(Cyclopentadienone)iron-Catalyzed Transfer Dehydrogenation of Symmetrical and Unsymmetrical Diols to Lactones

Article abstract of DOI:10.1021/acs.joc.9b01884

Air-stable iron carbonyl compounds bearing cyclopentadienone ligands with varying substitution were explored as catalysts in dehydrogenative diol lactonization reactions using acetone as both the solvent and hydrogen acceptor. Two catalysts with trimethylsilyl groups in the 2- A nd 5-positions, [2,5-(SiMe₃)₂-3,4-(CH₂)₄(δ⁴-C₄C= O)]Fe(CO)₃ (1) and [2,5-(SiMe₃)₂-3,4-(CH₂)₃(δ⁴-C₄C= O)]Fe(CO)₃ (2), were found to be the most active, with 2 being the most selective in the lactonization of diols containing both primary and secondary alcohols. Lactones containing five-, six-, and seven-membered rings were successfully synthesized, and no over-oxidations to carboxylic acids were detected. The lactonization of unsymmetrical diols containing two primary alcohols occurred with catalyst 1, but selectivity was low based on alcohol electronics and modest based on alcohol sterics. Evidence for a transfer dehydrogenation mechanism was found, and insight into the origin of selectivity in the lactonization of 1°/2° diols was obtained. Additionally, spectroscopic evidence for a trimethylamine-ligated iron species formed in solution during the reaction was discovered.

Full text of DOI:10.1021/acs.joc.9b01884

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Article
(Cyclopentadienone)iron-Catalyzed Transfer Dehydrogenation
of Symmetrical and Unsymmetrical Diols to Lactones
Yidan Tang, Rowan I. L. Meador, Casina T. Malinchak, Emily E. Harrison,
Kimberly A. McCaskey, Melanie C. Hempel, and Timothy W Funk
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b01884 • Publication Date (Web): 27 Dec 2019
Downloaded from pubs.acs.org on December 30, 2019
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(
Cyclopentadienone)iron-Catalyzed Transfer Dehydrogenation of
Symmetrical and Unsymmetrical Diols to Lactones
†
‡
§
ǁ
Yidan Tang, Rowan I. L. Meador, Casina T. Malinchak, Emily E. Harrison, Kimberly A.
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McCaskey, Melanie C. Hempel, and Timothy W. Funk*
Department of Chemistry, Gettysburg College, Gettysburg, Pennsylvania 17325, United
States
*
tfunk@gettysburg.edu
†
current address: Department of Chemistry, Vanderbilt University, Nashville, Tennessee
37235, United States
‡
1
current address: Department of Chemistry, Syracuse University, Syracuse, New York
3244, United States
§ current address: The Ph.D. Program in Chemistry, The Graduate Center of the City
University of New York, New York, New York 10016, United States
ǁ current address: Department of Chemistry, University of North Carolina at Chapel Hill,
Chapel Hill, North Carolina 27599, United States
ABSTRACT
Air-stable iron carbonyl compounds bearing cyclopentadienone ligands with varying
substitution were explored as catalysts in dehydrogenative diol lactonization reactions using
acetone as both the solvent and hydrogen acceptor. Two catalysts with trimethylsilyl groups
4
in the 2- and 5-positions—[2,5-(SiMe ) -3,4-(CH ) (η -C C=O)]Fe(CO) (1) and [2,5-
3
2
2 4
4
3
4
(
SiMe ) -3,4-(CH ) (η -C C=O)]Fe(CO) (2)—were found to be the most active, with 2 being
3 2 2 3 4 3
the most selective in the lactonization of diols containing both primary and secondary
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alcohols. Lactones containing five-, six-, and seven-membered rings were successfully
synthesized, and no over-oxidations to carboxylic acids were detected. The lactonization of
unsymmetrical diols containing two primary alcohols occurred with catalyst 1, but
selectivity was low based on alcohol electronics and modest based on alcohol sterics.
Evidence for a transfer dehydrogenation mechanism was found, and insight into the origin
of selectivity in the lactonization of 1°/2° diols was obtained. Additionally, spectroscopic
evidence for a trimethylamine-ligated iron species formed in solution during the reaction
was discovered.
0
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INTRODUCTION
Lactones are common structural features found in natural products and biologically
active compounds,1,2 and they can also be used as monomers in the synthesis of
3
biodegradable polyesters using ring-opening polymerizations. One efficient way to access
these versatile compounds is through the oxidation of diols (Scheme 1), and various methods
using stoichiometric oxidants—including Cr(VI) species,4,5 manganese oxides,6,7 sodium
8
9
10
bromite, Raney nickel, and silver carbonate —have been developed. Additionally,
oxidative lactonizations of diols using organic or metal-based catalysts with terminal
11
12,13
hypervalent iodine,14,15 or molecular oxygen,16–21
oxidants such as bleach, peroxides,
are also known. There are a few examples of acceptorless dehydrogenations22,23 of diols to
lactones catalyzed by Ru,24,25 Ir,26,27 Fe,28,29 and Co,30 which typically require high
temperatures and/or strong bases or have a limited substrate scope. A majority of the
catalytic approaches use strong oxidants, but there are concerns about safety and selectivity
when organic compounds are treated with them either alone or as terminal oxidants in
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catalytic reactions. Transfer dehydrogenations avoid strong oxidants by employing less
reactive organic hydrogen acceptors, and simple carbonyl compounds have been used as
3
1
32–37
both the solvent and terminal oxidant in iridium-catalyzed and ruthenium-catalyzed
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lactonizations of diols. While these processes avoid strong oxidants, they use rare metals.
Long-term environmental and economic sustainability are of growing importance, so new
catalytic methods using earth-abundant metals are desirable.
Scheme 1. Oxidative lactonization of a diol.
OH
O
O
O
OH
OH
O
[
O]
[O]
OH
Recently, it has been shown that (cyclopentadienone)iron carbonyl compounds can
catalyze transfer dehydrogenations of alcohols to carbonyl compounds using acetone as the
stoichiometric oxidant (i.e., Oppenauer-type oxidation), and even a few simple diols have
been lactonized.38–44 Scheme 2 illustrates the activation of the catalyst with trimethylamine
N-oxide to form unsaturated species A and the reversibility of the catalytic cycle. In addition
to being based on iron—the second most-abundant metal in the earth’s crust—these
compounds do not require a base to be activated, they have air-stable pre-catalysts, and even
during catalysis they are not moisture sensitive.45–47 Additionally, they react
chemoselectively and tolerate the presence of a variety of functional groups, including nitro
groups, esters, alkenes, alkynes, aryl halides, ethers, aliphatic epoxides, and
cyclopropanes.40,42,48 Due to their desirable properties and ease of use, we explored the
reactivity of a selection of (cyclopentadienone)iron carbonyl compounds in the transfer
dehydrogenation of symmetrical and unsymmetrical diols to lactones (Figure 1).
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Scheme 2. Transfer dehydrogenation of alcohols and transfer hydrogenation of carbonyls
with (cyclopentadienone)iron carbonyl compounds.
OH
O
0
1
2
3
4
5
6
7
8
9
0
1
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R1 R2
R1
R2
R
R
O
R
R
Fe
R
OC
OC
R
OH
A
R
R
Fe
OC
OC
H
B
R
R
R
O
R
O
Me3NO
–CO2
R
R
R
R
Fe
Fe
O
OC
OC
OC
OC
CO
–Me3N
A
OH
TMS
TMS
TMS
TMS
O
O
O
O
O
TMS
CO
TMS
CO
TMS
CO
TMS
NCCH3
Fe
Fe
Fe
Fe
OC
OC
OC
OC
OC
OC
OC
OC
1
2
3
4
Ph
Ph
Ph
CH3
O
O
O
O
O
Ph
Ph
CO
Ph
CH3
Fe
Fe
Fe
Fe
OC
Ph
CO
OC
OC
CO
OC
CO
OC
OC
OC
OC
5
6
7
8
DMPh
O
Ph
Et
CH3
Ph
Ph
O
Ph
O
Ph
O
Ph
DMPh
CO
Ph
Ph
Et
Ph
CH3
Fe
Fe
Fe
Fe
OC
OC
OC
CO
OC
CO
OC
CO
OC
10
OC
11
OC
12
9
Figure 1. Iron catalysts examined in this study. TMS = trimethylsilyl; DMPh = 3,5-dimethylphenyl.
