Oxidative cleavage of allyl ethers by an oxoammonium salt

Article abstract of DOI:10.1039/c5ob00270b

A method to oxidatively cleave allyl ethers to their corresponding aldehydes mediated by an oxoammonium salt is described. Using a biphasic solvent system and mild heating, cleavage proceeds readily, furnishing a variety of α,β-unsaturated aldehydes and ketones.

Full text of DOI:10.1039/c5ob00270b

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Organic & Biomolecular Chemistry
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Oxidative Cleavage of Allyl Ethers by an
Oxoammonium Salt
Cite this: DOI: 10.1039/x0xx00000x
Christopher B. Kellya, John M. Oviana, Robin M. Cywara, Taylor R. Gosselina,
Rebecca J. Wilesa and Nicholas E. Leadbeatera,b*
Received 00th January 2012,
Accepted 00th January 2012
A method to oxidatively cleave allyl ethers to their corresponding aldehydes mediated by the
oxoammonium
salt
4-acetylamino-2,2,6,6-tetramethylpiperidine-1-oxoammonium
DOI: 10.1039/x0xx00000x
-
tetrafluoroborate (4-NHAc-TEMPO+ BF4 , 1a) is described. Using a biphasic solvent system and
mild heating, cleavage proceeds readily, furnishing a variety of α,β-unsaturated aldehydes.
www.rsc.org/
Introduction
reduction, thus furnishing a robust and unusual protecting group
strategy (Scheme 1). We report our results here.
Oxoammonium salts are recyclable, metal-free species that can
allow for oxidation chemistry to be performed under extremely
mild conditions.1 Much of the literature involving
oxoammonium salts centres around the conversion of alcohols to
their corresponding carbonyl species.1,2,3 A range of functional
groups can be accessed using this strategy including aldehydes,
ketones, and carboxylic acids.2,3 However, their ability to
facilitate non-traditional oxidation reactions (e.g. oxidative
functionalisation) is of particular interest. As part of a broad
program to expand the scope of oxoammonium salt-based
transformations, we became interested in exploiting
-
4-NHAc-TEMPO+ BF4 (Bobbitt’s salt, 1a) as a “hydride
abstractor” in compounds or transient species bearing highly
active C-H bonds. Specifically, we were interested in systems
where we could capture the resulting oxidised species with a
secondary reaction effecting a net oxidative functionalisation
process. Such a strategy has been employed successfully by
Garcia-Mancheño, Bailey, and by us (Fig. 1).5-7 Bailey recently
reported on the successful cleavage of benzyl ethers via
treatment with 1a.6 Such a reaction is useful as a deprotection
strategy for benzyl-protected alcohols.6,8 We wondered whether
allyl ethers, which bear a somewhat less reactive C-H bond,
could also undergo oxidative cleavage. If successful, we
envisioned that we could not only develop a route to α,β-
unsaturated aldehydes but also effectively protect allyl alcohols
by simple methylation and deprotect by oxidation and then
Figure 1: Oxidative functionalisation reactions using oxoammonium
salts
Scheme 1: Envisioned strategy for allyl ether protection and
deprotection.
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& 6). This did not impede oxidation and we obtained near
quantitative yields of the corresponding aldehydes. Steric
hindrance did, however, retard the rate of the reaction similarly
to 2d. We next explored whether other alkyl groups could serve
as suitable replacements for the methyl ether group (Entries 7-
9). Both isopropyl and ethyl functionalities could be used
successfully without compromising yield or reaction rate. A
phenyl ether failed, likely due to electron density delocalisation
into the aromatic system thereby raising the activation barrier for
oxidation. This delocalisation concept was further evidenced by
the failure of the ester 2j to oxidise (Entry 10). Since preparation
of both the ethyl and isopropyl ethers proved more difficult than
our standard methylation approach, we elected to continue
exploring methylated substrates exclusively.
Results and Discussion
We began our study by preparing allyl ether 2a (via
deprotonation of the corresponding alcohol followed by
methylation with MeI) and subjecting it to a variety of conditions
(Table 1). We initially screened the conditions established by
Bailey for the cleavage of benzyl ethers.6 While we obtained
good conversion to the desired aldehyde, we observed significant
carboxylic acid formation (Table 1, Entry 1). To minimise the
formation of this over-oxidised product, we conducted a solvent
screen. Knowing that the presence of water would be critical to
the cleavage reaction, we screened a variety of solvent mixtures.
