Catalytic Allylic Oxidation of Cyclic Enamides and 3,4-Dihydro-2H-Pyrans by TBHP

Article abstract of DOI:10.1021/acs.joc.7b01163

Allylic oxidation of heteroatom substituted cyclic alkenes by tert-butyl hydroperoxide (70% TBHP in water) using catalytic dirhodium caprolactamate [Rh₂(cap)₄] forms enone products with a variety of 2-substituted cyclic enamides and 3,4-dihyro-2H-pyrans. These reactions occur under mild reaction conditions, are operationally convenient to execute, and are effective for product formation with as low as 0.25 mol% catalyst loading. With heteroatom stabilization of the intermediate allylic free radical two sites for oxidative product formation are possible, and the selectivity of the oxidative process varies with the heteroatom when R = H. Cyclic enamides produce 4-piperidones in good yields when R = alkyl or aryl, but oxidation of 2H-pyrans also gives alkyl cleavage products. Alternative catalysts for TBHP oxidations show comparable selectivities but give lower product yields.

Full text of DOI:10.1021/acs.joc.7b01163

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Article
Catalytic Allylic Oxidation of Cyclic Enamides
and 3,4-Dihydro-2H-Pyrans by TBHP
Yang Yu, Ranad Humeidi, James R. Alleyn, and Michael P Doyle
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b01163 • Publication Date (Web): 19 Jul 2017
Downloaded from http://pubs.acs.org on July 19, 2017
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The Journal of Organic Chemistry
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Catalytic Allylic Oxidation of Cyclic Enamides and 3,4-Dihydro-2H-
Pyrans by TBHP
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Yang Yu, Ranad Humeidi, James R. Alleyn, and Michael P. Doyle*
Department of Chemistry, The University of Texas at San Antonio, San Antonio, Texas 78249, United States
ABSTRACT: Allylic oxidation of
heteroatom substituted cyclic alkenes
by tert-butyl hydroperoxide (70% TBHP
in water) using catalytic dirhodium
caprolactamate [Rh2(cap)4] forms enone
products with a variety of 2-substituted
cyclic enamides and 3,4-dihyro-2H-
pyrans. These reactions occur under
mild
reaction
conditions,
are
operationally convenient to execute, and are effective for product formation with as low as 0.25 mol% catalyst loading.
With heteroatom stabilization of the intermediate allylic free radical two sites for oxidative product formation are
possible, and the selectivity of the oxidative process varies with the heteroatom when R = H. Cyclic enamides produce 4-
piperidones in good yields when R = alkyl or aryl, but oxidation of 2H-pyrans also gives alkyl cleavage products.
Alternative catalysts for TBHP oxidations show comparable selectivities but give lower product yields.
INTRODUCTION
Allylic oxidation is a popular methodology for the
selective preparation of enones.1 Initially investigated with
selenium dioxide,2 and reported with a wide variety of
oxidants,1d-e,3 this methodology is currently focused on
oxidations by tert-butyl hydroperoxide (TBHP), either in
an anhydrous hydrocarbon medium or as the less
expensive 70% solution in water (T-HYDRO).4 However,
activation of TBHP as an oxidant requires a catalyst, most
often a transition metal compound. A common role of
the catalyst is to oxidatively convert TBHP into the tert-
butylperoxy radical, which is selective for hydrogen atom
abstraction from the allylic position, and to then be
Dirhodium(II) caprolactamate [Rh2(cap)4] is reported to
reduced to its original state through reaction with TBHP
(Scheme 1).5 Subsequent reactions of the allyl radical with
be the most advantageous catalyst for allylic oxidations by
TBHP.7 One of the reasons for this is its low oxidation
dioxygen produce the enone.
Noteworthy is the
potential,8 but another is the facility of this catalytic
observation that although cyclic alkenes produce
conjugated cycloalkenones in high yield and are widely
reported, reactions with cyclic enamide have not been
described and with vinyl ethers with low (<10%) yields. 6
system to generate
a continual flow of the tert-
butylperoxy radical.4c Although trapping of the
intermediate allyl radical by dioxygen is dominant, minor
processes have been reported to involve trapping by the
tert-butylperoxy radical to form mixed peroxides,5 which
are relatively stable under the reaction conditions. With
only one known exception, attributable to steric factors,5
the more stable allyl radical is the primary product from
allylic oxidation by the tert-butylperoxy radical.
Scheme 1.
