) under the optimized reaction conditions. This is
particular noteworthy since hydroxyl groups usually inhibit
reactions that employ catalytic amounts of Lewis acids.12,27
Although one might have speculated that a mixture of structural
isomers would be formed, we found that secondary alkyl
residues migrated exclusively in the presence of primary alkyl
substituents (5ai−5ak). Likewise, high levels of selectivity were
achieved for substrates possessing structurally similar α-alkyl
substituents, favoring the migration of benzyl moieties (5ah).
Particularly noteworthy is the ability to undergo an elusive
[1,2]-methyl shift with α-silyloxy aldehydes (5al), even in the
presence of non-electron-rich aromatic motifs that could trigger
a [1,2]-aryl shift.7,28 These results clearly illustrate the potential
of our protocol for rigorously controlling the migratory
aptitude in [1,2]-shift events. In sharp contrast with the results
in Table 2, electron-rich and even electron-neutral aromatic
rings containing cyclic alkyl residues led to ring-expansion
products 5am and 5an. At present we believe that ring strain
release might be the driving force for such a migratory
event.29,30
a
b
As for Table 1, entry 4. Isolated yields, average of at least two
c
d
independent runs. FeBr3 (15 mol%) at T = 130 °C. T = 110 °C.
e
f
FeBr3 (10 mol%). T = 50 °C.
shown, a wide variety of α-aryl aldehydes could be employed,
affording in all cases the expected products resulting from an
exclusive [1,2]-aryl shift.18 It is worth noting that both cyclic
(4a−l) and acyclic α-alkyl substituents (4m−o) gave
comparable yields. The reaction proceeded smoothly in the
presence of aryl halides (4b−d,f−i,k−m), thus leaving ample
opportunities for further functionalization via conventional
cross-coupling reactions.2 Notably, ortho-alkyl substitution in
the aromatic motif did not hinder the reaction (4e). As
expected, the presence of an aromatic ketone does not interfere
with the formation of 4k and 4l. On the basis of these results,
we wondered whether high selectivities could be obtained with
aldehydes possessing two electronically different α-substituted
aromatic groups. Interestingly, we found a single regioisomer
for the skeletal rearrangement of 1o, in which the less electron-
rich aromatic ring was preferentially migrated (4o).19,20
We hypothesized that aryl groups that could significantly
stabilize a neighboring carbocation would cause a selectivity
switch,21 thus setting the stage for a [1,2]-alkyl shift event.22,23
As shown in Table 3, this was indeed the case, and a host of α-
aryl aldehydes could be coupled in high yields and with an
excellent [1,2]-alkyl shift selectivity when utilizing electron-rich
B
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Journal of the American Chemical Society
Communication
At present, we believe the reaction is initiated by activation of
the aldehyde through coordination of FeBr3 (I) that triggers a
Wagner−Meerwein [1,2]-shift of the α substituent en route to
II (Scheme 2, top).31 In principle, two mechanistic scenarios
effects.35 The wide scope and the selectivity profile suggest that
our protocol could be a powerful alternative en route to ketone
derivatives from available precursors without requiring
stoichiometric amounts of metal complexes. The asymmetric
version is currently under study in our laboratories.
Scheme 2. Mechanistic Proposal
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures and spectral data. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
rmartinromo@iciq.es
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank ICIQ Foundation, the European Research Council
(ERC-277883), and MICINN (CTQ2012-34054) for financial
support. Johnson Matthey, Umicore, and Nippon Chemical
Industrial are acknowledged for a gift of metal and ligand
sources. We sincerely thank MS and HPLC units at ICIQ and
Antonio de la Torre at URV for further assistance. R.M. and
A.F.-G. thank MICINN for a RyC and FPU fellowship. This
paper is dedicated to Prof. Teruaki Mukaiyama in celebration of
the 40th anniversary of the Mukaiyama aldol reaction.
are conceivable from II: [1,2]-hydride shift (III, path a)6a or
Meinwald-type rearrangement via the intermediacy of IV (path
b).32 To lend support for path b, we independently prepared 6
and studied its reactivity under our reaction conditions
(Scheme 2, bottom).15 As shown, a statistical mixture of 1a33
and 4a as well as 4aa, probably formed via [1,2]-alkyl shift, was
obtained. At present, we believe that a Meinwald-type
rearrangement through IV is highly unlikely since we did not
detect even traces of 4aa in our screening studies (Table 1).
Additionally, we did not observe a quantitative deuterium
transfer from 1ac-D1 to 5ac-D1, suggesting that the [1,2]-
hydride shift does not come exclusively from the aldehydic C−
H bond but also from other vicinal C−H bonds (V). In line
with the notion that cationic intermediates come into play, we
found that 1aj (96% ee) led to racemic 5aj (Scheme 3, top). A
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̈
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̀
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(17) FeBr3 (98% purity, Sigma Aldrich) was utilized. Identical
reactivity was found with other FeBr3 sources from Strem (99%
purity) and Alfa Aesar (98% purity). Atomic absortion spectroscopic
analysis showed that no significant traces of other transition metals
were present (ppm). The most abundant of these elements, however,
were tested in our screening, and we did not find any remarkable
catalytic behavior. See Supporting Information for details.
(18) No reaction took place in the absence of catalyst at 80, 110, or
even 150 °C.
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̈
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(19) This result is in sharp contrast with the ability of other catalytic
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G. Angew. Chem., Int. Ed. 2011, 50, 1702.
(20) It is worth noting that the use of α-aryl acid chlorides or α-aryl
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observed even traces of a migratory event.
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(26) We observed that the [1,2]-alkyl shift (Table 3) was significantly
faster than the [1,2]-aryl shift (Table 2). Such observation is in line
with the Hammond postulate that suggests a preferential carbon−
carbon bond cleavage for the most stable carbocation intermediate.
(27) Related substrates possessing a dimethylamino or a piperidine
substituent in the para position resulted in recovered starting material.
(28) The low yields of 5al−m are attributed to the decomposition
found when subjecting 1al−m to our optimized conditions.
(29) The reaction of a α-cyclopropyl or a α-cyclopentyl aryl aldehyde
led to decomposition.
D
dx.doi.org/10.1021/ja4068707 | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX