Enaminones via ruthenium-catalyzed coupling of thioamides and α-diazocarbonyl compounds

Article abstract of DOI:10.1021/jo5011312

Enaminones can be prepared via the Rh₂(OAc)₄- catalyzed coupling of α-diazocarbonyl compounds with thioamides. However, rhodium is the most expensive and least abundant among the dominant precious metals used for catalysis. Furthermore, a very limited substrate scope is known for the intermolecular rhodium catalyzed coupling reaction. Therefore, there is a need to find a more economical catalyst substitute with a broad substrate scope. In this paper, we describe the use of Ru(II) catalysts for the synthesis of enaminones. The reaction can be performed efficiently with the Grubbs first-generation catalyst or [(Ph)₃P]₃RuCl₂ in a sealed tube. Both catalysts are much less expensive than Rh ₂(OAc)₄. Secondary and tertiary thioamides, when reacted with α-diazodiesters, α-diazoketoesters, α-diazodiketones, and α-diazomonoketones give enaminones. Primary thioamides give thiazole derivatives when reacted with α-diazomonoketones. However, with other diazo compounds, primary thioamides also give enaminones. All enaminones are obtained in good yields and with good diastereoselectivity. Accordingly, the method described in this paper is an efficient and economical alternative to the Rh₂(OAc)₄-catalyzed coupling process.

Full text of DOI:10.1021/jo5011312

Article
pubs.acs.org/joc
Enaminones via Ruthenium-Catalyzed Coupling of Thioamides and
α‑Diazocarbonyl Compounds
Naga D. Koduri,† Zhiguo Wang,† Garrett Cannell,† Kate Cooley,† Tsebaot Mesfin Lemma,† Kun Miao,†
Michael Nguyen,† Bram Frohock,† Maria Castaneda,† Halee Scott,† Dragos Albinescu,‡
and Syed R. Hussaini*,†
†Department of Chemistry and Biochemistry, The University of Tulsa, Keplinger Hall, 800 South Tucker Drive, Tulsa, Oklahoma
74104, United States
‡Department of Natural Sciences, Science Building, Northeastern State University, 610 N. Grand Avenue, Tahlequah, Oklahoma
74464, United States
S
* Supporting Information
ABSTRACT: Enaminones can be prepared via the Rh2(OAc)4-catalyzed
coupling of α-diazocarbonyl compounds with thioamides. However,
rhodium is the most expensive and least abundant among the dominant
precious metals used for catalysis. Furthermore, a very limited substrate
scope is known for the intermolecular rhodium catalyzed coupling
reaction. Therefore, there is a need to find a more economical catalyst
substitute with a broad substrate scope. In this paper, we describe the use
of Ru(II) catalysts for the synthesis of enaminones. The reaction can be
performed efficiently with the Grubbs first-generation catalyst or
[(Ph)3P]3RuCl2 in a sealed tube. Both catalysts are much less expensive
than Rh2(OAc)4. Secondary and tertiary thioamides, when reacted with α-
diazodiesters, α-diazoketoesters, α-diazodiketones, and α-diazomonoketones give enaminones. Primary thioamides give thiazole
derivatives when reacted with α-diazomonoketones. However, with other diazo compounds, primary thioamides also give
enaminones. All enaminones are obtained in good yields and with good diastereoselectivity. Accordingly, the method described
in this paper is an efficient and economical alternative to the Rh2(OAc)4-catalyzed coupling process.
and Huang and co-workers reported the formation of
enaminones via a tertiary amide-based Knovenagel-type
reaction.16 The synthesis of cyclic enaminones has also been
achieved via the reaction of donor−acceptor cyclopropanes and
amines.17,18
INTRODUCTION
■
We investigated whether the synthesis of enaminones is
possible by a mild, economical, and selective Ru(II)-catalyzed
coupling reaction between thioamides and α-diazocarbonyl
compounds. Enaminone compounds possess great potential as
synthetic intermediates due to the existence of three electro-
philic and two nucleophilic sites present within the enaminone
functional group.1 Enaminones also show the ability to
participate in pericyclic and radical reactions.2 As a result,
pharmaceutical development and natural product syntheses
utilize the enaminone functional group.3 Common methods for
the preparation of enaminones include the following: the
condensation of amines with dicarbonyl compounds,4 the
reaction of lactams or lactims with active methylene
compounds and other nucleophiles,5,6 the conjugate addition
of amine derivatives to α,β-unsaturated compounds, addition
reactions on nitriles, the cleavage of heterocycles, addition
reactions of alkynes and an amine, rearrangement of cyclo-
butanones, intramolecular aza-Wittig reactions, Friedel−Crafts
and Vilsmeier reactions of enecarbamates, acylation of
enaminones,3,7−9 the Eschenmoser coupling reaction,10−12
and the metal-catalyzed coupling of thioamides with α-
diazocarbonyl compounds.13,14 Recently, Bolm and Priebbenow
reported the coupling of amides with α-silyl α-diazoacetates,15
Scheme 1. Enaminones via Coupling of Metal Carbenes and
Thioamides
A diazo compound converts into a metal carbene in the
metal-catalyzed coupling of thioamides with α-diazocarbonyl
compounds. The metal carbene reacts with a thioamide,
generating an ylide which, through an episulfide intermediate,
leads to the formation of an enaminone (Scheme 1).14,19
Traditionally, the transformation utilizes Rh2(OAc)4 for
intramolecular coupling reactions.13,14,20 In this case it amounts
Received: May 22, 2014
Published: July 24, 2014
© 2014 American Chemical Society
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Figure 1. Catalysts screened in the present study.
to the aza-Robinson annulation reaction21 and synthesizes
heterocyclic products.13 Even with this early success, the
rhodium-catalyzed reaction is not a common method for the
synthesis of enaminones. Danishefsky and co-workers reported
the only example for the intermolecular rhodium-catalyzed
coupling reaction.19 One reason for the lack of intermolecular
reaction examples is the homocoupling of diazo compounds.22
Other side reactions, such as the cyclopropanation reaction,
also occur.23 Rhodium is also the most expensive and least
abundant among the dominant precious metals used for
catalysis.24,25 Due to these reasons, chemists have not reported
the use of diazodiketones, or the use of primary and secondary
thioamides, in the rhodium-catalyzed reaction.
Scheme 2. Proposed Mechanisms for the Generation of
Ruthenacarbenes
We recently reported our preliminary findings on the use of
ruthenium in the coupling of thioamides with α-diazocarbonyl
compounds, which have broadened the scope of this trans-
formation.26 Still, the yields were low and the reaction required
harsh conditions. In this paper we address these issues, describe
the screening of seven different ruthenium catalysts, and discuss
the scope and limitations of the ruthenium-catalyzed coupling
of thioamides and α-diazocarbonyl compounds.
Table 1. Catalyst Screening for the Ruthenium-Catalyzed
Synthesis of Enaminones
RESULTS AND DISCUSSION
a
■
entry
catalyst
temp (°C)
time (h)
yield (%)
b
Figure 1 shows the catalysts that were screened. All of them are
commercially available, and they can be divided into two
different types, Grubbs-type catalysts (1−5) and Ru(II)
triphenylphosphine complexes (6, 7). Both types of catalysts
have been used in the generation of ruthenacarbenes by their
reaction with α-diazocarbonyl compounds.27,28
The two types of catalysts generate ruthenacarbenes by two
different mechanisms (Scheme 2).27,28 Therefore, the catalyst
selection in Figure 1 provides the opportunity to observe the
reactivity of catalysts that act by distinct mechanisms. It also
allows for the comparison of different catalysts within each
type.