RESULTS AND DISCUSSION
We expected the process outlined in Scheme 1 to occur with (cyclopentadienone)iron
carbonyl compounds: one primary alcohol would be oxidized to the aldehyde, the lactol
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would reversibly form, and it would undergo a second dehydrogenation to form the lactone.
A major advantage of using a transfer dehydrogenation catalyst was that no over-oxidation
4
9
of the aldehyde to the carboxylic acid would occur. We chose acetone as both the solvent
and hydrogen acceptor because it ranks favorably in health, safety, and environmental
considerations,50–52 but its relatively low oxidation potential meant the equilibrium between
a primary alcohol/acetone and aldehyde/isopropanol would favor the alcohol/acetone side
1
1
1
1
1
1
1
1
1
1
2
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(
eq. 1).49,53 Unfortunately, the oxidation of a primary alcohol to an aldehyde was the first step
in the desired transformation (Scheme 1). This challenge could be overcome if lactone
formation was irreversible, and (cyclopentadienone)iron carbonyl compounds do not
reduce esters, which suggested lactones could also be unreactive.42,44,54
OH
O
O
OH
(1)
R
R
Lactonization of symmetrical diols. Modifications to the cyclopentadienone substitution
affect the reactivity of this class of catalysts.40,41,43,44,55–60 Therefore, we examined a collection
of twelve known iron tricarbonyl compounds with varying cyclopentadienone substitution
(Figure 1) in the dehydrogenative lactonization of 1,5-pentanediol (13a), and the results are
shown in Figure 2. Trimethylamine N-oxide was added to activate the catalyst by oxidatively
4
0
removing a carbonyl ligand (Scheme 2). Catalysts 1, 2, 4, and 9, which have sterically bulky
TMS or 3,5-dimethylphenyl groups adjacent to the cyclopentadienone carbonyl, were the
most active. The substitution in the 3- and 4-positions of the cyclopentadienone also had a
large effect on catalyst reactivity, as can be seen when comparing lactone yields with
catalysts 5, 6, 7, and 10. Catalysts with oxygen atoms in the fused ring were less reactive
than those without (3 and 7 vs. 2 and 6, respectively). No aldehydes or lactols were observed
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by H NMR spectroscopy in the crude reaction mixtures after 24 h, which is consistent with
the disfavored equilibrium illustrated in equation 1.
Fe catalyst (2.5 mol %)
Me3NO (2.5 mol %)
O
HO
OH
O
acetone, 90 °C
24 h
13a
0
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9
0
13b
Figure 2. Lactonization of 1,5-pentanediol (13a) with (cyclopentadienone)iron tricarbonyl
catalysts. Reaction conditions: 1,5-pentanediol (1 equiv; 0.5 M in acetone), Fe catalyst (0.025
equiv), anhydrous trimethylamine N-oxide (0.025 equiv), and acetone at 90 °C for 24 h in a sealed,
1
thick-walled test tube. Lactone yield determined by H NMR spectroscopy.
The activity of 1, 2, 4, and 9 in the lactonization of a few other diols was examined
(
Table 1). The TMS-containing catalyst 1 and its acetonitrile derivative 4 afforded the
desired lactones in the highest yields. Compound 4 is activated by heat—the nitrile ligand
dissociates and unsaturated species A (Scheme 2) is generated in solution. While 1 and 4
have similar activities, an extra synthetic step is required to access 4, so 1 was used in
subsequent reactions. When the reactions were run at the reflux temperature of acetone, the
yields were reduced. It has been observed that 9 has alcohol dehydrogenation activity equal
to or greater than 1, but it may be decomposing under the elevated temperature required
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for diol lactonization (see below).44 Iron compound 1 has successfully catalyzed redox
transformations at temperatures >100 °C.46,61,62
Table 1. Comparison of 1, 2, 4, and 9 in diol lactonizations.a
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
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3
4
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4
5
5
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5
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5
6
0
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6
7
8
9
0
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9
0
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9
0
lactone NMR yield (%)
diol
lactone
1
2
4
9
O
OH
OH
>98
(87)
O
>
98 >98
62
14a
14b
OH
O
O
>
98
7
0
95
96
32
10
(
43)
HO
15a
15b
>
98
O
OH
OH
6a
93
(
87)
O
16b
1
aReaction conditions: diol (1 equiv; 0.5 M in acetone), Fe catalyst (0.025 equiv), anhydrous
trimethylamine N-oxide (0.025 equiv), and acetone at 90 °C for 24 h in a sealed, thick-walled test
1
tube. Lactone yield determined by H NMR spectroscopy. Values in parentheses are for reactions run
at reflux (oil bath at 60 °C) in an open vessel under N2.
Table 2 illustrates the scope of symmetrical diols lactonized by 1. Lactones composed
of five-, six-, and seven-membered rings could be generated using this procedure. In some
cases, 5 mol % of catalyst was required to achieve high yields (Table 2, entries 5, 6). Diols
with unrestricted rotation (Table 2, entries 7–11) were lactonized as well as those with less
conformational freedom (Table 2, entries 1–6), although seven-membered lactone 21b was
challenging to form with 2.5 mol % of 1. Lactones bearing coordinating functional groups
(
Table 2, entries 10 and 11) were isolated in low yields, which could be due either to
coordination to the catalyst—decreasing catalyst activity—or a decrease in the reduction
potential of the primary alcohols due to the inductively withdrawing oxygen or BOC-
53
protected nitrogen in 22a and 23a, respectively. The tricarbonyl compound 1 was the
superior catalyst with most substrates, but yields of lactones bearing coordinating functional
groups were a few percent higher when the nitrile-ligated catalyst 4 was used (Table 2,
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entries 10 and 11). A possible explanation for the small increase in yield relates to the
acetonitrile ligand. If the substrate coordinated to unsaturated species A, the nitrile ligand
could assist in dissociating it from the iron, regenerating the catalytically active species.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
Again, no aldehydes or lactols were observed in the H NMR spectra of the crude reaction
mixtures after 24 h.
Table 2. Symmetrical diols lactonized by 1.a
1 (2.5 mol %)
Me3NO (2.5 mol %)
OH
OH
O
O
acetone, 90 °C
24 h
yield (%)b
entry
1
diol
lactone
O
OH
OH
O
92
14a
14b
OH
O
O
2
3
87
89
HO
1
5a
15b
O
OH
OH
6a
O
16b
1
O
OH
OH
4
O
95
87
1
7a
1
7b
O
OH
OH
5c
O
1
8a
18b
HO
OH
O
O
6d
88
1
9a
0a
19b
O
O
OH
HO
77e
90
7
8
2
20b
O
O
O
HO
OH
13a
1
3b
O
HO
OH
~21e
34
9
21a
2
1b
O
O
HO
OH
O
1
0f
22a
O
2
2b
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O
O
HO
OH
N
1
1f
Boc
23a
N
38
Boc
2
3b
aReaction conditions: unless otherwise noted, diol (1 equiv, 0.5 M in acetone), 1 (0.025 equiv),
anhydrous trimethylamine N-oxide (0.025 equiv), and acetone at 90 °C for 24 h in a sealed, thick-
walled test tube. Isolated yield. 2 and trimethylamine N-oxide loadings of 0.05 equiv (5 mol %)
were used. 1 and trimethylamine N-oxide loadings of 0.05 equiv (5 mol %) were used. Isolated
with small amounts of impurities, including 1; see Experimental Section for details. Catalyst 4 (2.5
b
c
d
e
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
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2
3
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3
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4
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4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
f
mol %) with no trimethylamine N-oxide was used.