Catalytic Formation of the tert-
Butylperoxy Radical by One-Electron Transfer
Catalysts
Although not included in previous voluminous
investigations
heteroatom substituted cyclic olefins were considered to
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of
allylic
oxidation
reactions,1,4,9

The Journal of Organic Chemistry
be potential substrates. In contrast to oxidations of
cycloalkenes, heteroatom stabilization of the allyl radical
was expected to be a factor in hydrogen atom abstraction
and subsequent reactions.10 The intermediate allyl radical
can be trapped by dioxygen at either the position
proximal or distal to the heteroatom, thereby establishing
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direct routes to either β-heteroatom substituted enone I
or unsaturated lactone II (Scheme 2) through oxidative
processes previously reported to occur with cyclic
alkenes.5
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Scheme 2. Allylic Oxidation of Heteroatom-
Substituted Cyclic Alkenes
O
O
O
( )n
( )n
O2
O2
H
Z
Our evaluation of enamide oxidations was initiated using
N-Boc-1,2,3,4-tetrahydropyridine with 0.25 mol%
Z
( )n
( )n
I
Z
dirhodium caprolactamate and T-HYDRO as the
oxidant in dichloromethane, conditions that have
previously been reported as optimum for allylic
oxidations of cycloalkenes.7 However, only a 25% yield of
allylic oxidation products 2a and 3a was obtained with
TBHP in water, or a 24% yield of 2a + 3a with anhydrous
TBHP in decane after two days (entries 1-2, Table 1). 2,3-
Dihydro-4(1H)-pyridinone (2a) was formed in preference
to 5,6-dihydro-2(1H)-pyridinone (3a) in a ratio of nearly
5:1, so our challenges were to increase product yield and,
possibly, regioselectivity. In our initial discovery of TBHP
allylic oxidation, we reported that using 50 mol% of
K2CO3 had a dramatic improvement on the reaction yield
and rate,19 so we investigated the use of base additives on
product yields. The oxidation of enamide compounds
with potassium carbonate as an additive increased the
yield of allylic oxidation products to 46% and slightly
improved regioselectivity to 85:15 (entry 3, Table 1). By
screening other additives, we found that the addition of
50 mol% of NaOAc significantly increased the yield to
76% with a further modest increase in regioselectivity
(entry 5, Table 1). Other acetate salts and sodium formate
gave no further improvement (see SI). With TBHP in
decane a lower yield but similar regioselectivity was
obtained. Higher catalyst loading to 1.0 mol% has no
noticeable influence on yield or regioselectivity.
Z
tBuOOH
( )n
tBuOO
( )n
O
Z
O
Z
O
II
RESULTS AND DISCUSSION
Oxidation of Cyclic Eneamides. N-substituted 2,3-
dihydro-4-piperidones represent key intermediates in the
synthesis of biologically active piperidines, and their
synthetic utility is well documented.11 Recent efforts have
demonstrated that these compounds are useful substrates
for asymmetric conjugate addition12 and intramolecular
[2+2] cycloaddition13. Notably, however, only a few
methods exist for the construction of 2,3-dihydro-4(1H)-
pyridinones (Scheme 3). Published approaches involve
oxidative and reductive methods using reactants having
the oxygen functional group already at the 4-position
(with 4-oxypyridinium salts,14 4-piperidone,15 and pyridin-
4(1H)-one12) as well as cyclization methods (hetero Diels-
Alder reactions with imines16 and intramolecular 1,4-
addition of amino-ynones17), and some of these methods
have very limited scope. Cyclic enamides, which can be
readily prepared from commercial
-caprolactam,18 would provide an expedient route to
δ
-valerolactam18,19 or
ε
N-substituted 2,3-dihydro-4-piperidones via allylic
oxidation. We report here the direct allylic oxidation of
representative cyclic enamides that suggests the
generality of the method and the comparative advantage
of catalysis by dirhodium caprolactamate.
Table 1. Screening reaction conditions for the
oxidation of 1a.a
Scheme 3. General Approaches Towards the
Synthesis of 4-Piperidones.
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Entry
additives
yield (%) b
regioselectivity
c
1
2
3
4
5
6
7
8
9
1
2d
3
none
none
25
24
46
58
76
62
82:18
81:19
85:15
84:16
88:12
87:13
K2CO3
Cs2CO3
NaOAc
NaOAc
4
5
6e
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a.
Standard reaction conditions: T-HYDRO (1.0 mmol, 5.0
equiv) was added into a solution of 1a, additives (0.1
mmol, 0.5 equiv), Rh2(cap)4 (0.0005 mmol) in DCM (0.75
mL, 0.27 M) at room temperature. The oxidations are
complete within 2 h. b Isolated yield. c Regioselectivity was
determined by 500 MHz H NMR. TBHP (5.5 M in
decane) was used. e 0.1 equiv NaOAc was used.
1
d
The influence of sodium acetate in increasing the yield of
products and moderately increasing regioselectivity is
surprising. Moreover, the presence of 0.5 equiv of sodium
acetate significantly increased the reaction rate compared
to the reaction with no additive, but with only 0.1 equiv of
NaOAc the reaction becomes sluggish after 60%
conversion (Figure 1). The role of this reagent appears to
be as a mild base to increasing the rate of production of
the tert-butylperoxy radical by increasing the
concentration of the tert-butyl peroxy anion. Acetate does
not become an axial ligand for Rh2(cap)4 since its
presence does not inhibit reaction with TBHP.