Thioamide 8 and diazomalonate 9 were reacted with catalysts
1−7 (Table 1) in a sealed tube. This particular reaction was
selected because 8 contains a stereocenter and an additional
functional group, thus providing a reasonable test for the
suitability of reaction conditions to other functional groups and
stereocenters. Additionally, the same reaction was used in our
previous studies for screening purposes.26 Benzene was used as
the solvent, as we discovered that it is the best solvent for the
transformation.26 We first determined the lowest temperature
at which the conversion of 8 into 10 was observable within 26
1
1
1
2
2
3
3
4
4
5
6
6
7
7
70
70
70
70
70
70
90
90
70
70
70
90
90
9
26
26
26
9
80
c
2
(10)
b
3
71
c
4
(19)
b
5
71
c
6
9
(12)
b
7
9
77
c
8
26
26
10
26
4
(26)
d
9
(49)
b
10
11
12
13
82
c
(48)
b
79
c
26
(64)
a
Reactions were conducted in a pressure vessel. The temperature
indicates the temperature of the oil bath. In each reaction 1.3 equiv of
9 was used. Isolated yield with 5 mol % catalyst loading. Percent
b
c
1
conversion of 8 into 10 by H NMR with 1 mol % catalyst loading.
d
1
Percent conversion of 8 into 10 by H NMR with 5 mol % catalyst
loading.
h. This was done by checking TLCs of the reaction every 1 h at
room temperature and 50, 70, and 90 °C. Once the lowest
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temperature for the conversion was found, the reaction mixture
was stirred at that temperature until the reaction was complete
or for 26 h. The maximum time of 26 h and maximum
temperature of 90 °C were chosen because we wanted to find
conditions better than those in our preliminary report.26 Except
for 5, all other catalysts provided 100% conversion of thioamide
8 into enaminone 10. Attempts to lower the catalyst loading in
an appreciable amount (5 mol % to 1 mol %) resulted in an
incomplete reaction (entries 2, 4, 6, 8, 11, and 13). Among the
Grubbs type catalysts (1−5), catalyst 1 provided the product in
minimal time (entry 1), while between the Ru(II) triphenyl-
phosphine complexes (6, 7), catalyst 7 yielded the product in
the least amount of time (entry 12). Catalysts 1 and 7 were
selected for further reactions.
Table 2. Coupling of Primary and Secondary Thioamides
with α-Diazodicarbonyl Compounds
b
In addition to 9, the diazo compounds that were used in this
study are shown in Figure 2. They can generate ruthenacar-
Figure 2. Additional diazo compounds evaluated in the present study.
benes that can be classified into acceptor/acceptor and acceptor
substituted carbenoids as per Davies’ definition. The reactivity
profiles of these carbenoids are different from each other.
Within the acceptor/acceptor class the carbenoids from
diketones are usually more reactive than those from diesters.29
Table 2 showcases the substrate scope of the coupling
reaction of primary and secondary thioamides with α-
diazodicarbonyl compounds. Both primary (entries 1−3) and
secondary thioamides (entries 4−11) provided enaminones in
excellent yields. Both cyclically (entries 4−8) and acyclically
positioned (entries 9−11) thioamides were viable substrates.
The reaction was successful in coupling diazodiesters (Table 2,
entries 1, 6, and 9−11, and Table 1, entries 1 and 12),
diazoketoesters (Table 2, entries 2, 4, and 7), and
diazodiketones (Table 2, entries 3, 5, and 8) with thioamides.
Both cyclic (Table 2, entries 3, 5, and 8) and acyclic (Table 2,
entries 1, 2, 4, 6, 7, and 9−11) diazo compounds were able to
participate in the reaction. Only single diastereomers were
obtained when unsymmetrical diazo compounds were used
(Table 2, entries 2, 4 and 7). Such selectivity has been observed
before, and it is attributed to the hydrogen bonding between
the N−H and the ketone oxygen.30−32 The H spectral data
1
indicated the hydrogen bonding between the N−H and the
ketone oxygen. Hydrogen bonding lowers the energy of the
product. The E stereochemistry was assigned by comparing the
1H values of these compounds with literature reports.30−33 In
1
the H NMR spectrum, the signal of the N−H protons of 16,
18, and 22 appear at a higher chemical shift in comparison with
the N−H protons of 15, 10, and 21, respectively. These
comparisons indicate the existence of intramolecular hydrogen
bonding between the NH and the ketonic CO groups.31,33
Coupling of the tertiary thioamide 30 (Scheme 3) proved to
be more challenging than the coupling of primary and
secondary thioamides (Table 2). Catalyst 1, which previously
provided 100% conversion of thioamides into enaminones on
heating the reaction mixtures at 70 °C (Table 1, entry 1, and
Table 2, entry 6), changed only 28% of 30 into 31. Heating to
90 °C afforded slightly better results, but further heating
reduced the formation of 31. Thinking that the low conversion
a
b
Two equivalents of diazo compounds was used. Reactions were
conducted in a pressure vessel. The temperature indicates the
temperature of the oil bath.
into enaminone is due to the greater steric hindrance of 30, we
attempted the use of catalysts 3 and 4 in the transformation.
Catalysts 3 and 4 are more efficient catalysts than 1 in the olefin
metathesis reaction of sterically challenging substrates;34
however, these catalysts, in addition to 6 and 7, failed to
provide high conversion.
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Scheme 3. Synthesis of 31 and the Competing Dimerization of 9
It was suspected that the difficulty in the conversion of 30
into 31 could be due to the competing dimerization reaction of
9. Indeed, 9 dimerizes completely in the absence of thioamides
when it is reacted under the reaction conditions (Scheme 3).
Dimerization reactions of diazocarbonyl compounds are known
with Ru(II) catalysts.27,28 Competing dimerization also explains
the need for 2 equiv of diazo compounds (12) with the
secondary thioamides (8 and 20) (entries 4, 5, and 8, Table 2).
Compound 8 has greater steric hindrance than other secondary
thioamides discussed here, and compounds 11 and 12 generate
more reactive ruthenacarbenes than does 9. Therefore, 11 and
12 dimerize more quickly, requiring 2 equiv of 11 and 12 when
reacted with thioamide 8.29
Scheme 4. Synthesis of 35 with the Help of
Triphenylphosphine
With this information in hand, the amount of 9 was increased
to allow for the formation of unwanted product 32. Still, the
reaction did not go to completion. After some experimentation,
it was found that 10 mol % of the catalyst is necessary for the
complete conversion of 30 into 31 (Scheme 3).
Next, 30 was reacted with 11 (eq 1). In these cases, only 5
mol % of catalysts was needed to get the complete conversion
add an excess of PPh3, as only 60% conversion of 34 into 35
was observed after 26 h with 1 equiv of PPh3. The excess PPh3
could be recovered during column chromatography.
Enaminone 35 was obtained as a single diastereomer. The
stereochemistry was assigned as Z by NOE measurements and
by comparison of the spectroscopic data of 35 with the
literature values.37 Under these reaction conditions, the
reaction of the primary thioamide 14 to produce 36 did not
succeed and instead 37 was obtained in excellent yield (eq 2).
of 30 into 33. The need for a lesser amount of catalysts is
probably due to the greater reactivity of keto ruthenacarbenes
relative to that of ester ruthenacarbenes.29 The stereochemistry
of the major diastereomer of 33 was tentatively assigned as E.
Similar enaminoketoesters are known to preferentially exist as E
products.32,35 Simple molecular modeling calculations (Chem-
Bio3D Ultra 12.0 with MM2 parameters)36 suggested that the
E diastereomer was 4.7 kcal/mol more stable than the Z isomer.
The Z isomer suffers from A1,3 type strain caused by the steric
interactions between the C-3 hydrogen atoms and the methyl
ketone hydrogen atoms (eq 1).