A series of reactions was performed to provide evidence for the proposed mechanism
shown in Scheme 2, and Table 3 summarizes the results from the control experiments. When
no iron species was added, no lactone formed (Table 3, entry 1). Trimethylamine N-oxide is
an oxidant and could react similarly to TEMPO—which catalyzes diol lactonizations in the
presence of hypervalent iodine—but no evidence for even stoichiometric alcohol oxidation
was found in the absence of iron.14 At elevated temperature, it is possible for the
cyclopentadienone ligand to dissociate, and the remaining Fe(CO) species could be
x
catalytically active. The fact that cyclopentadienone substitution affected catalyst activity
suggested this was not the case, but a control experiment was done using Fe(CO) as the
5
catalyst (Table 3, entry 2). No lactone was detected, which is consistent with the need for a
cyclopentadienone ligand. Finally, evidence for a transfer dehydrogenation mechanism was
targeted. When toluene was used in place of acetone as the solvent, 12% of the lactone
formed indicating a few catalyst turnovers (Table 3, entry 3). It is highly unlikely toluene
served as a hydrogen acceptor, so hydrogen gas may be directly released under these
conditions (i.e., an acceptorless dehydrogenation occurred). Shvo’s catalyst, a diruthenium
bridging hydride structurally similar to this class of iron compounds, is known to perform
acceptorless dehydrogenations.63,64 To distinguish between transfer and acceptorless
dehydrogenation mechanisms under the typical conditions, the lactonization of 14a was run
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1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
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3
3
3
3
4
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4
4
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5
5
5
6
1
in acetone-d and a H NMR spectrum was taken. The reaction went to 92% conversion, and
6
a signal at 3.87 ppm indicated the presence of isopropanol-d in a 2:1 molar ratio relative to
6
the lactone (Figure 3). This evidence strongly supports the transfer dehydrogenation
mechanism where two oxidations are required for lactone formation.
Table 3. Control experiments.a
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Fe catalyst (2.5 mol %)
Me3NO (2.5 mol %)
O
HO
OH
O
solvent, 90 °C
24 h
13a
13b
entry
catalyst
solvent
acetone
acetone
toluene
NMR yield (%)
1
2b
3
none
Fe(CO)
1
ND
ND
12
5
aReaction conditions: unless otherwise noted, diol (1 equiv, 0.5 M in acetone), catalyst (0.025
equiv), anhydrous trimethylamine N-oxide (0.025 equiv), and acetone at 90 °C for 24 h in a sealed,
thick-walled test tube. NMR yields determined by peak areas in the H NMR spectrum relative to
biphenyl as an internal standard. ND = none detected. Trimethylamine N-oxide loading of 0.05
1
b
equiv (5 mol %) was used.
1
(2.5 mol %)
O
OH
CD3
OH
OH
Me3NO (2.5 mol %)
acetone-d6, 90 °C
O
D3C
24 h
14a
14b
9
2% conversion
1
:
2
Figure 3. Evidence for a transfer dehydrogenation mechanism.
Lactonization of unsymmetrical diols. We also explored how this class of catalysts reacted
with unsymmetrical diols, including substrates with two primary alcohols and those with
one primary and one secondary alcohol. These diols were expected to be challenging
substrates due to selectivity issues. For example, in the dehydrogenation of 1,5-hexanediol
(
24a), an initial oxidation of the primary alcohol would lead to the desired product (24b,
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Scheme 3, path 1), but oxidation of the secondary alcohol would not afford lactone (Scheme
3
, path 2). Unfortunately, secondary alcohols are typically more readily oxidized than
6
5
primary alcohols in transfer dehydrogenations with acetone as the hydrogen acceptor, but
the equilibrium-driven nature of most steps in the process could lead to high yields of lactone
if they were truly reversible, the catalyst remained active, and lactonization was irreversible.
Scheme 3. Possible reaction pathways in the oxidative lactonization of an unsymmetrical diol.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
OH
O
OH
[O]
[
O]
O
O
O
path 1
25
26
24b
OH
HO
24a
HO
path 2
O
[
O]
O
X
[
O]
HO
27
2
8
The same twelve iron tricarbonyl compounds were explored in the lactonization of
24a (Figure 4). Reaction outcomes were determined by gas chromatography, and both diol
consumption (conversion) and lactone formation (yield) were tracked. Quite a few catalysts
dehydrogenated the diol, but only the TMS-containing catalysts (1–4) afforded lactone 24b
in >50% yield, with 2 outperforming the rest. Structural changes to the 3- and 4-positions of
the cyclopentadienone again affected catalyst activity (catalysts 5, 6, 7, and 10 in Figure 4).
1
To gain insight into what other products were forming, H NMR spectra of the crude reaction
mixtures generated using catalysts 5, 7, 9, 10, and 12 were analyzed. In all cases the major
products were a mixture of 6-hydroxy-2-hexanone (27) and its lactol 28, indicating that path
2
in Scheme 3 was being followed when many of the catalysts were used.66–68 The presence
of these compounds is consistent with this class of catalysts being generally selective for
oxidizing secondary alcohols over primary.39,40,44
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1
1
1
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1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
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5
5
5
5
5
5
5
5
5
5
6
Fe catalyst (2.5 mol %)
Me3NO (2.5 mol %)
O
OH
O
acetone, 90 °C
HO
24 h
24a
24b
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Figure 4. Lactonization of 1,5-hexanediol with (cyclopentadienone)iron tricarbonyl catalysts.
Reaction conditions: 1,5-hexanediol (1 equiv, 0.5 M in acetone), Fe catalyst (0.025 equiv),
anhydrous trimethylamine N-oxide (0.025 equiv), biphenyl (0.25 equiv), and acetone at 90 °C for 24
h in a sealed, thick-walled test tube. Diol conversion and lactone yield determined by gas
chromatography relative to biphenyl.
Many of the catalyst systems that selectively form lactones from 1°/2° diols are also
selective for the oxidation of primary alcohols over secondary alcohols.14,18,34,35
(Cyclopentadienone)iron carbonyl compounds dehydrogenate secondary alcohols
efficiently but afford low yields of aldehydes from primary alcohols when acetone is used as
the hydrogen acceptor, presumably due to the disfavored equilibrium (eq. 1).39,40,42,44 The
selectivity of 1–4 for path 1 in Scheme 3 may be due to the sterically bulky TMS groups
decreasing the rate of secondary alcohol dehydrogenation relative to primary alcohols and
the irreversibility of the dehydrogenation leading to lactone formation. To gain insight into
the origins of selectivity, lactol 2669 (as a mixture of stereoisomers) was treated with
catalysts 2 and 10 under the established reaction conditions. One equivalent of isopropanol
relative to 26 was added because it would be present in solution under normal conditions
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after the dehydrogenation of the first alcohol. As shown in Figure 5, lactol 26 was converted
into lactone 24b with a small amount of ketone 27 and no detectable starting material with
both catalysts. Alternatively, ketone 27 was the major product when diol 24a was treated
with tetraphenyl catalyst 10 (Scheme 3, path 2). These results are consistent with the initial
oxidation of the diol acting as the selectivity-determining step, because once lactol 26 forms
(from the oxidation of the primary alcohol of diol 24a), it goes on to form lactone with both
catalysts. As noted above, the bulky TMS groups on the 2- and 5-positions of the
cyclopentadienone ring of 2 may decrease the rate of secondary alcohol oxidation and
initially favor the oxidation of the primary alcohol (Scheme 3, path 1). As shown in Figure 5,
the resulting lactol would then preferentially form lactone. With catalyst 10, it is likely that
lactol 26 does not form; instead, the secondary alcohol is oxidized directly to ketone 27. The
fact that a small amount of ketone 27 was present when both catalysts were used shows that
lactol formation from the diol was reversible, but formation of lactone from lactol was
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
favored.
