A Hantzsch Amido Dihydropyridine as a Transfer Hydrogenation Reagent for α,β-Unsaturated Ketones

Article abstract of DOI:10.1021/acs.joc.6b00041

An improved synthesis of the bis-methylamido Hantzsch dihydropyridine is described. The Hantzsch amide is demonstrated to be an effective transfer hydrogenation reagent using α,β-unsaturated ketones as the test case. Unreacted Hantzsch amide and the bis-methylamidopyridine byproduct are effectively removed by extraction in contrast to the commonly used Hantzsch diethyl ester. Several examples are given with the reaction being more effective for conjugated aromatic substrates than for aliphatics.

Full text of DOI:10.1021/acs.joc.6b00041

Article
pubs.acs.org/joc
A Hantzsch Amido Dihydropyridine as a Transfer Hydrogenation
Reagent for α,β-Unsaturated Ketones
Scott A. Van Arman,* Austin J. Zimmet, and Ian E. Murray
Department of Chemistry, Franklin and Marshall College, Lancaster, Pennsylvania 17604-3003, United States
S
* Supporting Information
ABSTRACT: An improved synthesis of the bis-methylamido Hantzsch dihydropyridine is described. The Hantzsch amide is
demonstrated to be an effective transfer hydrogenation reagent using α,β-unsaturated ketones as the test case. Unreacted
Hantzsch amide and the bis-methylamidopyridine byproduct are effectively removed by extraction in contrast to the commonly
used Hantzsch diethyl ester. Several examples are given with the reaction being more effective for conjugated aromatic substrates
than for aliphatics.
INTRODUCTION
■
Addition of hydrogen to unsaturated compounds is an essential
transformation in synthetic organic chemistry. While this is often
very effectively accomplished through the use of metal catalysts
under an atmosphere of hydrogen gas, it is frequently desirable to
avoid expensive and toxic metal catalysts and the explosive nature
of H2. For these reasons, over the last several decades a significant
quantityofresearchefforthasbeenexpendedonthedevelopment
of transfer hydrogenation methods that avoid such disadvan-
tages.1−5 Further avoiding metallocatalysts, the organic hydride
donorshavecapturedrecentattentionincludingbenzothiazolines
and related species6−13 and the Hantzsch dihydropyridines.14 Of
course, biological systems effect transfer hydrogenation trans-
formations via enzymes that utilize the organic hydride-donating
cofactors FADH and NAD(P)H.15 Not surprisingly then, the
Hantzsch dihydropyridines are among the best studied and most
used of the synthetic organic hydride donors stemming from their
initial utility as models for the active dihydropyridine moiety in
NADPH and NADH.14,16 Functionalities reduced early on by
Hantzsch esters (HEH) include α,β-unsaturated aldehydes and
ketones.17−22
Among the Hantzsch dihydropyridines in use for transfer
hydrogenation, the Hantzsch esters (e.g., 1) have garnered the
mostfavoramongorganicchemists. Theyareeasilysynthesizedin
good yield and have good stability.14,16,23,24 The discovery by
List,25 MacMillan,26 and others that organocatalytic chiral amines
or Bronsted acids could promote the HEH asymmetric transfer
hydrogenation has caused a hearty increase in the study of this
process.4,27−35 Most notably, apersistent and often cited problem
with the use of the Hantzsch esters for preparative transfer
hydrogenation is the necessity for chromatographic purification
of the product. Specifically, the pyridine byproducts of the
reaction are difficult to separate.9,34,36,37
Hantzsch esters have largely been ignored as transfer hyrogena-
tion reagents. Recent reports on the relative hydride-donating
ability of various organic species including dihydropyridines hint
that the diamide should be a slightly more potent hydride donor
than the diester.38−42 With this in mind, we have begun exploring
the utility of the Hantzsch bismethylamido dihydropyridine (2,6-
dimethyl-3,5-bis[(methylamino)carbonyl]-1,4-dihydropyridine,
HAH 2) as a reagent for transfer hydrogenation.
RESULTS AND DISCUSSION
■
The Hantzsch bismethylamide 2 was prepared by a modification
of the method of Gelbard et al.43 similar to that of Nomura,44
resulting in a significant improvement in simplicity and yield.