The reaction of the secondary thioamide 20 produced 38 in
excellent yield in just 1.5 h (eq 3). Compound 38 was obtained
The reaction of diazoacetophenone (13) with thioamides
required optimization (Scheme 4). Reaction conditions that
were previously successful for the reaction of secondary
thioamides (Table 2) gave mainly thioether 34, and less than
40% of enaminone 35 was formed. It was observed that the
formation of 34 was complete even at room temperature within
45 min in the presence of catalyst 1. Formation of 34 also
occurs in the Eschenmoser reaction. In the Eschenmoser
reaction, the use of PPh3 as a thiophile can convert 34 into
enaminone 35.32,35 Indeed, when PPh3 was added to the
reaction mixture after the formation of the thioether 34 and the
mixture heated to 70 °C for 20 h, an 83% yield of 35 was
obtained. Later, a more convenient protocol was adopted where
all reagents, including PPh3, were added together and heated
for 20 h to give a comparable yield of 35. It was necessary to
as a single isomer. The stereochemistry was assigned as Z by
the NOE measurements and by comparison of its spectroscopic
data with the literature values.38,39 As with 16, 18, and 22
(Table 2), the stereochemistry of 35 and 38 can be explained as
being a consequence of the greater stability of the Z isomer.
The hydrogen bonding between the N−H and the ketone
oxygen makes the Z isomer more stable.38
Triphenylphosphine was not necessary with tertiary thio-
amides, and 39 could be obtained as a single E diastereomer in
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excellent yield (eq 3). However, the reaction required an excess
of 13. This is because 13 undergoes the competing
dimerization reaction. In the absence of any thioamide, 13
gave olefin 40 in a diastereoselective manner (eq 4).40 Such Z
Scheme 6. Possible Pathways for the Formation of Thiazole
Derivatives
stereoselectivity has been observed previously with Ru(II)
catalysts.27,28 With catalyst 1, only the Z product could be
isolated, while with catalyst 7, the E product 40 was also
obtained in 25% yield. The stereochemistry of enaminone 39
was assigned as E by the NOE measurements and by
comparison of its 1H NMR data with literature values.41
Simple molecular modeling calculations (ChemBio3D with
MM2 parameters)36 suggested that the E diastereomer was 9.7
kcal/mol more stable than the Z isomer and that the Z isomer
possesses the A1,3 strain caused by the interactions between the
benzylic hydrogen atoms and the carbonyl oxygen.
giving the product 37. However, it cannot be ruled out that the
nitrogen first adds to the carbonyl carbon to give 49 and the
sulfur atom attacks the ruthenacarbene later. Mechanistic
studies are underway to test the validity of the proposed
mechanism (Scheme 5).
CONCLUSIONS
■
In summary, the screening of seven Ru(II) catalysts in the
coupling of thioamides with α-diazocarbonyl compounds has
been disclosed. Two different types of commercially available
Ru(II) catalysts coupled primary, secondary, and tertiary
thioamides with α-diazocarbonyl compounds to give enami-
nones. The method efficiently coupled secondary and tertiary
thioamides with α-diazodiesters, α-diazoketoesters, α-diazodi-
ketones, and α-diazomonoketones to provide the correspond-
ing enaminones. Primary thioamides could be coupled with α-
diazodiesters, α-diazodiketones, and α-diazoketoesters to
furnish enaminones, while their reaction with α-diazomonoke-
tones gave thiazole derivatives. Presently, efforts are underway
to study the scope of the thiazole derivative transformation.
The approach provided enaminones with good diastereose-
lectivity, and it is an economical alternative to the rhodium-
catalyzed reaction. The reaction was performed under milder
conditions and gave better yields in comparison to those in our
preliminary report.26 The reaction could be conducted by
catalyst 7, which is 41% more economical than catalyst 1, which
was communicated in our preliminary report.26 Ylides have
been suggested in the proposed mechanism, which could have
On the basis of these results and our previous studies,26 the
mechanism given in Scheme 5 is proposed. Ruthenacarbene 41,
generated by the action of ruthenium complexes on diazo
compounds,27,28 is attacked by the nucleophilic thioamide to
give the ruthenium complex associated thiocarbonyl ylide 42
and the free ylide 43. Ylide 42 dissociates, regenerating the
catalyst 44, while 43 cyclizes, giving episulfide 45, which
collapses to give the enaminone.14,19 Since we have isolated
thioethers 47 (for example 34), a shortcut path from 42 to 45 is
unlikely.
The proposed mechanism explains why the reaction was
slowest with Grubbs-3 (5; entry 9, Table 1), which is known to
have the fastest initiation rate in comparison with all of the
Grubbs-type catalysts shown in Figure 1.34,42 Unlike the case
for the olefin metathesis reaction,43 the formation of the active
catalyst (44 = 46) from catalyst 1 does not require dissociation
of one L-type ligand from the precatalyst.27
Formation of cyclic product 37 could also be explained by
the proposed mechanism (Scheme 6). Once thioether 48 is
formed, the imine nitrogen could attack the carbonyl carbon,
Scheme 5. Proposed Mechanisms for the Formation of Enaminones
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7.17−7.15 (m, 2H), 2.50 (s, 3H); 13C NMR (CDCl3) δ (major) 200.6,
138.7, 129.7, 127.1, 124.0, 36.1, (minor) 204.6, 138.1, 129.0, 128.0,
125.2, 30.1; HRMS (ESI+) m/z (M + H)+ calcd for C8H10NS
152.0528, found 152.0511.
great potential in sulfur ylide chemistry.13,44,45 Their ability to
perform cycloaddition reactions in one pot will be explored in
the future. We are also evaluating the possibility of copper as a
more economical catalyst for the coupling reaction.
N-(4-Methoxyphenyl)ethanethioamide (26).49 Following the
general procedure for the synthesis of thioamides, N-(4-
methoxyphenyl)acetamide (200 mg, 1.18 mmol) was converted into
crude 26 by stirring for 2 h at room temperature. Crude 26 was
concentrated and purified by column chromatography (20% ethyl
acetate in petroleum ether) to give 26 (off-white solid) as a mixture of
rotamers in a ratio of 1:1.15 (210 mg, 1.16 mmol, 98%): Rf = 0.53 (3:2
petroleum ether:EtOAc); mp 116−118 °C; IR (neat) νmax/cm−1 3496,
2092, 1640, 574; 1H NMR (CDCl3) δ (major) 8.77 (s, br, 1H), 7.52−
7.49 (m, 2H), 6.93−6.90 (m, 2H), 3.83 (s, 3H), 2.72 (s, 3H), (minor)
9.57 (s, br, 1H), 7.11−7.08 (m, 2H), 6.93−6.90 (m, 2H), 3.81 (s, 3H),
2.45 (s, 3H); 13C NMR (CDCl3) δ (major) 200.6, 158.4, 131.1, 126.0,
114.8, 55.7, 35.8, (minor) 205.1, 159.2, 131.7, 126.9, 114.2, 55.6, 29.9;
HRMS (ESI+) m/z (M + H)+ calcd for C9H12NOS 182.0634, found
182.0629.
EXPERIMENTAL SECTION
■
General Methods. NMR spectra were obtained with a 400 MHz
1
spectrometer: H NMR (400 MHz) and 13C (100 MHz). Chemical
shifts are referenced with the residual solvent peak (CDCl3: 7.26 ppm
1
for H NMR and 77.16 ppm for 13C NMR). Accurate mass spectra
were obtained in a positive ion electrospray mode using an orbitrap
analyzer. Petroleum ether refers to fractions that distill between 30−60
°C. Column chromatography refers to flash chromatography
performed using Sorbent silica gel 60 Å (40−63 μm). Benzene and
acetonitrile were dried by distillation from calcium hydride onto 4 Å
molecular sieves. The molecular sieves were activated by conventional
microwave heating until red (1:30−2:30 min). Catalysts 1−3 and 5−7
were purchased from Aldrich, and catalyst 4 was purchased from
STREM Chemicals. Catalysts 1, 3, and 7 were 97% pure, catalyst 4 was
95% pure, and the rest of the catalysts were 100% pure according to
the vendor’s web site.46 All of the ruthenium-catalyzed reactions were
conducted under an argon atmosphere. Compounds 8,47 12,26 14,26
N-(4-Nitrophenyl)ethanethioamide (28).50 The reaction was set
up according to the general procedure for the synthesis of thioamides,
with the exception that dry toluene (7 mL) was used as the solvent.