2 or 10 (2.5 mol %)
OH
Me3NO (2.5 mol %)
2-PrOH (1 equiv)
O
O
O
O
acetone, 90 °C
HO
24 h
>
98% conversion
26
24b
27
with 2:
with 10:
14
10
:
:
1
1
Figure 5. Dehydrogenation of lactol 26 to lactone 24b with catalysts 2 and 10.
The activity and selectivity of catalysts 1 and 2 in the lactonization of other
unsymmetrical diols were explored (Table 4). Lactonizations of diols with both primary and
secondary alcohols using catalyst 2 remained selective for the lactone when both alcohols
were either benzylic or aliphatic (Table 4, entries 1–4). When a diol with a secondary
benzylic and primary aliphatic alcohol was dehydrogenated, the lactone (32b) was the major
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1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
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5
5
5
5
5
5
5
5
5
6
product but the ketone from secondary alcohol oxidation also formed formed (Table 4, entry
5
). Unsymmetrical diols bearing two primary alcohols were also dehydrogenated using 1.
Table 4, entry 6 illustrates that selectivity based on diol electronics was low when it
contained both a benzylic and an aliphatic primary alcohol—only a slight excess of lactone
from the initial dehydrogenation of the benzylic alcohol occurred. Steric hindrance close to
one of the primary alcohols led to modest selectivity that favored the lactone formed by
dehydrogenation of the less hindered alcohol (Table 4, entry 7). Catalyst systems based on
Ru, W, Ir, and Cu all showed higher selectivity (>9:1) for 34b over 34c when using diol
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
4a.12,20,31–33
3
Table 4. Unsymmetrical diols lactonized by 1 and 2.a
1
or 2 (2.5 mol %)
OH
OH
O
O
Me3NO (2.5 mol %)
acetone, 90 °C
24 h
yield
entry
diol
lactone
b
(
%)
O
O
OH
1
HO
69c
86
24a
24b
O
OH
OH
O
2
2
3
9a
2
9b
O
OH
OH
3d
O
Ph
O
77
Ph
0a
3
0b
OH
OH
O
4d
5
88
H
H
O
3
1a
3
1b
OH
O
OH
72e
Ph
32a
Ph
32b
O
OH
OH
O
O
6f
91
O
33b
33c
33a
1.3
:
1
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O
O
O
O
HO
OH
7f
87
3
4a
3
4b
34c
2.6
:
1
aReaction conditions: unless otherwise noted, diol (1 equiv, 0.5 M in acetone), 2 (0.025 equiv),
anhydrous trimethylamine N-oxide (0.025 equiv), and acetone at 90 °C for 24 h in a sealed, thick-
walled test tube. Isolated yields. Isolated with small amounts of impurities, including 2; see
Experimental Section for details. Catalyst 2 and trimethylamine N-oxide loadings of 0.04 equiv (4
mol %) were used. The minor reaction product was 4-hydroxy-1-phenyl-1-butanone. Catalyst 1
and trimethylamine N-oxide (2.5 mol % of both) were used.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
b
c
d
e
f
Catalyst stability and active species. Cyclopentadienone structure dramatically affects
catalyst activity, but the origin of the effect is not clear. A series of NMR experiments was
performed to gain insight into catalyst structure under the reaction conditions (Figure 6).
1
13
First, H and C NMR spectra were taken of solutions of 1, trimethylamine N-oxide, and
either diol 13a or 14a in a 1:1:5 molar ratio in acetone-d at 80 °C. The solutions were held
6
at 80 °C in the spectrometer for approximately 10–15 minutes before spectral data were
collected. The reaction solutions were then cooled to 50 °C and additional spectra were
taken.
13b
1
1
Me3NO
Me3NO
13a
14a
14b
acetone-d6
0 °C, 50 °C
8
10
Me3NO
13a
limited reaction
Figure 6. NMR experiments performed; catalyst:Me NO:diol ratio = 1:1:5.
3
Diol lactonization occurred at 80 °C with catalyst 1; peaks corresponding to both
lactone 13b or 14b were observed along with isopropanol-d . With 13a, the ratio of diol to
6
lactone 13b was ~1:3; with 14a, the diol:lactone ratio was 1.1:1. No signal from
trimethylamine N-oxide (singlet at 3.16 ppm in acetone-d ) was observed, which is
6
consistent with it reacting rapidly with 1 to form unsaturated species A.40 Alcohols are
7
0
known to bind to A, but those compounds are only stable below room temperature. There
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
was no evidence for alcohol-bound species for either 13a or 14a because no shift in the
signals representing the HO-CH carbons or hydrogens were observed, which would occur
2
upon binding to iron.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
There were multiple peaks in the 0–0.4 ppm range of the H NMR spectra indicating
different types of TMS-containing species. The spectra at 80 °C had one major singlet at 0.27
ppm, and at 50 °C there was a second singlet at 0.28 ppm. These signals occurred in reactions
with both 13a and 14a. There were also two sets of signals corresponding to the (CH ) ring
2
4
on the cyclopentadienone of 1: one set at approximately 2.65 ppm and 1.87 ppm, and a
second set at 2.27 ppm and 1.61 ppm. The former are consistent with the spectrum of 1 in
1
3
acetone-d . The only cyclopentadienone signals that appeared in the C NMR spectrum at
6
8
0 °C also matched those found in 1. The latter set of signals for the (CH ) hydrogens were
2 4
shielded and had chemicals shifts similar to those found on the nitrile-ligated compound 4.42
1
A singlet at 2.62 ppm was present in all H NMR spectra using 1, but it was larger in the
1
3
spectra at 50 °C relative to those taken at 80 °C. Additionally, the peak at 1.1 ppm in the C
13
NMR spectra was also larger at 50 °C. Finally, a small signal at 105 ppm in the C NMR
spectrum of the reaction with 13a at 50 °C appeared and was consistent with the spectrum
4
2
of the iron-bound cyclopentadienone in 4. Together, these signals have been assigned to
the trimethylamine-ligated compound 35 (Figure 7). Replacement of the strongly pi-
accepting carbonyl ligand with an amine would be expected to have a similar electronic effect
1
to substituting it with a nitrile ligand. The singlet at 2.62 ppm in the H NMR spectrum was
assigned to the methyl groups of the bound trimethylamine ligand, and the chemical shift
7
1
was similar to those of the methyl groups in [CpFe(CO) (NMe )]Tf N. At lower
2
3
2
temperatures, the equilibrium favored the bound species 35 based on the relative heights of
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the peak at 2.62 ppm at 50 °C and 80 °C. At higher temperatures, trimethylamine dissociated,
giving less of compound 35. A spectrum of 1, trimethylamine N-oxide, and 13a taken at room
temperature—the solution was never heated—showed no lactone 13b, no trimethylamine
N-oxide, and a large singlet at 2.62, which is consistent with 35 forming in solution and being
favored at lower temperatures. Trimethylamine is volatile, but these reactions were
performed in sealed vessels where it was trapped.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
TMS
TMS
O
O
TMS
N
TMS
Fe
Fe
NMe3
OC
OC
35
OC
OC
A
Figure 7. Proposed catalyst resting state 35 and its reversible dissociation of trimethylamine.
1
13
As noted above, multiple TMS signals appeared in the H NMR spectra. In the C NMR
spectra, only three TMS signals appeared. While peaks corresponding to 1 and 35 were
found, no peaks corresponding to the non-TMS atoms of the cyclopentadienone ligand on
other species were present. Additionally, only one signal for CO ligands was observed in all
1
3
1
C NMR spectra and was assigned to 1. In the H NMR spectra of the reaction with 14a,
signals at –12 ppm were observed and are consistent with iron hydride B derived from 1
4
5
(
Scheme 2), which has a chemical shift of –11.62 in C D . Based on the integrations, there
6 6
was only a small amount of iron hydride present at both 50 °C and 80 °C. While iron species
other than 1, 35, and the iron hydride may be present during catalysis, they would need to
be present in small quantities because of the lack of peaks in the NMR spectra. These studies
are consistent with the cyclopentadienone retaining its hapticity and not dissociating when
the CO ligand is removed by trimethylamine N-oxide, but they do not rule out the possibility
of other catalytically active species forming in small amounts. The reaction of 13a with
Fe(CO) (Table 3, entry 2) showed that the presence of cyclopentadienone is important for
5
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
catalytic activity, but the exact nature of how the cyclopentadienone is bound to the iron
during catalysis is still unknown.