Gelbard’s method stipulates scrupulously deaerated water as
solvent and Schlenk tube filtration yielding 54% of the
bismethylamide (several other Hantzsch amides were also
synthesized with this method). In our improved method done
in a sealed tube (eq 1), ammonium carbonate is substituted for
ammonium acetate, solvent water is deaerated by brief sonication
alone, and the product is isolated open to the atmosphere and
washed with plain deionized water. Yield is improved to 69%,
Although NADH is an amide and 1-benzyl-1,4-dihydronico-
tinamide has been commonly used as a model,16 the symmetrical
3,5-diamido-1,4-dihydropyridines that are analogous to the
Received: January 7, 2016
© XXXX American Chemical Society
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making the dimethylamide synthesis competitive with that of the
Hantzsch ester.
The utility of the bis-methylamide has been tested in the
transfer hydrogenation of a series of α,β-unsaturated ketones
according to eq 2 using benzylammonium trifluoroacetate (20
mol % excess of the dihydropyridine is used, and extension of the
reaction time beyond 16 h does not appear to improve yields or
conversions.
Percent conversion is determined by comparing specifically the
integration of the terminal methyl groups of the unsaturated vs
saturated ketones as shown in Figure 1 using dehydrorheosmin
(4a) as the example reactant.48,49 Rheosmin (“raspberry ketone”)
is the principle aroma constituent of raspberries and has attracted
attention recently because of its reported antiobesity activ-
ity.50−54 As a test of the utility of 2 in this process, we have found
that scale up of the reaction to 12 mmol of the dehydrorheosmine
succeeds in giving >80% yield of the raspberry ketone without
chromatography. Similar scale-up using dehydrozingerone (4b)
has been accomplished in 89% yield.
Of particular importance is the relative ease of isolation of the
products. As noted above, using the Hantzsch ester requires
careful column chromatography for separation of the desired
hydrogenation products from the pyridine byproduct. By
contrast, use of the Hantzsch amide analog allows removal of
the pyridine (3) through acid extraction and a short silica plug.
Figure 2 shows the result of the analogous transfer hydrogenation
reaction between the Hantzsch ester and dehydrorheosmin. Even
after repeated aqueous acidic extraction and filtration through a
silica plug, the pyridine product and unreacted dihydropyridine
are not removed from the product mixture. This problem is the
root of the necessity for column chromatography that is avoided
with this process using HAH (2) (Figure 1). The calculated
basicity of the bisamidopyridine (3) is greater than that of the
analogous Hantzsch ester pyridine, and this may contribute to the
observed difference in the extractibility.55
mol %) as the organocatalyst. Yields and conversions for the
reaction using 2 are shown in Table 1 and are favorably
competitive with those found using the HEH (1).45−47 The
process is more effective with conjugated aromatic α,β-
unsaturated ketones than with the aliphatic example (4i). A 50
Table 1. Conversion and Yield for Transfer Hydrogenation of
4 (Eq 2)
The transfer hydrogenation of 4-[(4′-dimethylamino)phenyl]-
3-buten-2-one (4c) and the isolation of the reduced product
provide an interesting further example of the difference between
the Hantzsch ester and the amide. If the Hantzsch ester is used,
then the product can be isolated in reasonable purity by acid
extraction because theHantzsch materials arenotextracted under
these conditions. Basification of the acidic extract and back
extraction into CH2Cl2 result in removal of most Hantzsch
material.56 Alternatively, reasonable results can be obtained with
the Hantzsch amide by foregoing the extraction process
altogether and filtering a 1:1 CH2Cl2/hexane mixture of the
reaction materials through a 1 cm plug of silica.
CONCLUSION
■
In summary, we have developed an improved synthesis of the
Hantzsch amide (2) that gives higher yields under simpler
conditions. We have demonstrated that this dihydropyridine can
be used much as the Hantzsch ester for transfer hydrogenation
with similar yields and conversions. Importantly, the difficulty of
isolating hydrogenation products from the Hantzsch ester
pyridine byproducts requiring column chromatography is
completely overcome by the use of the Hantzsch amide. The
amide itself and the pyridine byproduct can be removed easily by
aqueous acidic extraction and traces further removed by filtration
through a very short plug of silica. We are currently exploring
additional applications of this methodology employing the
Hantzsch amide.
EXPERIMENTAL SECTION
■
3,4-Dihydrorheosmin and 3,4-dihydrozingerone were prepared accord-
ing to the method of Smith.57 All other enones were commercially
available and used as received or synthesized according to the method of
List and match spectroscopically with literature reports.47
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Figure 1. Extent of transfer hydrogenation of 4-(4′-hydroxyphenyl)but-3-en-2-one by Hantzsch bis-methylamide and the removal of Hantzsch materials
(2 and 3) after extraction and filtration through a 0.5 cm silica plug.