The reaction was refluxed for 1 h in order to convert N-(4-
nitrophenyl)acetamide (200 mg, 1.13 mmol) into crude 28. Crude 28
was concentrated and purified by column chromatography (40% ethyl
acetate in petroleum ether) to give pure 28 as a yellow solid (198 mg,
1.01 mmol, 89%): Rf = 0.41 (3:2 petroleum ether:EtOAc); mp 173−
175 °C; IR (neat) νmax/cm−1 3425, 1644, 1511, 1344, 1148, 1102; 1H
NMR (CDCl3 + DMSO-d6 (14%)) δ 11.06 (s, br, 1H), 8.21−8.09 (m,
4H), 2.68 (s, 3H); 13C NMR (CDCl3 + DMSO-d6 (14%)) δ 201.8,
145.3, 144.4, 124.3, 122.6, 36.4; HRMS (ESI+) m/z (M + H)+ calcd
for C8H9N2O2S 197.0379, found 197.0380.
General Procedure A: Coupling of Primary and Secondary
Thioamides with α-Diazodicarbonyl Compounds. A solution of
thioamide (114 μmol) in dry benzene (0.5 mL) was placed in a vial
containing the α-diazodicarbonyl compound (1.3 equiv). The well-
mixed solution was transferred to a vial containing the ruthenium
catalyst 1 or 7 (5 mol %). After it was mixed, the reaction mixture was
transferred to a pressure vessel. The vials were washed twice with 0.25
mL of dry benzene by using the above transfer protocol to ensure the
complete transfer of materials. The vessel was sealed, and the reaction
mixture was heated to 70 or 90 °C in an oil bath for the specified
period of time (Table 1). The crude product was purified by column
chromatography.
(S)-5-(Bis(ethoxycarbonyl)methylidene)pyrrolidine-2-carboxylic
Acid Ethyl Ester (10). With Catalyst 1. Following general procedure
A, 8 (20.0 mg, 116 μmol) was converted to crude 10 by heating the
reaction mixture to 70 °C for 9 h. Column chromatography (CH2Cl2,
then 10% ethyl acetate in CH2Cl2) of the crude 10 gave pure 10 as a
viscous yellow liquid (27.6 mg, 92.3 μmol, 80%).
With Catalyst 7. Following general procedure A, 8 (20.0 mg, 116
μmol) was converted to crude 10 by heating the reaction mixture to
90 °C for 4 h. Column chromatography (CH2Cl2, then 10% ethyl
acetate in petroleum ether) of crude 10 gave pure 10 as a viscous
yellow liquid (27.4 mg, 91.5 μmol, 79%). The 1H and 13C NMR
chemical shift values and the [α]D value match the data reported in the
literature.26
20,26 and 3032 were prepared by literature methods, and H and 13C
1
NMR was used to confirm their identity and purity.
Diethyl Diazomalonate (9). A solution of diethyl malonate (645
mg, 4.03 mmol) in dry CH3CN (11 mL) was added to a stirred
solution of p-toluenesulfonyl azide26 (806 mg, 4.09 mmol) in dry
CH3CN (8 mL) at 0 °C. DBU (98%, 0.93 mL, 6.06 mmol) was added
dropwise, and the solution was warmed to room temperature overnight.
The reaction mixture was concentrated and purified by column
chromatography using a short column (25% petroleum ether in
CH2Cl2). It gave pure 9 (612 mg, 3.29 mmol, 82%) as a viscous yellow
1
liquid. The H and 13C NMR chemical shift values match the data
reported in the literature.26
Ethyl 2-Diazo-3-oxobutanoate (11). A solution of ethyl
acetoacetate (345 mg, 2.64 mmol) in dry CH3CN (10 mL) was
added to a stirred solution of p-toluenesulfonyl azide26 (626 mg, 3.17
mmol) in dry CH3CN (2 mL). DBU (98%, 0.60 mL, 4.02 mmol) was
added dropwise at 0 °C, and the reaction mixture was warmed to room
temperature overnight. The reaction mixture was concentrated and
purified by column chromatography (10% acetone in pentane). It gave
pure 11 (338 mg, 2.16 mmol, 82%) as a viscous yellow liquid. The 1H
and 13C NMR chemical shift values match the data reported in the
literature.26
α-Diazoacetophenone (13). α-Bromoacetophenone (200 mg,
1.00 mmol) and N,N′-ditosylhydrazine (681 mg, 2.00 mmol, 2 equiv)
were dissolved in 5 mL of dry THF. The flask was kept in an ice bath,
and DBU (0.75 mL, 5.00 mmol, 5 equiv) was added dropwise. After 20
min the reaction mixture was concentrated and purified by column
chromatography (20% EtOAc in petroleum ether) to give pure 13
(139 mg, 0.95 mmol, 95%) as a yellow solid. Rf = 0.36 (4:1 petroleum
1
ether:EtOAc). The H and 13C NMR chemical shift values match the
data reported in the literature.48
General Experimental Procedure for the Synthesis of
Thioamides. A solution of amide in CH2Cl2 (0.50 M) was added
to a suspension of Lawesson’s reagent (0.5 equiv, 0.25 M) in CH2Cl2
and stirred at room temperature for the specified period of time. The
reaction mixture was concentrated and purified by column
chromatography.
Diethyl 2-(1-Amino-3-phenylpropylidene)malonate (15). With
Catalyst 1. Following general procedure A, 14 (20.0 mg, 121 μmol)
was converted to crude 15 by heating the reaction mixture to 90 °C for
12 h. Column chromatography (CH2Cl2, then 5% ethyl acetate in
CH2Cl2) of crude 15 gave pure 15 as a yellow oil (30.0 mg, 103 μmol,
85%).
N-Phenylethanethioamide (24).49 Following the general proce-
dure for the synthesis of thioamides, N-phenylacetamide (200 mg, 1.48
mmol) was converted into crude N-phenylethanethioamide by stirring
for 4 h at room temperature. The reaction mixture was chromato-
graphed (CH2Cl2) to give 24 (207 mg, 1.37 mmol, 93%) as a mixture
of rotamers in a ratio of 1:2 (pale yellow solid): Rf = 0.43 (in CH2Cl2);
mp 74−76 °C; IR (neat) νmax/cm−1 3193, 3017, 2971, 1596, 1495,
With Catalyst 7. Following general procedure A, 14 (20.0 mg, 121
μmol) was converted to crude 15 by heating the reaction mixture to
90 °C for 10 h. Column chromatography (CH2Cl2, then 5% ethyl
acetate in CH2Cl2) of crude 15 gave pure 15 as a yellow oil (29.5 mg,
1
1369, 1219, 1149, 1071, 994, 764, 708; H NMR (CDCl3) δ (major)
1
101 μmol, 84%). The H and 13C NMR chemical shift values match
9.00 (s, br, 1H), 7.66−7.64 (m, 2H), 7.44−7.33 (m, 2H), 7.28−7.24
(m, 1H), 2.71 (s, 3H), (minor) 9.91 (s, br, 1H), 7.44−7.33 (m, 3H),
the data reported in the literature.26
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(E)-Ethyl 2-Acetyl-3-amino-5-phenylpent-2-enoate (16).32 With
Catalyst 1. Following general procedure A, 14 (15.0 mg, 90.7 μmol)
was converted to crude 16 by heating the reaction mixture to 70 °C for
8 h. Column chromatography (10% petroleum ether in CH2Cl2) of
crude 16 provided pure 16 (19.7 mg, 75.4 μmol, 83%) as a single
diastereomer (viscous brown liquid).