Attempts to do the same experiments with catalyst 10 were less successful (Figure
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
6
). Upon heating an acetone-d solution of 10, trimethylamine N-oxide, and 13a to 80 °C,
6
almost no lactonization occurred and a precipitate formed, which caused dramatic peak
broadening in the spectra. No trimethylamine N-oxide was present indicating that it had
reacted with the iron compound, but no peaks similar to the trimethylamine-ligated iron
compound 35 appeared. No iron hydrides were observed out to –30 ppm. Upon dilution, the
precipitate dissolved, but the solution was too dilute to get a 13C NMR spectrum where
cyclopentadienone signals could be observed. It is important to note that no precipitate
formed when the reaction was run under normal conditions (i.e., more dilute) in a sealed
vessel. The main conclusion that can be drawn from this experiment is that the initial rate of
the lactonization of 13a with 10 is much slower than with 1. Peak broadening due to
precipitate formation limited the information available about cyclopentadienone
coordination.
CONCLUSION
The catalytic activity of a series of (cyclopentadienone)iron carbonyl compounds in
the dehydrogenative lactonization of diols was explored. Catalyst 1 and its acetonitrile-
ligated derivative 4 were the most active in the lactonization of symmetrical diols, and
catalyst 2 afforded lactones selectively from diols containing both 1° and 2° alcohols. Catalyst
loadings between 2.5–5 mol % were discovered to be optimal. Five-, six-, and seven-
membered ring lactones were formed, and no over-oxidations of primary alcohols were
observed. The presence of two equivalents of isopropanol-d in a diol lactonization supports
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the proposed transfer dehydrogenation mechanism. The lactonizations of simple diols with
catalysts 1 and 10 were observed by NMR spectroscopy, and reactions with 1 occurred
significantly more quickly. The presence of trimethylamine-ligated iron compound 35 was
proposed based on the spectral data, and its concentration decreased as the temperature
increased. No analogous compound generated from 10 was observed, but peak broadening
in the NMR spectra and the formation of a precipitate limited the amount of information that
could be collected. (Cyclopentadienone)iron carbonyl compounds other than 2 reacted with
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
°/2° diols, but only small amounts of lactone were detected. With catalysts 5, 7, 9, 10, and
2, the major products arose from the oxidation of the secondary alcohol. Both of the most
1
active catalysts contained trimethylsilyl groups in the 2- and 5-positions of their
cyclopentadienone ligands; results from reactions with a lactol intermediate suggest these
sterically bulky groups decrease the rate of secondary alcohol oxidation relative to primary
alcohol oxidation and lead to the higher selectivity observed in the 1°/2° diols. Steric bulk
around one of the alcohols in a diol with two primary alcohols led to the lactone where the
least hindered primary alcohol was dehydrogenated as the major product, but the selectivity
was modest. These results show that lactones derived from symmetrical diols and 1°/2° diols
can be synthesized efficiently using air-stable (cyclopentadienone)iron carbonyl compounds
and acetone as both the solvent and the hydrogen acceptor.
EXPERIMENTAL SECTION
1
13
General Information. All H and C NMR spectra were collected at ambient temperature at
13
4
00 MHz and 100 MHz, respectively. C NMR spectra were proton decoupled. Chemical
shifts are reported in parts per million (ppm) relative to tetramethylsilane. Multiplicities are
abbreviated as follows: singlet (s), doublet (d), triplet (t), quartet (q), quintet (quint), sextet
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
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3
3
3
3
4
4
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4
4
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5
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5
5
5
6
(
(
sext), septet (sept), multiplet (m), and broad (br). Analytical thin-layer chromatography
TLC) was performed using silica gel 60 F254 precoated plates (0.25 mm thickness) with a
fluorescent indicator. Visualization was performed with UV light and/or phosphomolybdic
acid stain. Flash column chromatography was performed using silica gel 60 (230-400 mesh).
Reagent grade acetone was degassed by bubbling nitrogen through it for at least 15 minutes
prior to use, but no attempts were made to dry it. All reactions were performed under a
nitrogen atmosphere unless otherwise noted. All commercial chemicals were used as
received. The following (cyclopentadienone)iron carbonyl compounds were prepared by
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
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5
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9
0
known methods: 1–2,72,73 3, 4, 5–6, 7, 8, 9–12. The following diols were prepared
73
42
74
41
75
44
7
6
77
29
26
78
by known methods: racemic 17a and 18a, 23a, 29a and 33a, 30a and 32a, 31a,
3
4a.79 Lactol 26 was prepared as a mixture of stereoisomers by DIBAL reduction of δ-
hexalactone.69,80
General procedure for diol lactonization: A solution of diol (0.5 M in acetone),
(
cyclopentadienone)iron carbonyl compound, and anhydrous trimethylamine N-oxide in
degassed acetone in a thick-walled, screw-top tube was placed in a 90 °C oil bath. After
stirring for 24 hours, the reaction solution cooled to room temperature, the solvent was
evaporated under reduced pressure, and the crude product was purified by flash
chromatography.
Phthalide (14b). Following the general procedure, 1,2-benzendimethanol (14a) (198 mg,
1.43 mmol, 1 equiv), 1 (15 mg, 0.036 mmol, 0.025 equiv), and trimethylamine N-oxide (2.7
mg, 0.036 mmol, 0.025 equiv) in acetone (2.9 mL) afforded 177 mg (92%) of 14b as a pale
yellow solid after purification by flash chromatography (80% hexanes/20% ethyl acetate, Rf
1
= 0.30). H NMR (CDCl , ppm): δ 7.92 (d, J = 7.6 Hz, 1H), 7.70 (t, J = 7.6 Hz, 1H), 7.55 (d, J = 8.0
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1
Hz, 2H), 7.52 (d, J = 7.6 Hz, 1H), 5.34 (s, 2H). C{ H} NMR (CDCl , ppm): δ 171.1, 146.6, 134.0,
3
1
29.0, 125.7, 122.2, 69.7. Spectral data matched those found in the literature.20,81
Dibenzo[c,e]oxepin-5(7H)-one (15b). Following the general procedure, 2,2’-
biphenyldimethanol (15a) (307 mg, 1.43 mmol, 1 equiv), 1 (15 mg, 0.036 mmol,
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
0
.025 equiv), and trimethylamine N-oxide (2.7 mg, 0.036 mmol, 0.025 equiv) in acetone (2.9
mL) afforded 261 mg (87%) of 15b as a pale yellow solid after purification by flash
1
chromatography (80% hexanes/20% ethyl acetate, R = 0.50). H NMR (CDCl , ppm): δ
f
3
7
2
1
6
.99 (d, J = 7.2 Hz, 1H), 7.70–7.61 (m, 3H), 7.57–7.51 (m, 2H), 7.48–7.42 (m, 2H), 5.02 (d, J =
1
3
1
3.2
Hz,
2H). C{ H}
NMR
(CDCl3,
ppm):
δ
70.3, 139.0, 137.3, 134.9, 132.6, 132.0, 130.7, 130.2, 128.74, 128.71, 128.6, 128.5,
9.2. Spectral data matched those found in the literature.20
3
,4,7,7-Tetrahydro-4,7-methanoisobenzofuran-1(3H)-one (16b). Following the general
procedure, 5-norbornene-2-endo,3-endo-dimethanol (16a) (221 mg, 1.43 mmol, 1 equiv), 1
15 mg, 0.036 mmol, 0.025 equiv), and trimethylamine N-oxide (2.7 mg, 0.036 mmol,
(
0
.025 equiv) in acetone (2.9 mL) afforded 191 mg (89%) of 16b as a colorless oil after
1
purification by flash chromatography (80% hexanes/20% ethyl acetate, R = 0.29). H NMR
f
(CDCl , ppm): δ 6.32–6.27 (m, 2H), 4.29 (dd, J = 9.6, 8.4 Hz, 1H), 3.80 (dd, J = 3.2, 9.6
3
Hz, 1H), 3.33–3.36 (m, 1H), 3.26 (dd, J = 4.4, 9.2 Hz, 1H), 3.14–3.07 (m, 2H), 1.65 (dt, J = 1.6,
1
3
1
7
.2 Hz, 1H), 1.47 (d, J
=
8.4 Hz, 1H). C{ H} NMR (CDCl3, ppm):
δ
178.1, 136.9, 134.4, 70.3, 51.8, 47.6, 46.1, 45.8, 40.3. Spectral data matched those found in
the literature.20
trans-Hexahydroisobenzofuran-1(3H)-one (17b). Following the general procedure,
racemic 17a (207 mg, 1.43 mmol, 1 equiv), 1 (15 mg, 0.036 mmol, 0.025 equiv), and
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2
2
2
2
2
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3
3
3
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trimethylamine N-oxide (2.7 mg, 0.036 mmol, 0.025 equiv) in acetone (2.9 mL) afforded 190
mg (95%) of 17b as a pale yellow oil after purification by flash chromatography (85%
1
hexanes/15% ethyl acetate, R = 0.30). H NMR (CDCl , ppm): δ 4.36 (dd, J = 6.4, 8.4 Hz, 1H),
f
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
1
.85 (dd, J = 8.4, 10.8 Hz, 1H), 2.19–2.14 (m, 1H), 2.04–1.84 (m, 5H), 1.32–
1
3
1
.23 (m, 4H). C{ H} NMR (CDCl , ppm): δ 177.6, 72.2, 45.2, 43.6, 28.1, 25.5, 24.9, 24.8.