Figure 1. Time course for the reactions of NaOAc at 20
⁰C. Catalyst loading was 0.25 mol% and the reaction
concentration was 0.27 M.
To further explore the scope of this reaction, alkyl and
aryl substituted enamides 1e-g were evaluated. Only 4-
piperidone compounds 2e-g were obtained with these
substrates. In particular, the oxidation of 2-methyl
substituted enamide (1f, Table 2) proceeded without
oxidation of the methyl group, clearly demonstrating the
efficiency and selectivity of this process.
Table 2. Allylic Oxidation of Enamides. a
Applying these conditions to other enamide compounds,
including N-tosyl and N-Cbz amides, gave comparable
outcomes with slightly different regioisomer ratios (1b
and 1c, Table 2), suggesting a modest influence of the
amide on regiocontrol. The reaction conditions do not
compromise the Cbz-protecting group, despite the
potential for dirhodium catalyzed benzylic oxidation by
TBHP. For the homologous ꢀ-caprolactamate derived N-
Boc enamide (1d, Table 2) the desired enone 2d was also
obtained (0.25 mol% catalyst loading). In all cases,
preference for oxidation is at the distal carbon position.
O
O
O
O
N
N
N
N
Boc
Boc
Ts
Cbz
2d, 62%
2d: 3d
2b
, 54%
2c
, 67%
2a, 76%
= 90:10
2b: 3b = 90:10
2c: 3c
= 86:14
2a 3a
:
= 88:12
O
O
O
N
Ph
N
Me
N
Ph
Boc
2e, 67%
Boc
Boc
2f
, 52%
2g, 60%
a
Standard reaction conditions: T-HYDRO (1.0 mmol, 5.0
equiv) was added into a solution of 1a-g (0.2 mmol),
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NaOAc (0.1 mmol, 0.5 equiv), Rh2(cap)4 (0.0005 mmol) in
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3
4
DCM (0.75 mL, 0.27 M) at room temperature. The
b
oxidations are complete within 2 h. Total isolated yield
c
for the two isomers. Regioselectivity was determined by
500 MHz 1H NMR.
5
6
7
8
9
entry
conditions a
substrate 1c
substrate 7
Allylic oxidation of 4-BPin substituted N-Boc-1,2,3,4-
tetrahydropyridine 1h gave the single oxidation product
from cleavage of the carbon-boron bond (2a) in 48% yield
without any detectable other regioisomers (eq 1). 5-
Membered enamide 1i was also investigated. Instead of
direct allylic oxidation, only dehydrogenation product 2i
was obtained (eq 2), suggesting that the allyl radical
undergoes more rapid hydrogen atom donation than
trapping by dioxygen.
total 2c:3 c total 2c:3 c
yield
(%) b
yield
(%) b
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1
Rh2(cap)4 (0.25
mol%), NaOAc
(0.5 eq.)
67
86:14
80:20
62
88:12
2
(tert-butyl-
30
37
12
82:18
84:16
peroxy)iodane d
3
4
5
6
CuBr (10 mol%)
CuI (5 mol%)e
RuCl3 (5 mol%)
15
26
7
83:17
85:15
87:13
83:17
BPin
O
T-HYDRO (5 equiv)
Rh2(cap)4 (0.25 mol%)
(eq 1)
9
86:14
85:15
NaOAc (0.5 equiv)
DCM (0.27 M), rt
N
N
Pd(OH)2 (5
mol%) and K2CO3
(0.5 eq.) f
45
40
Boc
1h
Boc
2a
yield: 48%
7
Co(OAc)2·4H2O
35
52
60
87:13
90:10
90:10
33
42
52
87:13
91:9
91:9
(2.5 mol%) g
T-HYDRO (5 equiv)
8
Rh2(OAc)4 (1
mol%)
Rh2(cap)4 (0.25 mol%)
(eq 2)
N
Cbz
N
NaOAc (0.5 equiv)
DCM (0.27 M), rt
Cbz
2i
9
Rh2(oct)4 (1
mol%)
1i
yield: 40%
a
Standard reaction conditions: T-HYDRO (1.0 mmol, 5.0
equiv) was added into a solution of 1c or 7 (0.2 mmol),
metal catalyst in DCM (1 mL) at room temperature. No
reacti0n occurred with ferric chloride in either
To ascertain if the site of allylic hydrogen atom
abstraction was a factor in determining regioselectivity,
the regioisomer of 1c, N-Cbz-1,2,3,6-tetrahydropyridine 7
was subjected to oxidation under the same conditions.