With Catalyst 7. Following general procedure A, 14 (15.0 mg, 90.7
μmol) was converted to crude 16 by heating the reaction mixture to
90 °C for 6 h. Column chromatography (10% petroleum ether in
CH2Cl2) of crude 16 provided pure 16 (20.2 mg, 77.3 μmol, 85%) as a
single diastereomer (viscous brown liquid): Rf = 0.54 (CH2Cl2); IR
(neat) νmax/cm−1 3423, 2925, 1714, 1650, 1532, 1454, 1373, 1312,
1264, 1092; 1H NMR (CDCl3) δ 11.06 (s, broad, 1H), 7.31−7.17 (m,
5H), 5.37 (s, broad, 1H), 4.27−4.20 (m, 2H), 2.91 (t, J = 7.6 Hz, 2H),
2.75 (t, J = 7.6 Hz, 2H), 2.28 (s, 3H), 1.31 (t, J = 7.2 Hz, 3H); 13C
NMR (CDCl3) δ 197.5, 169.7, 169.0, 140.2, 128.8, 128.5, 126.7, 103.4,
60.5, 38.1, 34.8, 30.3, 14.4; HRMS (ESI+) m/z (M + H)+ calcd for
C15H20NO3 262.1438, found 262.1447.
With Catalyst 7. General procedure A was followed in this
experiment, with the exception that 1 equiv of 12 was added at the
beginning and an additional 1 equiv was added after 8 h of heating to
90 °C. Thioamide 8 (15.0 mg, 86.5 μmol) was converted to crude 19
by heating to 90 °C for 16 h total. Column chromatography (20%
ethyl acetate in petroleum ether) of crude 19 provided pure 19 as a
1
white solid (21.4 mg, 76.6 μmol, 89%). The H NMR chemical shift
values of compound 19 prepared by catalyst 1 match those for the
compound prepared by catalyst 7: Rf = 0.21 (4:1 petroleum
24
ether:EtOAc); mp 197−198 °C; [α]D = −37.2° (c 0.03, CHCl3);
IR (neat) νmax/cm−1 3211, 2957, 1742, 1649, 1588, 1545, 1444, 1202,
1037; 1H NMR (CDCl3) δ 12.01 (s, br, 1H), 4.52 (dd, J = 6.0, 9.6 Hz,
1H), 4.23 (q, J = 7.2 Hz, 2H), 3.50−3.33 (m, 2H), 2.45−2.36 (m,
1H), 2.40 (s, 2H), 2.33 (s, 2H), 2.24−2.15 (m, 1H), 1.29 (t, J = 7.2
Hz, 3H), 1.04 (s, 3H), 1.02 (s, 3H); 13C NMR (CDCl3) δ 199.1,
196.6, 176.0, 170.5, 106.0, 62.2, 61.4, 52.7, 51.9, 34.8, 30.6, 28.7, 28.4,
25.2, 14.2; HRMS (ESI+) m/z (M + H)+ calcd for C15H22NO4
280.1543, found 280.1535.
Diethyl 2-(Pyrrolidin-2-ylidene)malonate (21). With Catalyst 1.
Following general procedure A, 20 (15.0 mg, 148 μmol) was
converted to crude 21 by heating to 70 °C for 22 h. Column
chromatography (25% ethyl acetate in petroleum ether) of crude 21
gave pure 21 as a yellow viscous liquid (28.9 mg, 127 μmol, 86%).
With Catalyst 7. Following general procedure A, 20 (15.0 mg, 148
μmol) was converted to crude 21 by heating to 90 °C for 6 h. Column
chromatography (25% ethyl acetate in petroleum ether) of crude 21
gave pure 21 a yellow viscous liquid (29.3 mg, 129 μmol, 87%). The
1H and 13C NMR chemical shift values match the data reported in the
2-(1-Amino-3-phenylpropylidene)-5,5-dimethylcyclohexane-1,3-
dione (17). With Catalyst 1. Following general procedure A, 14 (15.0
mg, 90.7 μmol) was converted to crude 17 by heating the reaction
mixture to 90 °C for 7 h. Column chromatography (20% ethyl acetate
in petroleum ether) of crude 17 provided pure 17 as a pale white solid
(18.3 mg, 67.4 μmol, 74%).
With Catalyst 7. Following general procedure A, 14 (15.0 mg, 90.7
μmol) was converted to crude 17 by heating the reaction mixture to
90 °C for 5 h. Column chromatography (20% petroleum ether in
CH2Cl2) of crude 17 provided pure 17 as a pale white solid (18.6 mg,
68.5 μmol, 76%). The 1H NMR chemical shift values of compound 17
prepared by catalyst 1 match those for the compound prepared by
catalyst 7: Rf = 0.44 (3:2 petroleum ether:EtOAc); mp 189−191 °C;
IR (neat) νmax/cm−1 3357, 3261, 2925, 1574, 1528, 1453, 1302, 1160,
literature.26
(E)-Ethyl 3-Oxo-2-(pyrrolidin-2-ylidene)butanoate (22)..30,33 With
Catalyst 1. Following general procedure A, 20 (20.0 mg, 198 μmol)
was converted to crude 22 by heating to 70 °C for 22 h. Column
chromatography (40% ethyl acetate in petroleum ether) of the crude
22 gave pure 22 (30.3 mg, 154 μmol, 78%) as a brown solid.
With Catalyst 7. Following general procedure A, 20 (20.0 mg, 198
μmol) was converted to crude 22 by heating to 90 °C for 5 h. Column
chromatography (40% ethyl acetate in petroleum ether) of crude 22
gave pure 22 (27.8 mg, 141 μmol, 71%) as a brown solid. The 1H and
13C NMR chemical shift values match the data reported in the
1
1097; H NMR (CDCl3) δ 7.78−7.76 (m, 1H), 7.27−7.22 (m, 4H),
6.33 (s, broad, 1H), 5.01 (s, broad, 1H), 3.14 (t, J = 7.6 Hz, 2H), 2.89
(t, J = 7.6 Hz, 2H), 2.39 (s, 4H), 1.02 (s, 6H); 13C NMR (CDCl3) δ
200.6, 196.9, 176.2, 140.4, 129.8, 128.7, 128.6, 126.6, 126.5, 107.1,
53.6, 52.6, 39.9, 34.2, 30.1, 28.3, 21.6; HRMS (ESI+) m/z (M + H)+
calcd for C17H22NO2 272.1645, found 272.1639.
(S,E)-Ethyl 5-(1-ethoxy-1,3-dioxobutan-2-ylidene)pyrrolidine-2-
carboxylate (18).31,51 With Catalyst 1. General procedure A was
followed in this experiment, with the exception that 1 equiv of 11 was
added at the beginning and an additional 1 equiv was added after 8 h
of heating to 90 °C. Thioamide 8 (15.0 mg, 86.6 μmol) was converted
to crude 18 by heating to 90 °C for 20 h total. Column
chromatography (20% ethyl acetate in petroleum ether) of crude 18
provided pure 18 (20.3 mg, 75.4 μmol, 87%) as a yellow viscous liquid.