Figure2. Extentoftransferhydrogenationof4-(4′-hydroxyphenyl)but-3-en-2-one byHantzschbis(ethylester)andthepersistenceofHantzschmaterials
(1 and 6) after extraction and filtration through a 0.5 cm silica plug.
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1,4-Dihydro-2,6-dimethyl-3,5-bis[(methylamino)carbonyl]-
pyridine (2). 70% N-methylacetoacetamide in H2O (16 g; 96 mmol)
was pipetted into a 100 mL pressure tube. To this was added
hexamethylenetetramine (6.40 g; 45.7 mmol) and ammonium carbonate
(5.92g;61.7mmol). Deaerated(sonication)H2Owasaddedalongwitha
magnetic stir bar, the tube was sealed, and the mixture stirred at room
temperature until all material had dissolved. The reaction tube was then
placed in an oil bath at 70 °C for 1 h to give a yellow mixture and
substantial precipitate. The reaction tube was removed from the oil bath,
cooled to room temperature, and then cooled in an ice/water bath. Solid
was collected by vacuum filtration and rinsed twice with 10 mL H2O to
give a yellow solid. This was further dried under vacuum to give 7.40 g
(33.2 mmol, 69.1%), mp 216−217 °C (lit 219−221 °C).43 1H NMR
(90.3 MHz, DMSO-d6) δ = 7.43 (s, 1H), 6.99 (q, J = 4.3 Hz, 2H), 3.08 (s,
2H),2.62(d,J=4.5Hz, 6H),2.02(s,6H). 13CNMR(22.7MHz, DMSO-
d6) δ = 169.0, 140.4, 99.6, 26.9, 26.3, 17.7.
General Procedure: 4-(4′-Hydroxyphenyl)butan-2-one
(Rheosmin) (5a). 1,4-Dihydro-2,6-dimethyl-3,5-bis[(methylamino)-
carbonyl]pyridine (2) (168 mg; 0.757 mmol), 4-(4′-hydroxyphenyl)-
3-buten-2-one (3,4-dehydrorheosmin) (81 mg; 0.50 mmol), and
benzylammonium trifluoroacetate (22 mg; 0.10 mmol) were placed in
a 15 mL reaction tube. To this was added a magnetic stir bar and 10 mL
dry THF. The tube was sealed and heated at 70 °C for 16 h. The mixture
wascooledtoroomtemperature, and25mLCH2Cl2 wasadded. Thiswas
washed with 3 M HCl (aq) (3 × 25 mL). All aqueous phases were pooled
and extracted with CH2Cl2 (3 × 10 mL). All CH2Cl2 was pooled and
dried over Na2SO4. The liquid was decanted off the Na2SO4, and the
drying agent was rinsed with CH2Cl2 (2 × 10 mL). All CH2Cl2 was
pooled, and the solvent removed by rotary evaporation to give a straw
colored oil. This was dissolved in3 mL CH2Cl2/hexane (1:1) and filtered
through a 0.5 cm plug of silica. The silica was rinsed further with 40 mL
CH2Cl2/hexane (1:1). All of the filtrate was pooled and evaporated to a
slightly straw colored oil (79 mg; 0.48 mmol; 96%). NMR spectroscopy
consistent with literature.58 1H NMR (500 MHz, CDCl3) 7.00 (d, J = 8.5
Hz, 3H), 6.76 (d, J = 8.5 Hz, 2H), 2.81 (t, J = 7.0 Hz, 2H), 2.73 (t, J = 7.0
Hz, 2H), 2.13 (s, 3H). 13C NMR (125 MHz, CDCl3) δ = 210.1, 154.3,
132.3, 129.3, 115.5, 45.5, 30.1, 29.0.