3
Spectral data matched those found in the literature.31
cis-Hexahydroisobenzofuran-1(3H)-one (18b). Following the general procedure,
racemic 18a (230 mg, 1.60 mmol, 1 equiv), 2 (32 mg, 0.080 mmol, 0.05 equiv), and
trimethylamine N-oxide (6.0 mg, 0.080 mmol, 0.05 equiv) in acetone (3.2 mL) afforded 195
mg (87%) of 18b as a pale yellow oil after purification by flash chromatography (85%
1
hexanes/15% ethyl acetate, R = 0.30). H NMR (CDCl , ppm): δ 4.20 (dd, J = 4.8, 8.8 Hz,
f
3
1
1
H), 3.95 (d, J = 8.8 Hz, 1H), 2.66–2.62 (m, 1H), 2.50–2.43 (m, 1H), 2.14–2.10 (m, 1H), 1.85–
1
3
1
.81 (m, 1H), 1.67–1.59 (m, 3H), 1.30–1.18 (m, 3H). C{ H} NMR (CDCl , ppm):
3
δ 178.5, 71.8, 39.5, 35.4, 27.2, 23.4, 22.9, 22.5. Spectral data matched those found in the
literature.31
1H,3H-Benzo[de]isochromen-1-one (19b). Following the general procedure, 1,8-
naphthalenedimethanol (19a) (270 mg, 1.43 mmol, 1 equiv), 1 (30 mg, 0.072 mmol, 0.05
equiv), and trimethylamine N-oxide (5.4 mg, 0.072 mmol, 0.05 equiv) in acetone (2.9 mL)
afforded 232 mg (88%) of 19b as a pale yellow solid after purification by flash
1
chromatography (85% hexanes/15% ethyl actate, R = 0.26). H NMR (CDCl , ppm): δ 8.41
f
3
(
dd, J = 0.8, 7.2 Hz, 1H), 8.12 (dd, J = 0.8, 8.0 Hz, 1H), 7.86 (d, J = 8.4 Hz, 1H), 7.67 (dd, J = 7.6,
1
3
1
8
.0 Hz, 1H), 7.57 (t, J = 8.0 Hz, 1H), 7.38 (dd, J = 1.2, 7.2 Hz, 1H), 5.84 (s, 2H). C{ H} NMR
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(
benzene-d , ppm): δ 163.1, 132.8, 132.1, 128.8, 128.5, 127.8, 126.5, 126.3, 126.2, 121.2,
6
1
21.1, 69.4. Spectral data matched those found in the literature.29
γ-Butyrolactone (20b). Following the general procedure, 1,4-butanediol (20a) (144 mg,
.60 mmol), 1 (17 mg, 0.040 mmol, 0.025 equiv), and trimethylamine N-oxide (3 mg, 0.04
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
mmol, 0.025 equiv) in acetone (3.2 mL) afforded 119 mg (89 wt. % of 20b; 77% yield) of a
mixture of 20b and 1 in a 40:1 ratio as a yellow oil after purification by flash chromatography
on a 1.8 cm wide column with 7–8 cm of silica gel. Attempts to visualize 20b on the TLC plate
using standard stains (KMnO , anisaldehyde, vanillin, phosphomolybdic acid, ceric
4
ammonium molybdate, and I ) were unsuccessful, so it was purified by eluting with
2
approximately 30 mL of 95% cyclohexane/5% MTBE until a yellow band came off, followed
by elution with 100 mL of 40% cyclohexane/40% dichloromethane/20% MTBE. The
4
0/40/20 fraction was evaporated to afford 20b, which contained small amounts of
1
impurities. H NMR (CDCl , ppm): δ 4.36 (t, J = 7.2 Hz, 2H), 2.51 (t, J = 8.0 Hz, 2H), 2.28 (quint,
3
1
3
1
J = 7.6 Hz, 2H). C{ H} NMR (CDCl , ppm): δ 177.8, 68.6, 27.8, 22.1. Spectral data matched
3
those found in the literature.20
δ-Valerolactone (13b). Following the general procedure, 1,5-pentanediol (13a) (166 mg,
1.60 mmol), 1 (17 mg, 0.040 mmol, 0.025 equiv), and trimethylamine N-oxide (3 mg, 0.04
mmol, 0.025 equiv) in acetone (3.2 mL) afforded 144 mg (90%) of 13b as a pale yellow solid
after purification by flash chromatography on a 1.8 cm wide column with 7–8 cm of silica gel.