With Catalyst 7. General procedure A was followed in this
experiment, with the exception that 1 equiv of 11 was added at the
beginning and an additional 1 equiv was added after 8 h of heating to
90 °C. Thioamide 8 (15.0 mg, 86.6 μmol) was converted to crude 18
by heating to 90 °C for 14 h total. Column chromatography (20%
ethyl acetate in petroleum ether) of crude 18 provided pure 18 (19.8
mg, 72.7 μmol, 84%) as a yellow viscous liquid: Rf = 0.31 (4:1
petroleum ether:EtOAc); [α]D24 = −23.6° (c 0.02, CHCl3); IR (neat)
literature.33
5,5-Dimethyl-2-(pyrrolidin-2-ylidene)cyclohexane-1,3-dione (23).
With Catalyst 1. General procedure A was followed in this
experiment, with the exception that 0.5 equiv of 12 was added after
8 h of heating to 90 °C. Thioamide 20 (15.0 mg, 148 μmol) was
converted to crude 23 by heating to 90 °C for 12 h. Column
chromatography (20% ethyl acetate in petroleum ether) of crude 23
gave pure 23 (27.2 mg, 131 μmol, 89%) as a white solid.
With Catalyst 7. General procedure A was followed in this
experiment, with the exception that 0.5 equiv of 12 was added after 8 h
of heating to 90 °C. Thioamide 20 (20.0 mg, 198 μmol) was
converted to crude 23 by heating to 90 °C for 12 h. Column
chromatography (20% ethyl acetate in petroleum ether) of crude 23
gave pure 23 (35.3 mg, 170.3 μmol, 86%) as a white solid. The 1H and
13C NMR chemical shift values match the data reported in the
literature.26
1
νmax/cm−1 3437, 2966, 2909, 1747, 1696, 1603, 1532, 1194, 1055; H
Diethyl 2-(1-(Phenylamino)ethylidene)malonate (25).52 With
Catalyst 1. Following general procedure A, 24 (15.0 mg, 86.5
μmol) was converted to crude 25 by heating to 90 °C for 6 h. Column
chromatography (10% ethyl acetate in petroleum ether) of crude 25
gave 25 (24.5 mg, 88.3 μmol, 89%) as a mixture of rotamers in a ratio
of 1:2.9 (yellow viscous liquid).
NMR (CDCl3) δ 11.91 (s, br 1H), 4.49 (dd, J = 5.6, 9.2 Hz, 1H),
4.27−4.14 (m, 4H), 3.27−3.12 (m, 2H), 2.42 (s, 3H), 2.37−2.29 (m,
1H), 2.20−2.12 (m, 1H), 1.33−1.27 (m, 6H); 13C NMR (100 MHz,
CDCl3) δ 198.2, 173.8, 170.8, 168.5, 99.7, 61.9, 61.4, 59.7, 34.3, 31.0,
25.3, 14.4, 14.1; HRMS (ESI+) m/z (M + H)+ calcd for C13H20NO5
270.1336, found 270.1327.
(S)-Ethyl 5-(4,4-Dimethyl-2,6-dioxocyclohexylidene)pyrrolidine-2-
carboxylate (19). With Catalyst 1. General procedure A was followed
in this experiment, with the exception that 1 equiv of 12 was added at
the beginning and an additional 1 equiv was added after 10 h of
heating to 90 °C. Thioamide 8 (15.0 mg, 86.5 μmol) was converted to
crude 19 by heating to 90 °C for 22 h total. Column chromatography
(20% ethyl acetate in petroleum ether) of crude 19 provided pure 19
as a white solid (22.6 mg, 80.9 μmol, 93%).
With Catalyst 7. Following general procedure A, 24 (15.0 mg, 86.5
μmol) was converted to crude 25 by heating to 90 °C for 4 h. Column
chromatography (10% ethyl acetate in petroleum ether) of crude 25
gave 25 (25.2 mg, 90.8 μmol, 92%) as a mixture of rotamers in a ratio
of 1:2.9 (yellow viscous liquid): Rf = 0.47 (3:2 petroleum
ether:EtOAc); IR (neat) νmax/cm−1 3350, 2981, 2925, 1714, 1651,
1
1593, 1501, 1434, 1367, 1244, 1072, 1023, 797, 743, 698; H NMR
(CDCl3) δ 11.24 (s, br, 1H), 7.26−7.23 (m, 2H), 7.38−7.34 (m, 1H),
7.10−7.08 (m, 2H), 4.26−4.19 (m, 4H), 3.36 (s, 3H (minor)), 2.08 (s,
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1
3H), 1.33−1.26 (m, 6H); 13C NMR (CDCl3) δ 168.9, 166.8, 161.7,
138.2, 129.4, 126.5, 126.0, 113.7 (minor), 94.7, 61.7 (minor), 60.8,
60.7 (minor), 59.9, 18.0, 14.5, 14.3; HRMS (ESI+) m/z (M + H)+
calcd for C15H20NO4 278.1387, found 278.1381.
mg, 67.4 μmol, 86%). The H and 13C NMR chemical shift values
match the data reported in the literature.32
Ethyl 2-(1-Benzylpyrrolidin-2-ylidene)-3-oxobutanoate (33). With
Catalyst 1. Following general procedure B, with the exception that 5
mol % of the catalyst was used, 30 (15.0 mg, 78.4 μmol) was
converted to crude 33 by heating to 90 °C for 24 h. Column
chromatography (40% ethyl acetate in petroleum ether) of crude 33
provided 33 as an inseparable mixture of diastereomers (yellow viscous
liquid) (17.6 mg, 61.2 μmol, 78%, E:Z = 3:1).
With Catalyst 7. Following general procedure B, with the exception
that 5 mol % of the catalyst was used, 30 (15.0 mg, 78.4 μmol) was
converted to crude 33 by heating to 90 °C for 22 h. Column
chromatography (40% ethyl acetate in petroleum ether) of crude 33
provided 33 as an inseparable mixture of diastereomers (yellow viscous
liquid) (18.2 mg, 63.3 μmol, 81%, E:Z = 3:1). The 1H NMR chemical
shift values of compound 33 prepared by catalyst 1 match those for the
compound prepared by catalyst 7: Rf = 0.36 (petroleum ether:EtOAc
4:1); IR (neat) νmax/cm−1 2924, 2852, 1736, 1595, 1454, 1379, 1136,
Diethyl 2-(1-((4-Methoxyphenyl)amino)ethylidene)malonate
(27). With Catalyst 1. Following general procedure A, 26 (15.0 mg,
82.7 μmol) was converted to crude 27 by heating to 90 °C for 4 h.
Column chromatography (20% ethyl acetate in petroleum ether) of
crude 27 gave pure 27 as a yellow liquid (21.1 mg, 68.6 μmol, 83%).
With Catalyst 7. Following general procedure A, 26 (15.0 mg, 82.7
μmol) was converted to crude 27 by heating to 90 °C for 3 h. Column
chromatography (20% ethyl acetate in petroleum ether) of crude 27
gave pure 27 as a yellow liquid (20.6 mg, 67.0 μmol, 81%) as a mixture
1
of rotamers. The H NMR chemical shift values of compound 27
prepared by catalyst 1 match those for the compound prepared by
catalyst 7: Rf = 0.64 (3:2 petroleum ether:EtOAc); IR (neat) νmax
/
cm−1 2981, 1712, 1651, 1578, 1594, 1514, 1443, 1245, 1074, 1033; 1H
NMR (CDCl3) δ 11.08 (s, broad, 1H), 7.02 (d, J = 9.0 Hz, 2H), 6.77
(d, J = 9.0 Hz, 2H), 4.26−4.18 (m, 4H), 3.80 (s, 3H), 2.01 (s, 3H),
1.31−1.28 (m, 6H); 13C NMR (CDCl3) δ 168.96, 168.93, 162.6,
158.3, 131.0, 127.6, 114.5, 93.9, 62.7 (minor), 61.7 (minor), 60.7, 59.8,
55.6, 17.9, 14.49, 14.46 (minor), 14.3, 13.9 (minor); HRMS (ESI+) m/
z (M + H)+ calcd for C16H22NO5 308.1493, found 308.1492.