4-(4′-N,N-Dimethylaminophenyl)butan-2-one (5c). 1,4-Dihy-
dro-2,6-dimethyl-3,5-bis[(methylamino)carbonyl]pyridine (2) (170
mg; 0.75 mmol), 4-(4′-N,N-dimethylaminophenyl)-3-buten-2-one (95
mg; 0.50 mmol), and benzylammonium trifluoroacetate (22 mg; 0.10
mmol) were placed in a 15 mL reaction tube. To this was added a
magnetic stir bar and 10 mL dry THF. The tube was sealed and heated at
70 °C for 16 h. Themixture was cooled to room temperature, and solvent
was removed by rotary evaporation to give an orange oil. This was
dissolved in 40 mL CH2Cl2/hexane (1:1) and filtered through a 1.5 cm
plug of silica. The silica plug was rinsed with 15 mL CH2Cl2/hexane
(1:2). All solvent was pooled and evaporated to a pale yellow oil (80 mg;
0.42 mmol; 84%). NMR spectroscopy consistent with literature.59 1H
NMR (500 MHz, CDCl3) δ = 7.06 (d, J = 8.7 Hz, 2H), 6.69 (d, J = 8.7 Hz,
2H), 2.91 (s, 6H), 2.80 (t, J= 7.3Hz, 2H), 2.71 (t, J= 7.3Hz, 2H), 2.13(s,
3H). 13C NMR (125 MHz, CDCl3) δ = 208.5, 149.2, 128.9, 113.0, 45.6,
40.9, 30.1, 28.9.
4-Phenylbutan-2-one (5d). Following the general procedure using
4-phenyl-3-buten-2-one (73mg;50mmol)providedapaleyellowoil(63
mg; 43 mmol; 86%). NMR spectroscopy consistent with literature.60 1H
NMR (500 MHz, CDCl3) δ = 7.27 (t, 2H), 7.18 (m, 3H), 2.89 (t, J = 7.6
Hz, 2H), 2.75 (t, J = 7.6 Hz, 2H), 2.13 (s, 3H). 13C NMR (125 MHz,
CDCl3) δ = 207.8, 141.0, 128.5, 128.3, 126.1, 45.2, 30.0, 29.8.
4-(4′-Bromophenyl)butan-2-one (5e). Following the general
procedure using 4-(4′-bromophenyl)-3-buten-2-one (110 mg; 50
mmol) provided a nearly colorless oil (110 mg; 49 mmol; 97%). NMR
spectroscopy consistent with literature.61 1H NMR (500 MHz, CDCl3) δ
=7.38(d, J=8.2Hz, 2H), 7.05(d, J=8.2Hz, 2H), 2.84(t, J=7.4Hz, 2H),
2.73 (t, J = 7.4 Hz, 2H), 2.13 (s, 3H). 13C NMR (125 MHz, CDCl3) δ =
207.4, 140.0, 131.5, 130.1, 119.8, 44.8, 30.1, 29.0.
4-(2′,4′-Dichlorophenyl)butan-2-one (5f). Following the general
procedure using 4-(2′,4′-dichlorophenyl)-3-buten-2-one (110 mg; 50
mmol) provided an amber oil (110 mg; 50 mmol; 100%). NMR
spectroscopy consistent with literature.61 1H NMR (500 MHz, CDCl3) δ
= 7.34 (d, J = 2.0 Hz, 1H), 7.18 (d, J = 8.2 Hz, 1H), 7.15 (dd, J = 8.2, 2.0
Hz, 1H), 2.96(t, J=7.5Hz, 2H), 2.75 (t, J=7.5Hz, 2H), 2.15(s, 3H). 13C
NMR (125 MHz, CDCl3) δ = 207.1, 137.2, 134.4, 132.6, 131.5, 129.2,
127.1, 42.9, 29.9, 27.1.
4-(4′-Nitrophenyl)butan-2-one (5g). Following the general
procedure using 4-(4′-nitrophenyl)-3-buten-2-one (96 mg; 50 mmol)
provided a light red oil (70 mg; 36 mmol; 73%). NMR spectroscopy
consistent with literature.61 1H NMR (500 MHz, CDCl3) δ = 8.13 (d, J =
8.8 Hz, 2H), 7.35 (d, J = 8.8 Hz, 2H), 3.00 (t, J = 7.4 Hz, 2H), 2.82 (t, J =
7.4 Hz, 2H), 2.16 (s, 3H). 13CNMR (125 MHz, CDCl3) δ= 206.5, 148.9,
146.5, 129.2, 123.7, 44.1, 30.0, 29.3.
4-(1′-Naphthyl)butan-2-one (5h). Following the general proce-
dure using 4-(1′-naphthyl)-3-buten-2-one (98 mg; 50 mmol) provided
anamberoil(85mg;43mmol;87%). NMRspectroscopyconsistentwith
literature.60 1H NMR (500 MHz, CDCl3) δ = 7.97 (d, J = 8.3 Hz, 1H),
7.84 (d, J= 7.8 Hz, 1H), 7.70 (d, J = 8.1 Hz, 1H), 7.48 (m, 2H), 7.37 (t, J =
7.6 Hz, 1H), 7.31 (d, J = 6.9 Hz, 1H), 3.34 (t, J = 7.8 Hz, 2H), 2.85 (t, J =
7.8 Hz, 2H), 2.13 (s, 3H). 13CNMR (125 MHz, CDCl3) δ= 207.9, 137.0,
133.9, 131.6, 128.9, 127.0, 126.03, 125.97, 125.59, 125.58, 123.4, 44.4,
30.1, 26.7.
