Concerning the mechanism of the FeCl3-catalyzed α-oxyamination of aldehydes: Evidence for a non-SOMO activation pathway

Article abstract of DOI:10.1021/ja1043006

The mechanism of a recently reported aldehyde α-oxyamination reaction has been studied using a combination of kinetic, spectrometric, and spectrophotometric techniques. Most crucially, the use of a validated cyclopropane-based radical-clock substrate has demonstrated that carbon-oxygen bond formation occurs predominantly through an enamine activation manifold. The mechanistic details reported herein indicate that, as has been proposed for previously studied alcohol oxidations, complexation between TEMPO and a simple metal salt leads to electrophilic ionic reactivity.

Full text of DOI:10.1021/ja1043006

Published on Web 07/07/2010
Concerning the Mechanism of the FeCl -Catalyzed r-Oxyamination of
3
Aldehydes: Evidence for a Non-SOMO Activation Pathway
Jeffrey F. Van Humbeck, Scott P. Simonovich, Robert R. Knowles, and David W. C. MacMillan*
Merck Center for Catalysis at Princeton UniVersity, Princeton, New Jersey 08544
Received May 18, 2010; E-mail: dmacmill@princeton.edu
generated. In an effort to understand this mechanistic discrepancy, we
initiated an investigation into the role of 2,2,6,6-tetramethylpiperidine-1-
oxyl (TEMPO) as a purported SOMO-phile in the R-oxyamination
catalytic cycle. Surprisingly, our findings revealed that the Sibi reaction
does not operate by a SOMO activation mechanism but instead proceeds
via a more traditional enamine catalysis pathway.
The R-oxyamination mechanism proposed by Sibi (Scheme 1)
begins with condensation of imidazolidinone catalyst 1 and an
Abstract: The mechanism of a recently reported aldehyde R-oxyam-
ination reaction has been studied using a combination of kinetic,
spectrometric, and spectrophotometric techniques. Most crucially,
the use of a validated cyclopropane-based radical-clock substrate
has demonstrated that carbon-oxygen bond formation occurs
predominantly through an enamine activation manifold. The mecha-
nistic details reported herein indicate that, as has been proposed
for previously studied alcohol oxidations, complexation between
aldehyde to generate electron-rich enamine 2. Oxidation of this
intermediate with FeCl was proposed to produce radical cation 3,
3
TEMPO and a simple metal salt leads to electrophilic ionic reactivity.
which would then combine with TEMPO to yield iminium ion 4.
Hydrolysis of such a species would liberate the observed R-oxygen-
ated product 5, while an oxygen atmosphere, assisted by catalytic
NaNO , was believed to replenish the requisite Fe(III) species.
2
Given that the capture of R-carbonyl radicals by TEMPO has been
In 2007, simultaneous publications from MacMillan and Sibi described
the progression of organocatalysis beyond closed-shell bond-forming
pathways, as each report detailed the R-functionalization of aldehydes via
1
a radical cation intermediate. Our laboratory has further developed this
known for more than a decade, this catalytic cycle appears to be more
catalysis manifold, termed singly occupied molecular orbital (SOMO)
activation, to enable a wide range of transformations, including aldehyde
4
than reasonable. Moreover, the R-oxyamination of aldehydes with
5
TEMPO has been performed recently using both photoredox catalysis
1
a
2a
2b
2c
2d
R-alkylation, enolation, vinylation, nitroalkylation, arylation,
6
and electrochemical techniques, and in both cases an identical mechanism
2e
2f
carbo-oxidation, and polyene cyclization. During the course of these
was suggested. However, a wealth of mechanistic studies pertaining to
studies, however, we have continually met with failure when attempting
7
CuCl
2
/TEMPO-catalyzed alcohol oxidations has clearly demonstrated the
3
to translate the Sibi oxidative conditions (FeCl
3
, NaNO
2
, and O
2
) to
8
capacity of TEMPO to undergo metal complexation to form the reactive
oxidant. Specifically, the recent theoretical work of Baerends has shown
catalytic bond constructions beyond the initial report. This is intriguing,
given that the key activated intermediate should be identical in each case
that CuX
pairing of CuX
2
·TEMPO can behave as an ionic electrophile via single-electron
(an imidazolidinone-derived radical cation); however, the observed reactiv-
9 10
2
and TEMPO, while Sheldon’s kinetic isotope studies
ity of these species appears related to the manner in which they are
have shown that copper-TEMPO complexes do not generate free
+
oxoammonium itself ([R
2
NdO] ). Thus, an alternative pathway for the
Scheme 1. Proposed Mechanism for FeCl3-Catalyzed Oxidation
1
0012 9 J. AM. CHEM. SOC. 2010, 132, 10012–10014
10.1021/ja1043006  2010 American Chemical Society