Diethyl 2-(1-((4-Nitrophenyl)amino)ethylidene)malonate (29).
With Catalyst 1. Following general procedure A, 28 (15.0 mg, 76.4
μmol) was converted to crude 29 by heating to 90 °C for 18 h.
Column chromatography (20% ethyl acetate in petroleum ether) of
crude 29 gave 29 (19.2 mg, 59.6 μmol, 78%) as a mixture of rotamers
in a ratio of 1:1.2 (brown liquid).
1
1081; H NMR (CDCl3) δ 7.34−7.24 (m, 4H), 7.11−7.07 (m, 1H),
4.93 (s, broad, 2H, major), 4.67 (s, broad, 2H, minor), 4.13−4.07 (m,
2H), 3.46−3.40 (m, 4H major and 2H minor), 2.86−2.82 (m, 2H,
minor), 2.31 (s, 3H, minor), 2.02−1.95 (m, 2H), 2.00 (s, 3H, major),
1.25−1.20 (m, 3H); 13C NMR (CDCl3) δ 197.6 (minor), 196.3, 169.5,
168.6, 137.0, 136.4 (minor), 128.8, 128.6 (minor), 127.8 (minor),
127.4, 126.7, 105.2, 60.1, 55.8, 55.3 (minor), 53.3, 37.7, 37.4 (minor),
29.8 (minor), 28.7, 21.2, 20.3 (minor), 14.6, 14.24 (minor); HRMS
(ESI+) m/z (M + H)+ calcd for C17H22NO3 288.1594, found
288.1570.
General Procedure C: Coupling of Thioamides with 13. A
solution of thioamide (114 μmol) in dry benzene (0.5 mL) was placed
in a vial containing 13 (1.3 equiv). The well-mixed solution was
transferred to a vial containing the ruthenium catalyst 1 or 7 (5 mol
%). After it was mixed, the reaction mixture was transferred to a
pressure vessel and 4.3 equiv of triphenylphosphine was added. The
vials were washed twice with 0.25 mL of dry benzene by using the
above transfer protocol to ensure the complete transfer of materials.
The vessel was sealed, and the reaction mixture was heated to 70 or 90
°C in an oil bath for the specified period of time. The crude product
was purified by column chromatography.
With Catalyst 7. Following general procedure A, 28 (15.0 mg, 76.4
μmol) was converted to crude 29 by heating to 90 °C for 16 h.
Column chromatography (20% ethyl acetate in petroleum ether) of
crude 29 gave 29 (19.9 mg, 61.7 μmol, 81%) as a mixture of rotamers
in a ratio of 1:2 (brown liquid). The 1H NMR chemical shift values of
compound 29 prepared by catalyst 1 match those for the compound
prepared by catalyst 7: Rf = 0.53 (3:2 petroleum ether:EtOAc); IR
(neat) νmax/cm−1 3383, 2984, 2925, 2848, 1738, 1600, 1506, 1478,
1
1371, 1323, 1230, 1159, 1112, 1021, 838, 753; H NMR (CDCl3) δ
11.45 (s, broad, 1H), 8.23−8.18 (m, 2H), 7.19−7.15 (m, 2H), 4.30−
4.23 (m, 4H), 2.22 (s, 3H), 2.20 (s, 3H, minor), 1.34−1.27 (m, 6H);
13C NMR (CDCl3) δ 168.4, 167.7, 158.0, 144.5, 125.1, 123.4, 99.2,
(S)-Ethyl 5-((2-Oxo-2-phenylethyl)thio)-3,4-dihydro-2H-pyrrole-2-
carboxylate (34). With Catalyst 1. Following general procedure C,
with the exception that no PPh3 was added, 8 (15 mg, 86.6 μmol) was
converted to crude 34 by stirring at room temperature for 45 min.
Column chromatography (25% ethyl acetate in petroleum ether) of
crude 34 gave pure 34 as a yellow viscous liquid (21.2 mg, 72.8 μmol,
62.5 (minor), 61.0, 60.4, 18.1, 14.2, 14.1, 13.8 (minor); HRMS (ESI+)
m/z (M + H)+ calcd for C15H19N2O6 323.1238, found 323.1237.
General Procedure B: Coupling of 30 with α-Diazodicar-
bonyl Compounds. A solution of 30 (114 μmol) in dry benzene
(0.1 mL) was placed in a vial containing the α-diazocarbonyl
compound (1 equiv). The well-mixed solution was transferred to a
vial containing the ruthenium catalyst 1 or 7 (10 mol %). The contents
were mixed, and the reaction mixture was transferred to a pressure
vessel. The vials were washed twice with 0.25 mL of dry benzene by
using the above transfer protocol to ensure the complete transfer of
materials. The vessel was sealed, and the reaction mixture was heated
to 90 °C in an oil bath. After 8 h at a given temperature another 1
equiv of the α-diazocarbonyl compound was dissolved in 0.2 mL of dry
benzene and added to the pressure vessel. The vial containing the α-
diazocarbonyl compound was washed twice with 0.1 mL of dry
benzene, and the contents were transferred to the pressure vessel.
Heating was continued for the specified period of time (eqs 2 and 3).
The crude product was purified by column chromatography.
84%). The H and 13C NMR chemical shift values match the data
1
reported in the literature.32 [α]D = −19.3° (c 0.015, CHCl3).
25
(S,Z)-Ethyl 5-(2-Oxo-2-phenylethylidene)pyrrolidine-2-carboxy-
late (35). With Catalyst 1. Following general procedure C, 8 (20
mg, 115.4 μmol) was converted to crude 35 by heating to 70 °C for 20
h. Column chromatography (25% ethyl acetate in petroleum ether) of
crude 35 gave pure 35 (24.9 mg, 96.0 μmol, 83%) as a yellow viscous
liquid.
With Catalyst 7. Following general procedure C, 8 (15 mg, 86.5
μmol) was converted to crude 35 by heating to 70 °C for 20 h.
Column chromatography (25% ethyl acetate in petroleum ether) of
crude 35 gave pure 35 (19.5 mg, 75.2 μmol, 87%) as a yellow viscous
liquid. The stereochemistry of 35 was determined by the NOE
measurements. The 1H and 13C NMR chemical shift values match the
data reported in literature.37 [α]D = −18.4° (c 0.01, CHCl3).
23
Diethyl 2-(1-Benzylpyrrolidin-2-ylidene)malonate (31). With
Catalyst 1. Following general procedure B, 30 (15.0 mg, 78.4
μmol) was converted to crude 31 by heating to 90 °C for 26 h.
Column chromatography (20% then 30% ethyl acetate in petroleum
ether) of crude 31 provided pure 31 as a yellow viscous liquid (22.3
mg, 70.3 μmol, 90%).
With Catalyst 7. Following general procedure B, 30 (15.0 mg, 78.4
μmol) was converted to crude 31 by heating to 90 °C for 26 h.
Column chromatography (20% then 30% ethyl acetate in petroleum
ether) of crude 31 provided pure 31 as a yellow viscous liquid (21.4
2-Phenethyl-4-phenyl-4,5-dihydrothiazol-4-ol (37). With Catalyst
1. Following general procedure C, 14 (15 mg, 90.7 μmol) was
converted to crude 37 by heating to 90 °C for 15 h. Column
chromatography (25% ethyl acetate in petroleum ether) of crude 37
gave pure 37 as a brown viscous liquid (24.2 mg, 85.4 μmol, 94%).
With Catalyst 7. Following general procedure C, 14 (15 mg, 90.7
μmol) was converted to crude 37 by heating to 90 °C for 11 h.