2-Decanone (5i). Following the general procedure using 3-decen-2-
one(77mg;0.50mmol)providedacolorlessoil(65mg;0.42mmol;85%
yield+recovery). NMRspectroscopy consistentwithliterature62 asa20/
80 mixture of 2-decenone and 2-decanone. 1H NMR (500 MHz, CDCl3)
δ = 2.41 (t, J = 7.5 Hz, 2H), 2.13 (s, 3H), 1.57 (quintet, J = 7.3 Hz, 2H),
1.28 (m, 10H), 0.88 (t, J = 6.5 Hz, 3H). 13C NMR (125 MHz, CDCl3) δ =
209.3, 43.8, 31.8, 29.8, 29.33, 29.17, 29.10, 23.9, 22.6, 14.0.
4-(4′-Hydroxyphenyl)butan-2-one (Rheosmin) (5a, Large
Scale). 1,4-Dihydro-2,6-dimethyl-3,5-bis[(methylamino)carbonyl]-
pyridine (2) (3.01 g; 12.7 mmol), 4-(4′-hydroxyphenyl)-3-buten-2-
one (3,4-dehydrorheosmin) (1.38 g; 8.52 mmol), and benzylammonium
trifluoroacetate (0.47 g; 2.1 mmol) were placed in a 300 mL reaction
tube. To this was added a magnetic stir bar and 125 mL dry THF. The
tube was sealed and heated at 70 °C for 16 h. The mixture was cooled to
roomtemperature and 160 mL CH2Cl2 was added. This was washed with
3 M HCl (aq) (3 × 100 mL). All aqueous phases were pooled and
extracted with CH2Cl2 (3 × 25 mL). All CH2Cl2 was pooled and dried
over Na2SO4. The liquid was decanted off the Na2SO4, and the drying
agent was rinsed with CH2Cl2 (2 × 10 mL). All CH2Cl2 was pooled, and
the solvent removed by rotary evaporation to give a straw colored oil (1.2
g; 7.2 mmol; 84%).
4-(4′-Hydroxy-3′-methoxyphenyl)butan-2-one (zingerone)
(5b). Following the general procedure using 4-(4′-hydroxy-3′-
methoxyphenyl)but-3-en-2-one (96 mg; 0.50 mmol) provided a pale
yellow oil (90 mg; 46 mmol; 93%). NMR spectroscopy consistent with
literature.58 1H NMR (500 MHz, CDCl3):δ = 82 (d, J = 8.0 Hz, 1H), 6.70
(d, J = 2.0 Hz, 1H), 6.66 (dd, J = 8.0, 2.0 Hz, 1H), 5.60 (s, 1H), 3.86 (s,
3H), 2.82 (t, J = 7.4 Hz, 2H), 2.73 (t, J = 7.4 Hz, 2H), 2.13 (s, 1H). 13C
NMR (125 MHz, CDCl3) δ = 208.2, 146.4, 143.9, 132.9, 120.7, 114.4,
111.1, 55.9, 45.5, 30.1, 29.5.
4-(4′-Acetamidophenyl)butan-2-one (5j). 1,4-Dihydro-2,6-di-
methyl-3,5-bis[(methylamino)carbonyl]pyridine (2) (168 mg; 0.757
mmol), 4-(4′-acetamidophenyl)-3-buten-2-one (100 mg; 0.50 mmol),
and benzylammonium trifluoroacetate (22 mg; 0.10 mmol) were placed
in a 15 mL reaction tube. To this was added a magnetic stir bar and 10 mL
dry THF. The tube was sealed and heated at 70 °C for 16 h. The mixture
wascooledtoroomtemperature, and25mLCH2Cl2 wasadded. Thiswas
washed with 3 M HCl (aq) (3 × 25 mL). All aqueous phases were pooled
and extracted with CH2Cl2 (3 × 10 mL). All CH2Cl2 was pooled and
dried over Na2SO4. The liquid was decanted off the Na2SO4, and the
4-(4′-Hydroxy-3′-methoxyphenyl)butan-2-one (Zingerone)
(5b, Large Scale). Following the large scale procedure above using 4-
(4′-hydroxy-3′-methoxyphenyl)but-3-en-2-one (1.73g; 9.01 mmol),
1,4-dihydro-2,6-dimethyl-3,5-bis[(methylamino)carbonyl]pyridine (2)
(3.01 g; 13.5 mmol), and benzylammonium trifluoroacetate (0.41 g; 1.9
mmol) provided an amber oil. This was dissolved in 10 mL CH2Cl2/
hexane (1:1) and filtered through a 1 cm plug of silica in a 5 cm Buchner
funnel. The silica was rinsed further with 200 mL CH2Cl2/hexane (1:1).