Ether solvents (Entries 3 & 4) gave less promising results while
acetone (Entry 2) gave multiple products, which could result
from Aldol or Michael-like pathways. Dichloromethane gave
somewhat more promising results with no observed acid
formation (Entry 5). Attempts to enhance conversion by altering
the CH2Cl2 to H2O ratio gave only modest improvement (Entries
6 & 7) with a ratio of 8:2 CH2Cl2:H2O proving optimal. We next
decided to heat the reaction to 45 oC and found that the
conversion could be nearly doubled (Entry 8). However,
extending the reaction time failed to improve conversion (Entry
9). We decided to increase the loading of 1a because we believed
that both heating in an aqueous medium, and the methanol
generated as a by-product of the reaction would consume some
of the oxidant.9 Using 2.1 equiv of 1a and extending the reaction
time to 12 h, we obtained complete conversion to the desired
aldehyde 3a (Entry 10). Isolation of the resulting aldehyde
Table 2 Scope of the methodology for oxidative cleavage of allyl ethers a
Entry
1
Allyl Ether
Product
Yield (%)b
93
2
3
79
54
90
4c
proved simple, giving an excellent yield of 3a
.
5c
6d
99
91
Table 1 Optimisation of reaction conditions for the oxidative cleavage of
allyl ethersa
7
8
93
88
9
-
Entry
Solventb
Temp.
(oC)
rt
rt
rt
rt
rt
rt
rt
1a
(eq.)
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
2.1
Time
(h)
2
2
2
2
2
2
2
3a (%)c
1
2
3
4
5
6
7
8
9
MeCN: H2O (9:1)
Acetone:H2O (9:1)
THF:H2O (9:1)
84
-
17
Trace
28
35
32
68
66
100 (93)
10
11
-
Et2O:H2O (9:1)
90
CH2Cl2: H2O (9:1)
CH2Cl2: H2O (9:1)
CH2Cl2: H2O (9:1)
CH2Cl2: H2O (9:1)
CH2Cl2: H2O (9:1)
CH2Cl2: H2O (9:1)
12
13
14
89
45
45
45
2
4
12
10
14e
15f
16g
72
86
73
a Conditions unless otherwise noted: 2a (0.5 mmol, 1 equiv), solvent (2.5
mL). b Solvent ratios are by volume. c Values in parentheses indicate isolated
yields, all other values are percent conversions by 1HNMR spectroscopy.
We next turned our attention to examining the substrate scope
of this oxidative cleavage process. The results are shown in Table
2. Initially, we elected to screen various cinnamyl analogues
because they would be sterically similar to 2a (Entries1-4).
Electronic changes to this extended π-system generally had little
to no effect on reaction yield. The exception to this was 2c (Entry
3) which gave only a moderate yield of 3c. Variance in the
electronic nature of these substrates did have a marked effect on
reaction rate with 2d requiring 72 h and additional loadings of
1a to reach complete conversion. We next introduced steric
hindrance at and nearby the reactive methylene group (Entries 5
17
83
a Conditions: allyl ether (10 mmol, 1 equiv), 1a (21 mmol, 2.1 equiv), CH2Cl2
(40 mL), H2O (10 mL). b Isolated yield. c 3.3 equiv of 1a were used over the
course of the reaction d 2.9 equiv of 1a were used over the course of the
reaction e 2.5 equiv of 1a were used over the course of the reaction f 3.7 equiv
of 1a were used over the course of the reaction g 3.1 equiv of 1a were used
over the course of the reaction
2 | J. Name., 2012, 00, 1-3
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A
representative polycyclic example (Entry 11) proved
To conclude our study, we subjected a representative allyl
amenable to oxidative cleavage, but a heterocycle-containing alcohol to our posited protection/deprotection strategy to assess
system (Entry 12) gave markedly diminished yield, due to its viability from the standpoint of simplicity and yield. We were
polymerisation. Extended conjugation did not pose a problem pleased to find that we could readily protect and deprotect 4r in
and gave excellent yield of the desired aldehyde (Entry 13).
good yield over the three chemical steps. Indeed the intermediate
The success of cleavage does not necessitate conjugation into aldehyde (in this case 3r) need not be purified; the crude
an aromatic system. Distancing the aryl ring from the olefin had aldehyde can be carried directly into the reduction step. These
little effect on the success or the yield of the oxidative cleavage high yielding steps therefore validate this approach as a plausible
(Entries 14 & 15). Furthermore, reactivity was unaffected by protecting group strategy.
complete removal of the ring (Entry 16). These systems (Entries
14-16) did require longer reaction times, likely due to the
diminished stabilisation of the intermediate oxonium ion. A non-
Conclusions
In summary, we describe a mild, facile approach to the oxidative
cleavage of allyl ethers to their corresponding aldehydes
mediated by an oxoammonium cation. The reaction is
compatible with a variety of allyl ethers, both those with
extended conjugation and those without. The suggested
mechanism hinges on a hydride transfer from the reactive
methylene of the allyl ether. Hydrolysis of the intermediate
oxonium ion yields the desired aldehyde.
aryl substituted diene retained reactivity towards oxidative
cleavage in both yield and reaction rate, thus supporting this
assertion (Entry 17).