Attempts to visualize 13b on the TLC plate using standard stains (KMnO , anisaldehyde,
4
vanillin, phosphomolybdic acid, ceric ammonium molybdate, and I ) were unsuccessful, so it
2
was purified by eluting with approximately 30 mL of 95% cyclohexane/5% MTBE until a
yellow band came off, followed by elution with 100 mL of 40% cyclohexane/40%
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2
2
2
2
2
2
2
3
3
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3
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5
5
5
5
5
5
5
5
5
6
1
dichloromethane/20% MTBE. The 40/40/20 fraction was evaporated to afford 13b. H NMR
1
3
1
(
CDCl , ppm): δ 4.35 (t, J = 6.0 Hz, 2H), 2.56 (t, J = 6.8 Hz, 2H), 1.96-1.83 (m, 4H). C{ H} NMR
3
(CDCl , ppm): δ 171.5, 69.5, 29.8, 22.3, 19.1. Spectral data matched those found in the
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
literature.20
ε-Caprolactone (21b). Following the general procedure, 1,6-hexanediol (21a) (189 mg,
1.60 mmol), 1 (17 mg, 0.040 mmol, 0.025 equiv), and trimethylamine N-oxide (3 mg, 0.04
mmol, 0.025 equiv) in acetone (3.2 mL) afforded 42 mg (approximately 90 wt. % of 21b;
approximately 21% yield) of a mixture of 21b and 1 in a 33:1 ratio (as well as other small
impurities) as a yellow oil after purification by flash chromatography on a 1.8 cm wide
column with 7–8 cm of silica gel. Attempts to visualize 21b on the TLC plate using standard
stains (KMnO , anisaldehyde, vanillin, phosphomolybdic acid, ceric ammonium molybdate,
4
and I ) were unsuccessful, so it was purified by eluting with approximately 30 mL of 95%
2
cyclohexane/5% MTBE until a yellow band came off, followed by elution with 100 mL of 40%
cyclohexane/40% dichloromethane/20% MTBE. The 40/40/20 fraction was evaporated to
1
afford 21b. H NMR (CDCl , ppm): δ 4.23 (t, J = 4.8 Hz, 2H), 2.66-2.63 (m, 2H), 1.87-1.76 (m,
3
1
3
1
6
H). C{ H} NMR (CDCl , ppm): δ 176.2, 69.3, 34.6, 29.3, 29.0, 22.9. Spectral data matched
3
those found in the literature.20
,4-Dioxan-2-one (22b). Following the general procedure, diethylene glycol (22a) (148
1
mg, 1.39 mmol) and 4 (15 mg, 0.035 mmol, 0.025 equiv) in acetone (2.8 mL) afforded 49 mg
(34%) of 22b as a yellow oil after purification by flash chromatography on a 1.8 cm wide
column with 7–8 cm of silica gel. Attempts to visualize 22b on the TLC plate using standard
stains (KMnO , anisaldehyde, vanillin, phosphomolybdic acid, ceric ammonium molybdate,
4
and I ) were unsuccessful, so it was purified by eluting with approximately 30 mL of 95%
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cyclohexane/5% MTBE until a yellow band came off, followed by elution with 100 mL of 40%
cyclohexane/40% dichloromethane/20% MTBE. The 40/40/20 fraction was evaporated to
1
afford 22b. H NMR (CDCl , ppm): δ 4.50 (t, J = 4.8 Hz, 2H), 4.37 (s, 2H), 3.88 (t, J = 4.8 Hz,
3
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
13
1
2
H). C{ H} NMR (CDCl , ppm): δ 166.6, 68.6, 66.3, 62.6. Spectral data matched those found
3
in the literature.20
tert-Butyl 2-oxomorpholine-4-carboxylate (23b). Following the general procedure, 23a
(
285 mg, 1.39 mmol) and 4 (15 mg, 0.035 mmol, 0.025 equiv) in acetone (2.8 mL) afforded
07 mg (38%) of 23b as a light yellow, waxy solid after purification by flash chromatography
1
on a 1.8 cm wide column with 7–8 cm of silica gel. Attempts to visualize 23b on the TLC plate
using standard stains (KMnO , anisaldehyde, vanillin, phosphomolybdic acid, ceric
4
ammonium molybdate, and I ) were unsuccessful, so it was purified by eluting with
2
approximately 30 mL of 95% cyclohexane/5% MTBE until a yellow band came off, followed
by elution with 100 mL of 40% cyclohexane/40% dichloromethane/20% MTBE. The
1
4
0/40/20 fraction was evaporated to afford 23b. H NMR (CDCl , ppm): δ 4.42 (br t, J = 4.4
3
13
1
Hz, 2H), 4.25 (s, 2H), 3.65 (t, J = 5.2 Hz, 2H), 1.48 (s, 9H). C{ H} NMR (CDCl , ppm): δ 153.5,
3
8
1.3, 67.5 (br), 46.0 (br), 39.8 (br), 28.3; the lactone carbonyl carbon was lost in the baseline.
Spectral data matched those found in the literature.20
δ-Hexalactone (24b). Following the general procedure, 1,5-hexanediol (24a) (189 mg, 1.60
mmol), 2 (16 mg, 0.040 mmol, 0.025 equiv), and trimethylamine N-oxide (3 mg, 0.04 mmol,
0.25 equiv) in acetone (3.2 mL) afforded 150 mg (87 wt. % 24b, 69% yield) of a 42/2.8/1
mixture of 24b, 6-hydroxy-2-hexanone (27), and 1 as a yellow oil after purification by flash
chromatography on a 1.8 cm wide column with 7–8 cm of silica gel. Attempts to visualize
24b on the TLC plate using standard stains (KMnO , anisaldehyde, vanillin,
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2
2
2
2
2
2
2
3
3
3
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3
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4
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4
4
4
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5
5
5
5
5
5
5
6
phosphomolybdic acid, ceric ammonium molybdate, and I ) were unsuccessful, so it was
2
purified by eluting with approximately 30 mL of 95% cyclohexane/5% MTBE until a yellow
band came off, followed by elution with 100 mL of 40% cyclohexane/40%
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
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4
5
6
7
8
9
0
1
2
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dichloromethane/20% MTBE. The 40/40/20 fraction was evaporated to afford 24b, which
1
contained small amounts of impurities. H NMR (CDCl , ppm): δ 4.50-4.40 (m, 1H), 2.62-2.52
3
(m, 1H), 2.40-2.50 (m, 1H), 1.82-1.98 (m, 3H), 1.49-1.59 (m, 1H), 1.38 (d, J = 6.4 Hz, 3H).
1
3
1
C{ H} NMR (CDCl , ppm): δ 171.9, 76.9, 29.5, 29.2, 21.7, 18.5. Spectral data matched those
3
found in the literature.20
-Methylisobenzofuran-1(3H)-one (29b). Following the general procedure, 29a (226 mg,
.48 mmol, 1 equiv), 2 (15 mg, 0.037 mmol, 0.025 equiv), and trimethylamine N-oxide (2.8
3
1
mg, 0.037 mmol, 0.025 equiv) in acetone (3.0 mL) afforded 189 mg (86%) of 29b as a
colorless oil after purification by flash chromatography (80% hexanes/20% ethyl acetate, Rf
1
=
=
0.30). H NMR (CDCl , ppm): δ 7.90 (d, J = 7.6 Hz, 1H), 7.68 (td, J = 1.2, 7.6 Hz, 1H), 7.53 (t, J
3
1
3
1
7.6 Hz, 1H), 7.45 (dd, J = 0.4, 7.6 Hz, 1H), 5.57 (q, J = 6.4 Hz, 1H), 1.65 (d, J = 6.4, 3H). C{ H}
NMR (CDCl , ppm): δ 170.5, 151.2, 134.1, 129.1, 125.74, 125.65, 121.6, 77.8, 20.4. Spectral
3
data matched those found in the literature.20
3-Phenylisobenzofuran-1(3H)-one (30b). Following the general procedure, 30a (285 mg,
1
.33 mmol, 1 equiv), 2 (22 mg, 0.053 mmol, 0.04 equiv), and trimethylamine N-oxide (4.0
mg, 0.053 mmol, 0.04 equiv) in acetone (2.7 mL) afforded 216 mg (77%) of 30b as a pale