Column chromatography (25% ethyl acetate in petroleum ether) of
crude 37 gave pure 37 as a brown viscous liquid (22.4 mg, 79.0 μmol,
1
87%). The H NMR chemical shift values of compound 37 prepared
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by catalyst 1 match those for the compound prepared by catalyst 7: Rf
= 0.23 (4:1 petroleum ether:EtOAc); IR (neat) νmax/cm−1 3349, 2920,
2850, 1675, 1604, 1496, 1448, 746; H NMR (CDCl3) δ 7.34−7.25
(m, 10H), 4.38 (s, br, 1H), 3.62 (d, J = 12.0 Hz, 1H), 3.38 (d, J = 12.0
Hz, 1H), 3.07−2.97 (m, 2H), 2.93−2.80 (m, 2H); 13C NMR (CDCl3)
δ 175.3, 144.6, 140.2, 128.7, 128.6, 128.4, 128.1, 126.5, 125.0, 107.8,
46.7, 36.0, 33.7; HRMS (ESI+) m/z (M + H)+ calcd for C17H18NOS
284.1103, found 284.1075.
With Catalyst 7. Following general procedure D, 25 (20.0 mg, 137
μmol) was converted to crude 40 by stirring at room temperature for
40 min. Column chromatography (20% ethyl acetate in petroleum
ether) of the crude gave (Z)-40 (16.7 mg, 70.7 μmol, 52%, yellow
solid) and (E)-40 (8.2 mg, 34.7 μmol, 25%, yellow solid).
1
(2Z)-1,4-diphenylbut-2-ene-1,4-dione: Rf = 0.35 (petroleum ether:-
EtOAc 4:1); mp 138−140 °C; IR (neat) νmax/cm−1 2921, 2843, 1664,
1
1597, 1448, 1395, 1230, 1005, 709; H NMR (CDCl3) δ 7.95−7.94
(m, 2H), 7.93−7.92 (m, 2H), 7.58−7.54 (m, 2H), 7.47−7.43 (m, 4H),
7.16 (s, 2H); 13C NMR (CDCl3) δ 192.5, 136.2, 135.7, 133.7, 128.9,
128.8 ; HRMS (ESI+) m/z (M + H)+ calcd for C16H13O2 237.0910,
found 237.0913.
(Z)-1-Phenyl-2-(pyrrolidin-2-ylidene)ethanone (38). With Cata-
lyst 1. Following general procedure C, 20 (15 mg, 148 μmol) was
converted to crude 38 by heating to 70 °C for 1.5 h. Column
chromatography (20% ethyl acetate in petroleum ether) of crude 38
gave pure 38 (23.2 mg, 124 μmol, 84%) as a white solid.
(2E)-1,4-diphenylbut-2-ene-1,4-dione: Rf = 0.39 (petroleum ether:-
EtOAc 4:1); mp 104−106 °C; IR (neat) νmax/cm−1 2924, 2853, 1665,
With Catalyst 7. Following general procedure C, 20 (15 mg, 148
μmol) was converted to crude 38 by heating to 70 °C for 1.5 h.
Column chromatography (20% ethyl acetate in petroleum ether) of
crude 38 gave pure 38 (22.6 mg, 121 μmol, 82%) as a white solid. The
1H and 13C NMR chemical shift values match the data reported in the
1
1596, 1449, 1378, 1230, 1005, 687; H NMR (CDCl3) δ 8.09−8.08
(m, 2H), 8.064−8.056 (m, 2H), 8.02 (s, 2H), 7.66−7.62 (m, 2H),
7.56−7.52 (m, 4H); 13C NMR (100 MHz, CDCl3) δ 189.9, 136.9,
135.1, 133.9, 128.9; HRMS (ESI+) m/z (M + H)+ calcd for C16H13O2
237.0910, found 237.0890.
literature.38,39
(E)-2-(1-Benzylpyrrolidin-2-ylidene)-1-phenylethanone (39).41
With Catalyst 1. General procedure C was followed in this
experiment, with the exception that 13 (5.00 mg, 34.0 μmol every 1
h, total 25.0 mg, 171 μmol) was added gradually. Thioamide 30 (15.0
mg, 78.4 μmol) was converted to crude 39 by heating to 70 °C for 6 h.
Column chromatography (25% ethyl acetate in petroleum ether) of
crude 39 gave pure 39 (20.6 mg, 74.2 μmol, 95%) as a brown liquid.
With Catalyst 7. General procedure C was followed in this
experiment, with the exception that 13 (0.44 μmol every 1 h, total 25.0
mg, 171 μmol) was added gradually. Thioamide 30 (15 mg, 78.4
μmol) was converted to crude 39 by heating to 70 °C for 7 h. Column
chromatography (25% ethyl acetate in petroleum ether) of crude 39
gave pure 39 (19.8 mg, 71.3 μmol, 91%) as a brown liquid: Rf = 0.29
(petroleum ether:EtOAc 3:2); IR (neat) νmax/cm−1 3059, 2923, 2854,
1725, 1624, 1577, 1540, 1479, 1453, 1299, 1065, 701; 1H NMR
(CDCl3) δ 7.83−7.80 (m, 2H), 7.40−7.31 (m, 5H), 7.25−7.23 (m,
3H), 5.90 (s, 1H), 4.53 (s, 2H), 3.51−3.43 (m, 4H), 2.06 (p, J = 7.6
Hz, 2H); 13C NMR (CDCl3) δ 188.2, 167.7, 142.1, 135.7, 130.5,
129.6, 128.1, 127.9, 127.4, 127.3, 87.0, 52.8, 50.5, 34.0, 21.1; HRMS
(ESI+) m/z (M + H)+ calcd for C19H20NO 278.1539, found 278.1510.
General Procedure D: Dimerization of α-Diazocarbonyl
Compounds. A solution of the α-diazocarbonyl compound (107
μmol) in dry benzene (0.5 mL) was added to a vial containing the
ruthenium catalyst 1 or 7 (5 mol %). The contents were mixed, and
the reaction mixture was transferred to a pressure vessel. The vials
were washed twice with 0.25 mL of dry benzene by using the above
transfer protocol to ensure the complete transfer of materials. The
vessel was sealed, and the reaction mixture was stirred at a specified
temperature and time in order to get the crude product. The crude
alkene was purified by column chromatography.
ASSOCIATED CONTENT
■
S
* Supporting Information
1
Figures giving H and 13C NMR spectra of all compounds
1
described in the Experimental Section, H NMR spectra for
enaminones prepared by catalysts 1 and 7, 1D NOESY
(DPFGSE NOE) spectra of compounds 35, 38, and 39 and the
2D NOESY spectrum of 39. This material is available free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail for S.R.H.: syed-hussaini@utulsa.edu.
Notes
■
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support was provided by The University of Tulsa new
faculty lab-startup funds and The University of Tulsa Faculty
Research Grant Program. The authors are grateful to Dr. K. P.
Roberts and Ms. J. Holland, The University of Tulsa, for their
help with the spectrometric measurements. We are grateful to
Dr. Margaret Eastman and Dr. Dongtao Cui, Oklahoma State
University, for their help with the 1D NOESY studies. We are
also grateful to Dr. Chalker for providing some of the Grubbs
catalysts. This material is based upon work supported by the
National Science Foundation under Grant No. CHE-1048784.
Tetraethyl Ethene-1,1,2,2-tetracarboxylate (32).53 With Catalyst
1. Following general procedure D, 9 (20.0 mg, 107 μmol) was
converted to crude 32 by heating to 90 °C for 24 h. Column
chromatography (CH2Cl2) of crude 32 provided pure 32 as a yellow
liquid (25.8 mg, 81.6 μmol, 76%).
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