The same products as from 1c were formed in comparable
yields (Table 3). The product ratio is, within experimental
error, also the same, and potential products from
hydrogen atom abstraction from the 5-position were not
observed. This outcome is consistent with selective
hydrogen atom abstraction from the 2-position of 7 and
formation of the allyl radical corresponding to that
formed from enamide 1c whose subsequent oxidative
reactions are the same.
b
c
acetonitrile or DCM. Isolated yield. Regioselectivity
1
d
was determined by 500 MHz H NMR. TBHP (5.5 M in
decane, 0.8 mmol) was added into a solution of 7 (0.2
mmol), PhI(OAc)2 (0.6 mmol) and K2CO3 (0.1 mmol) in
CH3COOn-Bu (1.0 mL) at -20 °C. e Reaction performed in
acetonitrile. f 10 equiv. TBHP (5.5 M in decane) was used. g
CH3CN was used as the solvent at 50 °C.
This system provided an excellent opportunity to assess
whether other catalysts promote allylic oxidation by
TBHP in the same way. In addition to the use of
dirhodium catalysis for allylic oxidation by TBHP,
copper(I),21 palladium(II) hydroxide,22 cobalt acetate,23
.and ruthenium(III)24 have also been employed. Also, the
stoichiometric reactions with hypervalent (tert-
butylperoxy)iodane, which is a direct precursor of the
tert-butylperoxy radical,25 was also used. Although the
tert-butylperoxy radical is the most likely hydrogen
abstraction agent, the possibility of oxo-metal
involvement, especially with ruthenium catalysts,1
Table 3. Comparison of Methods for Oxidation of 1c
and 7.
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unsaturated lactone 6 as a 1:1 mixture in 77% total yield
persists. If these reactions form the same allyl radical, and
1
2
3
4
5
6
7
8
there is no further involvement by the catalyst, the same
regioselectivity found with Rh2(cap)4 is expected. If,
however, there is a difference in oxygen delivery, a change
in regioselectivity would indicate this. Although product
yields using different catalysts were significantly lower,
the same regioselectivities were obtained (Table 3). Even
Rh2(OAc)4 and Rh2(oct)4 catalyze the allylic oxidation of
compounds 1c and 7 by TBHP, but they occur with lower
yields (entries 8-9, Table 3). Longer reaction times and
higher catalyst loadings are required to obtain the
reported yields with the dirhodium carboxylate catalysts,
and the induction period for observation of the pink
colored Rh2(5+) oxidative intermediate several hours after
TBHP was added (both Rh2(OAc)4 and Rh2(oct)4), while
only several seconds for reactions catalyzed by Rh2(cap)4.
The nearly identical regioselectivities from reactions with
1c and 7 implies that they share the same allyl radical
intermediate.
(entry 1, Table 4), and in the reaction without sodium
acetate the 5a:6 ratio was 24:76 (35% yield). Consistent
with the matching outcome for oxidations of 1c and 7
(Table 3), the oxidation of 3,6-dihydropyran gave the
same 5a:6 product ratio (53:47, 67% yield) as did 3,4-
dihydropyran 4a under the same reaction conditions. Not
surprisingly, 2-alkyl-substituted 2H-pyran compounds 4b-
d underwent oxidation only at the 4-position to form 5b-
d, respectively (entries 2-3, Table 4). Moreover, only the
endocyclic allylic oxidation products were obtained when
these dihydropyrans were employed, and the potentially
oxidizable benzylic methylene group underwent benzylic
oxidation only after extended reaction times. The 1:1
regioselectivity in the oxidation of 4a contrasts with the
significant regiocontrol that was obtained for the
oxidation of enamides 1a-d, and this evidence suggests
that the ether oxygen does not exert directive influence
on product formation. In contrast with results with
enamide 1c, reactions with dihydropyran 4a using the
same set of alternative oxidation catalysts for TBHP
oxidation gave variable selectivities with RuCl3 and
Co(OAc)2, but not with (tert-butylperoxy)iodane or CuI
(Table 5). The indication from regioselectivities with
RuCl3 and Co(OAc)2 catalysts is that oxygen delivery is
different,29 at least in part, but the common
regioselectivities obtained with Rh2(cap)4, CuI, and (tert-
butylperoxy)iodane describe the same allyl radical
pathway. The influence of sodium acetate in increasing
the yield of products and increasing regioselectivity is
uncertain.