Allof the filtrate was pooled and evaporated to a strawcolored oil(1.55 g;
7.99 mmol; 88.7%).
D
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drying agent was rinsed with CH2Cl2 (2 × 10 mL). All CH2Cl2 was
pooled, and the solvent removed by rotary evaporation to give an off-
white solid (0.10 g; 100%, mp =113−116 °C). NMR spectroscopy
consistent with literature.63 1H NMR (500 MHz, CDCl3) δ = 8.23 (s,
1H), 7.41 (d, J = 8.4 Hz, 1H), 7.09 (d, J = 8.4 Hz, 1H), 2.84 (t, J = 7.5 Hz,
1H), 2.73 (t, J= 7.5Hz, 1H), 2.130(s, 1H), 2.126 (s, 1H). 13C NMR(125
MHz, CDCl3) δ = 208.2, 168.8, 136.7, 136.1, 128.5, 120.2, 45.0, 30.0,
29.0, 24.2.
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ASSOCIATED CONTENT
* Supporting Information
■
S
TheSupportingInformationisavailablefreeofchargeontheACS
Publications website at DOI: 10.1021/acs.joc.6b00041.
(33) Marcelli, T. Asymmetric Transfer Hydrogenations Using Hantzsch
1H NMR and 13C NMR for all transformations. Calculated
pKa and log D values for Hantzsch pyridines and
dihydropyridines (PDF)
Esters; Springer-Verlag: Berlin, 2011.
(34) Zheng, C.; You, S.-L. Chem. Soc. Rev. 2012, 41, 2498.
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403.
(36) de Vries, J. G.; Mrsic, N. Catal. Sci. Technol. 2011, 1, 727.
(37) Modified bezothiazolenes have been demonstrated to be readily
removable hydrogen sources for transfer hydrogenation; see ref 5.
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(39) Shi, J.; Huang, X. Y.; Wang, H. J.; Fu, Y. J. Chem. Inf. Model. 2012,
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AUTHOR INFORMATION
Corresponding Author
*E-mail: scott.vanarman@fandm.edu
Notes
■
(40) Zhu, X.-Q.; Tan, Y.; Cao, C.-T. J. Phys. Chem. B 2010, 114, 2058.
(41) Horn, M.; Schappele, L. H.; Lang-Wittkowski, G.; Mayr, H.; Ofial,
A. R. Chem. - Eur. J. 2013, 19, 249.
(42) Personal communication with X.-Q. Zhu
(43) Gelbard, G.; Lin, J.; Roques, N. J. Org. Chem. 1992, 57, 1789.
(44) Nomura, M.; Nakata, S.; Hamada, F. Nippon Kagaku Kaishi 2002,
141.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to Lisa Mertzman for procurement of materials,
Beth Buckwalter for NMR spectroscopy, Ed Fenlon and Laszlo
Kurti for helpful discussions, and Franklin and Marshall College
̈
(45)Tuttle, J. B.;Ouellet, S. p. G.;MacMillan, D. W. C. J. Am. Chem. Soc.
2006, 128, 12662.
for funding.
(46) Martin, N. J. A.; List, B. J. Am. Chem. Soc. 2006, 128, 13368.
(47) Zumbansen, K.; Doehring, A.; List, B. Adv. Synth. Catal. 2010, 352,
1135.
(48) Percent yield + recovery is presented as the mass percent of
isolated ketone product and enone starting material relative to the
starting mass of the enone.
(49) See the Supporting Information for additional NMR spectra.
(50)Morimoto, C.;Satoh, Y.;Hara, M.;Inoue, S.;Tsujita, T.;Okuda, H.
Life Sci. 2005, 77, 194.
(51) Bhutani, K. K.; Birari, R.; Kapat, K. Nat. Prod. Commun. 2007, 2,
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DOI: 10.1021/acs.joc.6b00041
J. Org. Chem. XXXX, XXX, XXX−XXX