C O M M U N I C A T I O N S
Scheme 2. Differentiating SOMO Activation and Enamine Addition
Scheme 3. Radical-Clock Investigation of the Oxygenation Mechanism
(
i) The identity of the solvent (DMF vs THF) has a significant
effect on the relative rates of TEMPO radical trapping versus
cyclopropane isomerization. Direct comparison of [FeCp ][PF ] and
FeCl in the same solvent is complicated by two factors: FeCl delivers
only traces of product in THF, while ferrocenium species are known to
2
6
3
3
1b
13
steadily decompose in DMF to liberate Fe(III), which in turn could
activate TEMPO toward enamine addition (resulting in a net increase in
8
a formation). In the present work, we were able to qualitatively account
for the liberation of free iron in the following comparison experiment
Scheme 4). [FeCp ][PF ] and catalyst 1·HBF were aged in DMF for
(
2
6
4
various periods of time prior to the addition of TEMPO and aldehyde 6.
Since the amount of free iron should increase with the duration of
premixing, we could assume that the amount of direct enamine trapping
to generate cis product 8a should increase accordingly. Indeed, this is
exactly what was observed. However, when no aging step was employed,
there was almost no difference between the product distributions obtained
using ferrocenium in DMF and THF (15% 8a in THF, 22% 8a in DMF).
R-oxyamination reaction wherein enamine addition to an Fe(III)-bound
TEMPO species is operative must be considered (see the alternative
mechanism). With this in mind, we have undertaken several mechanistic
studies to determine whether the Sibi reaction proceeds via a SOMO
activation pathway involving a radical cation (as originally proposed) or
by direct enamine addition to an iron-TEMPO complex.
(
ii) The 2.0 M ferrocenium case involves a diminished
concentration of free TEMPO in comparison with the 2.0 M
Sibi protocol. ReactIR experiments clearly demonstrated that the
in situ concentration of free TEMPO was effectively 2.0 M for
Design Plan. We recognized that implementation of a suitable radical-
clock-containing substrate should allow the detection of a SOMO-activated
11
both the FeCl
Supporting Information).
(iii) The FeCl system acts by enamine addition rather
3 2 2 6
/NaNO /DMF and [FeCp ][PF ]/THF cases (see the
pathway (Scheme 2). The cis-cyclopropane-substituted aldehyde 6 was
chosen as a mechanistic probe, as the corresponding cyclopropylcarbinyl
12
3
radical 7 should undergo rapid ring opening and ring closing prior to
C-O bond formation (an equilibration step that would predominantly lead
to trans-cyclopropyl oxyamination products). In contrast, such radical
intermediates would be absent from an enamine addition mechanism, so
only cis-substituted cyclopropane products should be observed if an ionic
pathway dominates.
than a SOMO-type pathway. These combined results clearly indicate
that whereas the ferrocenium case predominantly leads to radical-clock
opening in DMF, the preferred Sibi protocol does not, which implies that
the latter does not involve a radical cation as the major reaction pathway.
Importantly, the observation of small amounts of rearranged product when
FeCl was used at low TEMPO concentration (15% trans product at 0.75
3
M TEMPO) was shown to arise from increased content of the unbound
iron oxidant (see the Supporting Information).
Results. To test the validity of this radical-clock study, we exposed
the cis-cyclopropyl substrate 6 to established SOMO activation conditions
(
specifically, [FeCp
2 6
][PF ] in THF, a reliable outer-sphere oxidant)
(
Scheme 3). It should be noted that this oxidation system was initially
2 6
Scheme 4. Product Distribution Using [FeCp ][PF ] in DMF
1b
employed in the original Sibi publication but did not become the
optimized or preferred protocol. As expected, initial experiments with high
concentrations of TEMPO (4.0 M) delivered a mixture of nonisomerized
cis product 8a (71%) and trans product 8b (29%). As the concentration
of TEMPO was decreased to 0.75 M, direct radical trapping to yield 8a
became a minor pathway (10%) while cyclopropyl rearrangement to the
trans adduct 8b became dominant. Having validated the use of formyl-
cyclopropane 6 as a mechanistic probe, we next focused on the Sibi
protocol. Indeed, when the optimal conditions from the initial study were
employed (FeCl
3
/NaNO
2
, DMF, 2.0 M TEMPO), we observed that cis
6
][PF ]
product 8a was delivered in 95% yield. In contrast, the use of [FeCp
2
in THF yielded only a minor amount of the cis adduct (35%).
These results can be explained by one of three scenarios:
J. AM. CHEM. SOC. 9 VOL. 132, NO. 29, 2010 10013