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Oxidation of Dihydropyrans. Polyfunctional pyran
derivatives commonly appear in numerous natural products
and biologically active compounds.26 Although many
synthetic methods have been developed for their synthesis,
limited substrate scope and expensive or difficult synthetic
precursors restrict their applications.27 Oxidative methods
have had very limited applications and success.6,28 As a
comparison with the corresponding enamide analogues we
examined the use of dirhodium caprolactamate for the
TBHP oxidation of 3,4ꢀdihydroꢀ2Hꢀpyrans. Would the
same oxidative efficiencies and selectivities prevail? In an
earlier investigation of oxidations by hypervalent (tert-
butylperoxy)iodanes involving oxoradical hydrogen atom
abstraction, non-cyclic allyl ethers were converted to
acrylate esters in moderate to good yields,25a and we
found the same outcome from Rh2(cap)4 catalyzed
oxidation reactions (Scheme 4).
Table 4. Allylic Oxidation of 2H-Pyrans Compounds. a
Scheme 4. Allylic Oxidation of Acrylate Esters
entry substrate
Product
yield (%)b
77
1
2
52
Oxidation of 3,4-dihydropyran 4a was conducted under
the same conditions as were employed for oxidations of
enamide compounds. Surprisingly, 2H-pyran-4-one 5a
was obtained together with its regioisomeric α,β-
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65
During our investigation of the oxidation of 2H-pyran
compounds 4b, we isolated minor, but reproducible,
amounts of alkyl cleavage product 6 (14% isolated yield)
in addition to the anticipated allylic oxidation products
5b (eq 3, Scheme 5). Similar cleavage reactions were also
found with substituted 2H-pyrans 4c and 4d (eq 4,
Scheme 5). Cleavage products were not observed in
reactions of emamides. Increasing the oxygen content of
the solvent led to a higher yield of cleavage product,
albeit with lower overall yield.
4
5
6
7
8
9
4d
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a
Standard reaction conditions: T-HYDRO (1.0 mmol, 5.0
equiv) was added into a solution of 4a-d (0.2 mmol),
NaOAc (0.1 mmol, 0.5 equiv), Rh2(cap)4 (0.0005 mmol) in
DCM (0.75 mL, 0.27 M) at room temperature. The
Scheme 5. C-C Single Bond Cleavage
T-HYDRO (5 eq.)
O
Rh2(cap)4
b
c
(0.25 mol%)
oxidations are complete within 2 h. Isolated yield.
+
(eq 3)
1
NaOAc (0.5 eq.)
DCM (0.27 M),
rt
Regioselectivity was determined by 500 MHz H NMR
analysis. d The product derived from oxidizing benzylic
and allylic methylenes is generated when the reaction
time is over 24 h.
O
nBu
O
nBu
O
O
4b
5b
6
14%
without bubbling O2
52%
with bubbling O2
28%
28%
Table 5. Other Methods for Oxidation of
Dihydropyran
Radical.
T-HYDRO (5 eq.)
Rh2(cap)4
O
Involving
the
tert-Butylperoxy
(0.25 mol%)
+
(eq 4)
NaOAc (0.5 eq.)
DCM (0.27 M),
bubbling O2, rt
O
R
O
R
O
O
6, 20%
6, 12%
R = PhCH2CH2CH2, 4d
R = i-Bu, 4c
5d, 32%
5c, 48%
entry
conditions a
total
yield of
5a and 6
(%) b
5a: 6 c
The formation of 6 in the oxidation of 4b represents the
cleavage of the C-C single bond between the n-butyl
substituent and 2H-pyran. Although not previously
reported in allylic oxidation reactions, this C-C single
bond cleavage reaction can be considered to be the
outcome of the trapping of the initially formed allyl
radical at the 2-position, subsequent hydrogen atom
transfer to the peroxy radical, and oxidative cleavage of
the hydroperoxide to form an oxo-radical (Scheme 6).30
1
(tert-butylperoxy)iodane d
CuBr (10 mol%)
28
40
53:47
55:45
63:37
n.d.
2
3
4
RuCl3 (5 mol%)
20
Pd(OH)2 (5 mol%) and
K2CO3 (0.5 eq.)
trace
5
Co(OAc)2·4H2O (2.5
52
77
34:66
52:48
Scheme 6. Plausible Pathway for C-C Bond Cleavage.
mol%) e
6
Rh2(cap)4 (0.25 mol%),
NaOAc (0.5 eq.)
a
Standard reaction conditions: T-HYDRO (3.0 mmol, 5.0
equiv) was added into a solution of 4a (0.6 mmol), metal
catalyst in DCM (2 mL) at room temperature. Isolated
yield. Regioselectivity was determined by 500 MHz H
NMR analysis. TBHP (5.5 M in decane, 2.0 mmol) was
added into a solution of 4a (0.5 mmol), PhI(OAc)2 (1.5
mmol) and K2CO3 (0.25 mmol) in CH3COOn-Bu (1.0 mL)
at -20 °C. e CH3CN was used as the solvent at 50 °C.