yellow solid after purification by flash chromatography (85% hexanes/15% ethyl acetate, Rf
1
=
=
0.30). H NMR (CDCl , ppm): δ 7.97 (d, J = 7.6 Hz, 1H), 7.65 (td, J = 0.8, 7.6 Hz, 1H), 7.56 (t, J
3
1
3
1
7.6 Hz, 1H), 7.40–7.33 (m, 4H), 7.29-7.27 (m, 2H), 6.41 (s, 1H). C{ H} NMR (CDCl , ppm):
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δ 170.5, 149.7, 136.4, 134.4, 129.4, 129.3, 129.0, 127.0, 125.64, 125.59, 122.9, 82.7. Spectral
data matched those found in the literature.82
(3R,3aS,6R,7aR)-3,6-Dimethylhexahydrobenzofuran-2(3H)-one (31b). Following the
general procedure, 31a (250 mg, 1.45 mmol, 1 equiv), 2 (23.5 mg, 0.058 mmol, 0.04 equiv),
and trimethylamine N-oxide (4.4 mg, 0.058 mmol, 0.04 equiv) in acetone (2.9 mL) afforded
214 mg (88%) of 31b as a colorless oil after purification by flash chromatography (87%
1
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hexanes/13% ethyl acetate, R = 0.37). H NMR (CDCl , ppm): δ 4.00 (td, J = 3.6, 11.2 Hz, 1H),
f
3
2
2
.64 (quint, J = 7.6 Hz, 1H), 2.25 (dt, J = 3.6, 11.2 Hz, 1H), 1.98–1.89 (m, 1H), 1.83–1.74 (m,
H), 1.66–1.53 (m, 1H), 1.38–1.20 (m, 2H), 1.15 (d, J = 7.6 Hz, 3H), 1.11–1.04 (m, 1H), 1.02
1
(
d, J = 6.8 Hz, 3H). 13C{ H} NMR (CDCl , ppm): δ 180.3, 81.4, 47.1, 38.7, 34.2, 31.3, 23.8, 22.0,
3
1
3
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.6. Note that two peaks in the C NMR spectrum are overlapping at 38.7 ppm, which is
consistent with reports of two peaks with almost identical chemical shifts.20,83
5-Phenyldihydrofuran-2(3H)-one (32b). Following the general procedure, 32a (266 mg,
1
0
.60 mmol, 1 equiv), 2 (16 mg, 0.040 mmol, 0.025 equiv), and trimethylamine N-oxide (3 mg,
.04 mmol, 0.025 equiv) in acetone (3.2 mL) afforded 187 mg (72%) of 32b as a pale yellow
oil after purification by flash chromatography (75% cyclohexane/25% ethyl acetate, R =
f
1
0.34). H NMR (CDCl , ppm): δ 7.40-7.31 (m, 5H), 5.50 (dd, J = 6.4, 8.0 Hz, 1H), 2.70-2.61 (m,
3
13
1
3
3
H), 2.24-2.12 (m, 1H). C{ H} NMR (CDCl , ppm): δ 177.0, 139.4, 128.8, 128.5, 125.3, 81.3,
3
1.0, 29.0. Spectral data matched those found in the literature.84
Isochroman-1-one (33b) and isochroman-3-one (33c). Following the general procedure,
3a (243 mg, 1.60 mmol, 1 equiv), 1 (16.7 mg, 0.040 mmol, 0.025 equiv), and trimethylamine
3
N-oxide (3.0 mg, 0.040 mmol, 0.025 equiv) in acetone (3.2 mL) afforded 216 mg (91%) of a
1.3:1 mixture of 33b and 33c, respectively, as a colorless oil after purification by flash
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chromatography (80% cyclohexane/20% ethyl acetate, R = 0.26; both compounds had the
f
1
same R value). Spectral data for 33b and 33c: H NMR (CDCl , ppm): δ 8.08 (dd, J = 1.2, 8.0
f
3
Hz, 1H, 33b), 7.54 (td, J = 1.6, 7.6 Hz, 1H, 33b), 7.41-7.21 (m, 6H, 33b and 33c), 5.31 (s, 2H,
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3c), 4.53 (t, J = 6.0 Hz, 2H, 33b), 3.71 (s, 2H, 33c), 3.06 (t, J = 6.0 Hz, 2H, 33b). C{ H} NMR
(
CDCl , ppm): δ 170.8, 165.2, 139.6, 133.7, 131.6, 131.0, 130.3, 128.8, 127.7, 127.4, 127.3,
3
127.1, 125.3, 124.7, 70.1, 67.3, 36.2, 27.8. Spectral data matched literature values for 33b85
and 33c.86
5
,5-Dimethyltetrahydro-2H-pyran-2-one (34b) and 3,3-dimethyltetrahydro-2H-
pyran-2-one (34c). Following the general procedure, 34a (212 mg, 1.60 mmol, 1 equiv), 1
16.8 mg, 0.040 mmol, 0.025 equiv), and trimethylamine N-oxide (3.0 mg, 0.040 mmol, 0.025
(
equiv) in acetone (3.2 mL) afforded 179 mg (87%) of a 2.6:1 mixture of 34b and 34c,
respectively, as a colorless oil after purification by flash chromatography (20% hexanes,
1
8
2
7
2
0% ethyl acetate, R = 0.25). Spectral data for 34b: H NMR (CDCl , ppm): δ 3.98 (s, 2H),
f
3
1
3
1
.56 (t, J = 7.6 Hz, 2H), 1.70 (t, J = 7.6 Hz, 2H), 1.06 (s, 6H). C{ H} NMR (CDCl , ppm): δ 171.4,
3
1
8.7, 32.9, 29.4, 27.3, 24.8. Spectral data for 34c: H NMR (CDCl , ppm): δ 4.35 (t, J = 5.6 Hz,
3
1
3
1
H), 1.94–1.88 (m, 2H), 1.78–1.75 (m, 2H), 1.31 (s, 6H). C{ H} NMR (CDCl , ppm): δ 177.1,
3
2
0
12
70.6, 38.7, 35.1, 27.8, 20.6. Spectral data for 34b and 34c matched those found in the
literature.
Evidence of transfer dehydrogenation mechanism (Figure 3). A solution of 1,2-
benzenedimethanol 14a (207 mg, 1.50 mmol), 1 (15.7 mg, 0.0375 mmol), and anhydrous
trimethylamine N-oxide (2.8 mg, 0.038 mmol) in 3.0 mL of degassed acetone-d was stirred
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at 90 °C for 24 h in a sealed, thick-walled test tube. After cooling to rt, the yellow reaction
1
solution was filtered through celite, and a H NMR spectrum was taken of 0.7 mL of the
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filtrate. The integrals of the signals corresponding to phthalide 14b (s, 5.38 ppm, CH2),
unreacted 14a (s, 4.69 ppm, 2 x CH ), and isopropanol-d (s, 3.87 ppm, CH) were used to
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determine that 92% of 14b formed and the 14b to isopropanol-d ratio was 1:2.
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Dehydrogenation of lactol 26 (Figure 5). A 50 µL aliquot of a solution of lactol 26 (185 mg,
1
.60 mmol) and biphenyl (62 mg, 0.40 mmol; internal standard) in 3.2 mL of acetone was
1
taken, the solvent was removed by evaporation, and a H NMR spectrum labeled “time 0”
was collected. Catalyst 2 or 10 (0.04 mmol), isopropanol (96 mg, 0.12 mL, 1.6 mmol), and
anhydrous trimethylamine N-oxide (3.0 mg, 0.04 mmol) were added to the remaining
solution, the thick-walled test tube was sealed with a PTFE cap, and it was stirred at 90 °C.
After 24 h, 0.2 mL of the reaction solution was added to 1 mL of cyclohexane. The resulting
solution was added to a glass pipet half filled with silica gel, and it was eluted with 4 mL of
ethyl acetate. The filtrate from the pipet column was evaporated under reduced pressure,
1
and a H NMR spectrum (CDCl ) was taken. The integrals of the signals corresponding to
3
lactone 24b (m, 4.46–4.42 ppm, CH) and ketone 27 (t, 3.63 ppm, CH ) were used to
2
determine the relative amounts of the two compounds.
NMR experiment with 1 and 13a at rt. A solution of 1 (25 mg, 0.060 mmol), trimethylamine
N-oxide (4.5 mg, 0.060 mmol), and 1,5-pentanediol (13a) (12.4 mg, 0.12 mmol) in 1 mL of
acetone-d was stirred at room temperature under nitrogen for 5 minutes. The solution was
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1
13
transferred to a screw-cap NMR tube under nitrogen, and H and C NMR spectra were
collected.
NMR experiment with 1 and 13a at elevated temperature. A solution of 1 (60 mg, 0.143
mmol), trimethylamine N-oxide (10.8 mg, 0.143 mmol), and 1,5-pentanediol (13a) (74.7 mg,
0.72 mmol) in 1 mL of acetone-d was stirred at room temperature under nitrogen for 5
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