C O M M U N I C A T I O N S
Scheme 5. Revised Mechanism for R-Oxygenation of Aldehydes
Figure 1. Cyclic voltammetry measurements in DMF.
Evidence for a TEMPO complexation/enamine addition pathway
was further substantiated by consideration of the oxidation potentials
of the reagents and intermediates involved (Figure 1). It is well-
established that DMF solvation of FeCl
3
induces disproportionation
14a
to [Fe(dmf)
3
Cl
2
][FeCl
4
], a salt which is less oxidizing than FeCl
3
1
4b
by ∼0.5 V. We measured the irreversible oxidation potential of
enamine 2 (derived from catalyst 1) and found that it is well-
matched for oxidation with [FeCp
2 6
][PF ], while oxidation by
[
Fe(dmf) Cl ][FeCl
3
2
4
] is endergonic by ∼0.5 V.
Acknowledgment. Financial support was provided by NIH
NIGMS (R01 01 GM093213-01) and gifts from Merck and Amgen.
J.F.V.H. thanks the Natural Sciences and Engineering Research
Council (NSERC) for a predoctoral fellowship (PGS D).
Table 1. Other Systems for Catalytic Aldehyde R-Oxyamination
Supporting Information Available: Experimental procedures,
kinetic investigations, and spectral data for all new compounds. This
material is available free of charge via the Internet at http://pubs.acs.org.
a
entry
oxygen source
metal catalyst
% yield
1
2
3
4
5
6
7
TEMPO
none
none
Sc(OTf)
Zn(NTf
[Fe(dmf)
Co(salen)
CuCl
11
19
17
12
72
75
82
b
oxoammonium
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TEMPO
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2
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(
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7-10
(
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1
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(
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5
1
(
(
4
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1
5
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3
2 2
)
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2
003, 1, 3232.
(
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3
is essential, identical levels of conversion were
and O [the oxidant for the Sibi protocol is likely
to be TEMPO, which is known to reoxidize Cu(I) to Cu(II) in related
obtained without NaNO
2
2
16
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972, 39, 335.
17
alcohol oxidations ]. The sum of our results indicate that a significant
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(
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3
(
15) A background reaction with aldehyde and oxoammonium (which can also
be formed in situ from TEMPO) was also observed.
nation of aldehydes is required. The mechanistic picture that best fits
literature precedent and the results contained herein is shown in Scheme
(16) Use of 2 equiv of TEMPO allowed it to act as both the oxygen atom source
and the stoichiometric reoxidant for iron (see ref 1b).
18
3 2 2
5. While the results of our investigations suggest that FeCl /NaNO /O
(
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will not find application in SOMO catalysis, we expect that activation of
TEMPO by metal complexation will lead to several new and efficient
oxygenation protocols.
(18) Enamine/metal-TEMPO electron transfer followed by solvent-cage radical
combination cannot be excluded on the basis of the studies herein.
JA1043006
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