b
c
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d
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The Journal of Organic Chemistry
vials under air atmosphere. Analytical thin layer
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2
3
4
5
6
7
8
chromatography (TLC) was carried out using silica gel
plates; visualization was accomplished with UV light (254
nm). Liquid chromatography was performed by flash
chromatography of the indicated system on silica gel
Results obtained for allylic oxidation of cyclic enamides
and dihydropyrans show limitations relative to allylic
oxidations of their carbocyclic counterparts. Although
product yields are comparable in many cases,
regioselectivity and cleavage issues have been identified
as potential concerns. A possible explanation for the
absence of cleavage products in reactions with cyclic
eneamides may be the relative stability of the dioxygen
captured allyl radical. If that step is reversible, and the C-
C bond cleavage reaction is dependent on hydrogen atom
transfer, then C-C bond cleavage will be dependent on
the lifetime of the intermediate peroxy radical (Scheme
7). Similarly, the relative stability of peroxy radical
intermediates may be the cause of the observed
regioselectivities found with the tetrahydropyridines and
dihydropyran. However, an alternative explanation is that
there is a stabilizing stereoelectronic effect originating
from strong anomeric nO→σ*CO interactions with
dioxygen capture at the 2-position that is absent in the
peroxy radical intermediate from oxygen capture at the 4-
position.31 With enamides, this anomeric stabilization by
nitrogen is much less, and the regioselectivity differences
observed in this investigation are consistent with this
explanation.
1
(230-400 mesh). H NMR spectra were recorded on a 500
MHz spectrometer, and chemical shifts were reported in
ppm. The peak information was described as: br = broad,
s = singlet, d = doublet, t = triplet, q = quartet, m =
multiplet, comp = composite; coupling constant(s) in Hz.
The number of protons (n) for a given resonance was
indicated by nH. Coupling constants were reported as J-
values in Hz. 13C NMR spectra were recorded on a 125
MHz spectrometer with complete proton decoupling.
High-resolution mass spectra (HRMS) were performed on
a TOF-CS mass spectrometer using CsI as the standard.
Accurate masses were reported for the molecular ion [M +
Cs]+, [M + Na]+, or [M + H]+.
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Materials. Rh2(cap)4 was prepared according to the
literature procedure.7 Substrates 1a-d,19 1e,32 1f33 and 4a-
c,34 and 3,6-dihydro-2H-pyran35 were synthesized and
characterized according to literature procedures. The
iodinate reagent was generated in situ following Yeung’s
procedure.25b Other metal catalysts, solvents and the
other reagents were obtained from commercial sources
and used without further purification.
Synthetic Procedure for tert-Butyl 7-Phenyl-2,3,4,5-
tetrahydro-1H-azepine-1-carboxylate (1g). Sodium
bis(trimethylsilyl)amide (2.0 M in THF, 2.40 mL, 4.8
mmol) was added into a pre-cooled solution of tert-butyl
2-oxoazepane-1-carboxylate (0.8531 g, 4.0 mmol) in 10 mL
dried THF at -78 °C. The reaction mixture was stirred at
that temperature for 1 h. Diphenylphosphinic chloride
(1.14 g, 4.8 mmol) was added dropwise via syringe at -78
°C and stirred for additional 2 h, and the reaction solution
was then warmed to room temperature. The reaction was
quenched by H2O. The two layers were separated, and the
aqueous phase was extracted with ethyl acetate (10 mL ×
3). The combined organic phase was dried over anhydrous
MgSO4 and concentrated under vacuum. The residue was
directly used without further purification. To a 50 mL
flame-dried Schlenk flask containing a magnetic stirring
bar, Pd(OAc)2 (26.9 mg, 0.12 mmol, 0.10 equiv) and PPh3
(94.2 mg, 0.359 mmol, 0.3 equiv.) were added, and the
atmosphere above these reactants was vacuum and
nitrogen purge three times. 1,2-Dimethoxyethane (12 mL)
was added into the reaction flask, and the resulting
mixture was stirred for 15 min. Then the crude enol
phosphinate (495.6 mg, 1.199 mmol), PhB(OH)2 (336.3 mg,
2.758 mmol, 2.30 equiv) and 2M Na2CO3 aqueous solution
(1.8 mL, 3.6 mmol, 3.0 equiv) were added sequentially
under a nitrogen atmosphere. The reaction mixture was
then heated to 80 °C and maintained at that temperature
for 4 h. The reaction was quenched by the addition of
H2O, and the two layers were separated, the aqueous
phase was extracted with ethyl acetate (10 mL × 3), and
the combined organic phase was dried over anhydrous
Scheme 7. A Possible Explanation for Different
Outcomes in Reactions between Eneamides and
Dihydropyrans.
In summary, dirhodium caprolactamate has been shown
to be a viable catalyst for the allylic oxidation of cyclic
enamides and enol ethers. The reaction conditions are
mild, occur with 70% TBHP in water, and require low
catalyst loading. The oxidation of enamides offers a facile
route to substituted 2,3-dihydro-4-piperidones, and
applications to enol ethers provide substituted 4-
pyranone compounds but with competitive C-C cleavage.