A plausible mechanism for the oxidative cleavage is given in
Fig. 2. We suggest that the key step in the mechanism is the
transfer of a hydride from the allyl ether to the electrophilic
oxygen of the oxoammonium cation. Subsequent hydration of
the resulting oxonium ion yields a hemiacetal. The equilibrium
of this species favours the keto-form, leading to the formation of
the desired aldehyde.10 Such a mechanism is consistent with the
mechanism proposed by Bailey for the oxidative cleavage of
benzyl ethers.6,11
Experimental section
Representative Procedure for Oxidative Cleavage: Synthesis
of Cinnamaldehyde (3a)
To a 100 mL round bottom flask equipped with a stir bar was
added 2a (1.48 g, 0.010 mol, 1 equiv). CH2Cl2 (40 mL), and
deionized water (10 mL). After stirring for five minutes, the
oxoammonium salt 1a (6.302 g, 0.021 mol, 2.1 equiv) was added
to the flask and the flask was equipped with a reflux condenser.
The flask was heated to 45 °C and allowed to stir overnight. The
reaction mixture gradually became orange during this time.
Reaction progress was monitored by 1H NMR spectroscopy.
After 12 h the reaction was judged to be complete. At this time
the reaction mixture was cooled to room temperature and
transferred to a separatory funnel. The mixture was diluted with
deionized water (100 mL) and Et2O (150 mL) the layers were
separated. The aqueous layer was extracted with Et2O (5 × 50
mL). The combined organic layers were washed with deionized
water (2 × 100 mL) and brine (150 mL). The organic layer was
dried with Na2SO4 and the solvent was removed in vacuo by
rotary evaporation to give the crude aldehyde. Further
purification was accomplished by SiO2 plug (95:5 Hex:EtOAc to
90:10 Hex:EtOAc), giving the pure aldehyde (1.23 g, 93%) as
Figure 2: Plausible reaction mechanism.
Given this mechanism, we suggest that the biphasic reaction
conditions are critical to efficacious and selective formation of
the aldehyde.12 Due to the limited solubility of 1a in
dichloromethane, only a small amount of the active oxidant is
available at any given time. This deters indiscriminate oxidation
(e.g. over-oxidation to the corresponding carboxylic acid). In
addition, the organic layer serves to protect the resulting
aldehyde from hydration as only a minimal amount of water
would be present. Finally, the methanol produced during the
course of cleavage would enter the aqueous phase, potentially
driving the equilibrium forward.
1
clear, pale yellow oil. H NMR (CDCl3, 400 MHz) δ ppm 6.75
(dd, J=15.97, 7.71 Hz, 1 H) 7.43 - 7.50 (m, 3 H) 7.52 - 7.64 (m,
3 H) 9.74 (d, J=7.68 Hz, 1 H) 13C NMR (CDCl3, 100 MHz) δ
ppm 128.66 (CH) 128.76 (CH) 129.27 (CH) 131.43 (CH) 134.18
(C) 152.89 (CH) 193.80 (C) GC-MS (EI) 132 ([M]+, 58%) 131
(100%) 103 (62%) 77 (51%) 63 (12%) 51 (38%).
Acknowledgements
This work was supported by the National Science Foundation
CAREER Award CHE-0847262). We acknowledge Dr. James
Bobbitt and Michael Mercadante of the University of
Connecticut as well as Dr. Leon Tilley of Stonehill College for
helpful discussions.
Scheme 2: Protection and deprotection sequence of an allyl alcohol.
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Notes and references
9
1a is not stable for extended periods of time at elevated temperature in
a Department of Chemistry, University of Connecticut, 55 North Eagleville
water. Additionally, methanol is can be oxidised to formaldehyde and
Road,
Storrs,
CT
06269,
United
States.
E-mail:
then further to formic acid thus consuming additional 1a.
nicholas.leadbeater@uconn.edu
10 (a) H. Maltz, Chem. Commun., 1968, 843; (b) S. Winstein and H. J.
Lucas, J. Am. Chem. Soc., 1937, 59, 1461-1465.
b
Department of Community Medicine & Health Care, University of
Connecticut Health Center, The Exchange, 263 Farmington Ave, 11 Another possibility would be nucleophilic attack on the methyl group
Farmington,
CT
06030,
United
States.
E-mail:
by H2O during the second step of the mechanism. While plausible, we
have no evidence for this alternate mechanistic pathway.
nicholas.leadbeater@uconn.edu
† Electronic supplementary information (ESI) available: Experimental
details, characterization of substrate precursors/substrates/products, and
copies of 1H, 13C, and 19F NMR spectra. See DOI: 10.1039/b000000x/
12 A similar biphasic strategy using 1a has been utilized to effect the
deracemisation of 3H indolines and tetrahydroquinolines, see: A. D.
Lackner, A. V. Samant and F. D. Toste J. Am. Chem. Soc., 2013, 135
14090–14093.
,
1
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and N. E. Leadbeater Nat. Protoc., 2013, , 666-676; (c) C. B. Kelly
,
8
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2
3
TEMPO-Based Oxoammonium Salts: (a) J. M. Bobbitt, J. Org. Chem.,
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,
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8
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