EXPERIMENTAL SECTION
General Information. For anhydrous reactions, unless
noted, were performed in oven-dried (120 °C) glassware
with magnetic stirring under an inert atmosphere of dry
nitrogen. Allylic oxidation reactions were performed in
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MgSO4 and concentrated in vacuum. The residue was Hz, 1H), 5.21 (d, J = 10.6 Hz, 1H), 3.97 – 3.86 (m, 2H), 2.66
(t, J = 6.5 Hz, 2H), 2.10 – 1.98 (m, 2H), 1.54 (s, 9H); 13C
NMR (126 MHz, CDCl3) δ 201.0, 152.0, 137.7, 108.7, 83.4,
42.7, 28.0, 27.9, 22.7. HRMS (ESI) calculated for C11H18NO3
[M+H] +: 212.1281; found: 212.1285.
1
2
3
4
5
6
7
8
purified by flash chromatography on silica gel using
hexanes/ethyl acetate (5:1) as the eluent to afford the
corresponding product 1g as a colorless liquid (204.2 mg,
62% for 2 steps). The spectral characteristics of this
compound are identical to those reported in the
literature.36
tert-Butyl
6-Methyl-4-oxo-3,4-dihydropyridine-1(2H)-
1
carboxylate (2f). 52% yield. Light yellow oil. H NMR (500
MHz, CDCl3) δ 5.31 (s, 1H), 4.01 (t, J = 6.9 Hz, 2H), 2.47 (t,
J = 6.9 Hz, 2H), 2.31 (s, 3H), 1.54 (s, 9H); 13C NMR (126
Synthetic Procedure for 6-(3-Phenylpropyl)-3,4-
dihydro-2H-pyran (4d). t-BuLi (1.2 M in pentane, 8.0 mL,
9.6 mmol, 1.2 equiv) was added to a pre-cooled solution of
3,4-dihydro-2H-pyran (672.1 mg, 7.990 mmol) in 20 mL
dried THF at -78 °C. The reaction mixture was warmed to
0 °C and stirred for 1 h. Then the reaction was cooled to -
78 °C, and 3-phenylpropyl bromide (1.9113 g, 9.588 mmol,
1.20 equiv) was added dropwise. The reaction solution was
stirred for additional 2 h, then slowly warmed to room
temperature. Saturated aqueous NH4Cl (ca. 10 mL) was
added to quench the reaction. The two layers were
separated, and the aqueous phase was extracted with
diethyl ether (10 mL × 3). The combined organic phase
was dried over anhydrous MgSO4 and concentrated in
vacuum. The residue was purified by flash
chromatography on silica gel using hexanes:ethyl acetate
(5:1) as the eluent to afford the corresponding product 4d
9
MHz, CDCl3) δ 194.3, 157.6, 152.1, 111.8, 83.1, 46.0, 36.7, 28.1,
+
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23.8. HRMS (ESI) calculated for C11H18NO3 [M+H]
212.1281; found: 212.1285.
:
tert-Butyl 5-Oxo-7-phenyl-2,3,4,5-tetrahydro-1H-azepine-
1
1-carboxylate (2g). 60% yield. Colorless oil. H NMR (500
MHz, CDCl3) δ 7.51 – 7.31 (m, 5H), 5.85 (s, 1H), 3.96 (t, J =
7.0 Hz, 2H), 2.69 (t, J = 7.1 Hz, 2H), 2.30 – 2.15 (m, 2H), 1.12
(s, 9H); 13C NMR (126 MHz, CDCl3) δ 200.5, 158.4, 152.8,
130.0, 128.4, 126.6, 120.5, 81.8, 51.0, 40.9, 27.6, 26.4. HRMS
(ESI) calculated for C17H22NO3 [M+H]+: 288.1594; found:
288.1594.
6-Butyl-2H-pyran-4(3H)-one (5b). 62% yield. Colorless
1
oil. H NMR (500 MHz, CDCl3) δ 5.34 (s, 1H), 4.45 (t, J =
6.8 Hz, 2H), 2.51 (t, J = 6.8 Hz, 2H), 2.24 (t, J = 7.6 Hz, 2H),
1.54 (p, J = 7.5 Hz, 2H), 1.35 (h, J = 7.4 Hz, 2H), 0.92 (t, J =
7.3 Hz, 3H); 13C NMR (126 MHz, CDCl3) δ 192.3, 178.1, 104.5,
67.9, 35.6, 34.5, 28.4, 22.1, 13.7. HRMS (ESI) calculated for
C9H15O2 [M+H]+: 155.1067; found: 155.1069.
1
as a colorless liquid (727.2 mg, 45%). H NMR (500 MHz,
acetonitrile-d3) δ 7.28 – 7.25 (m, 2H), 7.20 – 7.15 (m, 3H),
4.47 (t, J = 3.7 Hz, 1H), 3.92 (t, J = 5.3 Hz, 2H), 2.59 (t, J =
7.9 Hz, 2H), 1.98 – 1.94 (m, 4H), 1.76 – 1.69 (m, 4H); 13C
NMR (126 MHz, acetonitrile-d3) δ 155.0, 143.7, 129.4,
129.2, 126.6, 96.4, 66.8, 35.8, 34.5, 29.8, 23.3, 21.0.
6-Isobutyl-2H-pyran-4(3H)-one
(5c).
65%
yield.
1
Colorless oil. H NMR (500 MHz, CDCl3) δ 5.32 (s, 1H),
4.45 (t, J = 6.8 Hz, 2H), 2.51 (t, J = 6.8 Hz, 2H), 2.11 (d, J =
7.2 Hz, 2H), 2.00 – 1.93 (m, 1H), 0.94 (d, J = 7.0 Hz, 6H);
13C NMR (126 MHz, CDCl3) δ 192.2, 177.1, 105.6, 67.9, 44.0,
35.7, 26.5, 22.3. HRMS (ESI) calculated for C9H15O2 [M+H]+:
155.1067; found: 155.1070.
+
HRMS (ESI) calculated for C14H19O [M+H] : 203.1430;
found: 203.1433.
General Procedure for the Oxidation of Enamides 1
and 2H-Pyrans 4. TBHP (70 wt% in water, 0.17 mL, 1.0
mmol) was added in one portion into a mixture of 1 or 4
(0.2 mmol, 1 equiv), NaOAc (8.2 mg, 0.1 mmol, 0.5 equiv)
and Rh2(cap)4 (0.32 mg, 0.00049 mmol, 0.25 mol%) in
0.75 mL of DCM at room temperature under air
atmosphere. Characteristic of the oxidative conversion of
dirhodium(4+) to dirhodium(5+), the color of the reaction
mixture turned a red color. The reaction was complete in
1-2 hours. After concentration, the residue was purified by
flash chromatography on silica gel using hexanes:ethyl
acetate (5:1→3:1) as the eluent to afford the corresponding
product 2 or 5. Product yields are the isolated yields of
both regioisomers if R2 is H. Product ratios were
determined by 1H NMR.
6-(3-Phenylpropyl)-2H-pyran-4(3H)-one (5d). 55% yield.
Colorless oil. H NMR (500 MHz, CDCl3) δ 7.33 – 7.27 (m,
1
2H), 7.23 – 7.13 (m, 3H), 5.34 (s, 1H), 4.44 (t, J = 6.8 Hz,
2H), 2.65 (t, J = 7.6 Hz, 2H), 2.51 (t, J = 6.8 Hz, 2H), 2.27 (t,
J = 7.6 Hz, 2H), 1.90 (p, J = 7.6 Hz, 2H); 13C NMR (126 MHz,
CDCl3) δ 192.2, 177.4, 141.2, 128.4, 126.1, 104.8, 104.7, 68.0,
35.7, 35.1, 34.2, 27.8. HRMS (ESI) calculated for C14H17O2
[M+H] +: 217.1223; found: 217.1225.
ASSOCIATED CONTENT
The Supporting Information is available free of charge on the
ACS Publications website at DOI: Experimental tables,
1
details of reaction time courses with additives, and H and
Characterization data for 2 and 5. Characterization
data of compounds 2a,15a 2b,12c 2c,13 2e,37 2i,38 3a,39 3b,40
3c,41 3d,42 5a,43 644 were previously reported and their
spectral or HPLC confirmation are provided in the
Supporting Information.
13C NMR spectra of new compounds.
AUTHOR INFORMATION
Corresponding Author
tert-Butyl
5-Oxo-2,3,4,5-tetrahydro-1H-azepine-1-
carboxylate (2d). 62% yield of 2d and 3d (2d:3d = 90:10).
Colorless oil 1H NMR (500 MHz, CDCl3) δ 7.44 (d, J = 10.6
*michael.doyle@utsa.edu
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Notes
The Journal of Organic Chemistry
Chem. Soc. 2003, 125, 4018. d) Andeassen, T.; Haland, T.; Hansen,
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2
L. K.; Gautun, O. R. Tetrahedron Lett. 2007, 48, 8413. e)
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Soc. 2004, 126, 13622.
The authors declare no competing financial interest.
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ACKNOWLEDGMENT
Support for this research from the The Welch Foundation
(AX−1871) is gratefully acknowledged. The HRMS used in this
research is supported by a grant from the National Institutes
of Health (G12MD007591).
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47
48
49
50
51
52
53
54
55
56
57
58
59
60
10
ACS Paragon Plus Environment