Copper-catalyzed chemoselective cross-coupling reaction of thioamides and α-diazocarbonyl compounds: Synthesis of enaminones

Article abstract of DOI:10.1016/j.tetlet.2017.01.004

The development of operationally simple and cost-effective methods for C[sbnd]C bond formation reactions are highly important in pharmaceutical, agrochemical and material research. In this article we describe the first copper-catalyzed cross-coupling reaction of thioamides with acceptor/acceptor-substituted and acceptor-only substituted α-diazocarbonyl compounds to yield enaminones. The reaction shows broad substrate scope in terms of thioamides and diazocarbonyl compounds. Primary, secondary and tertiary thioamides all give enanminones when reacted with α-diazodiesters, α-diazoketoesters, α-diazodiketones, α-diazoketoamides, α-diazoesteramides, α-diazoketosulfones and α-diazomonoketones.

Full text of DOI:10.1016/j.tetlet.2017.01.004

Accepted Manuscript
Copper-Catalyzed Chemoselective Cross-Coupling Reaction of Thioamides
and α-Diazocarbonyl Compounds: Synthesis of Enaminones
Arpal Pal, Naga D. Koduri, Zhiguo Wang, Erika Lopez Quiroz, Alexandra
Chong, Matthew Vuong, Nisha Rajagopal, Michael Nguyen, Kenneth P.
Roberts, Syed R. Hussaini
PII:
S0040-4039(17)30003-5
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.01.004
TETL 48507
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
28 November 2016
21 December 2016
2 January 2017
Please cite this article as: Pal, A., Koduri, N.D., Wang, Z., Lopez Quiroz, E., Chong, A., Vuong, M., Rajagopal, N.,
Nguyen, M., Roberts, K.P., Hussaini, S.R., Copper-Catalyzed Chemoselective Cross-Coupling Reaction of
Thioamides and α-Diazocarbonyl Compounds: Synthesis of Enaminones, Tetrahedron Letters (2017), doi: http://
dx.doi.org/10.1016/j.tetlet.2017.01.004
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Copper-Catalyzed Chemoselective Cross-Coupling Reaction of
Thioamides and α-Diazocarbonyl Compounds: Synthesis of Enaminones
Arpal Pala, Naga D. Koduria ,Zhiguo Wanga, Erika Lopez Quiroza, Alexandra Chonga, Matthew
Vuonga, Nisha Rajagopala, Michael Nguyena, Kenneth P. Robertsa, and Syed R. Hussainia*
aDepartment of Chemistry and Biochemistry, The University of Tulsa, 800 S Tucker Dr, Tulsa, Oklahoma 74104, USA
The development of operationally simple and cost-effective methods for C–C bond formation reactions are highly important in
pharmaceutical, agrochemical and material research. In this article we describe the first copper-catalyzed cross-coupling reaction of
thioamides with acceptor/acceptor-substituted and acceptor-only substituted α-diazocarbonyl compounds to yield enaminones. The
reaction shows broad substrate scope in terms of thioamides and diazocarbonyl compounds. Primary, secondary and tertiary thioamides
all give enanminones when reacted with α-diazodiesters, α-diazoketoesters, α-diazodiketones, α-diazoketoamides, α-diazoesteramides, α-
diazoketosulfones and α-diazomonoketones
.
Enaminone
Copper
Heterocycle
Diazocarbonyl compounds
Cross-coupling
catalyzed versions of this reaction is the competing formation of
the homocoupled products.35 Another issue is that, in the
coupling of thioamides with the monocarbonyl diazo compounds,
the reaction stops at the thioether stage. A large excess of
thiophile is needed to convert the thioethers into enaminones.35
There are also no reports of the coupling of the thioformamides
and diazo compounds for the formation of enaminones. Coupling
with thioformamides could provide disubstituted enaminones that
are useful intermediates in natural product synthesis.36
Furthermore, Rh2(OAc)4 and Ru(II)-catalysts used in
transformation are more expensive than common Cu catalysts
that have been used in the generation of copper carbenoids.1 To
address these challenges, we tested selected copper catalysts
(Table 1). Copper is not a precious metal, and many copper
catalysts are better in avoiding dimerization reactions than
Rh2(OAc)4.3 Copper catalysts also have a broad tolerance of
functional groups present on substrates.37
Introduction
Copper-catalyzed reactions of diazocarbonyl compounds
contribute to a number of valuable transformations in organic
synthesis.1-8 Numerous methods are known for the construction
of C–C and C–X (X= N, O, S and Si) bonds using copper-
carbenoids.1 Despite these significant advances, the copper-
catalyzed cross-coupling reaction of thioamides and α-
diazocarbonyl compounds for the synthesis of enaminones have
never been reported.9 Here, for the first time, we disclose the
synthesis of enaminones via a copper-catalyzed chemoselective
cross-coupling of thioamides and α-diazocarbonyl compounds.
Enaminones are versatile synthetic intermediates in organic
chemistry.10-14 They are widely used for the construction of
heterocycles and pharmaceutically active compounds.10-14
Enaminones are also found to exert anticonvulsant,15 proteasome
inhibition,16 molluscicidal and larvicicidal17 activities. Because of
their importance, the development of new and efficient methods
for the synthesis of enaminones is an active area of research.18-24
Results and discussion
We initiated our studies with the screening of copper catalysts
for the coupling of thiolactam 1a and diazoester 2a (Table 1). All
catalysts shown in Table 1 are known to generate copper
A variety of methods are available for the synthesis of
enaminones.10-14 Among the reported methods, the Eschenmoser
sulfide contraction (ESC) reaction has been used extensively for
38, 39
carbenoids from acceptor-substituted diazo compounds.1,
25, 26
the construction of enaminones.14,
However, the ESC
We tested Cu(OTf)2 (5 mol%) as a catalyst in benzene at 90 ˚C
and monitored the progress of the reaction up to 26 hours.
However, the reaction did not undergo complete conversion into
the product and starting materials remained (Table 1, entry 1). A
higher yield of 3aa was obtained when 1,2-dichloroethane was
used as the solvent ( Table 1, compare entries 1 3). The best
yield of 3aa (92%) was obtained when the reaction was carried
out with (CuOTf)2·Tol in 1,2-dichloroethane (Table 1, entry 7).
Other electrophilic copper catalysts (Table 1, entries 9, 10 and
reaction suffers from significant drawbacks. The preparation of
suitable α-bromocarbonyl compounds can be difficult. The ESC
also requires a long time for completion.27-30 Furthermore, the
ESC method is unsuccessful in coupling sterically hindered
31
thioamides with α-halocarbonyl compounds.14,
Modified
versions of the ESC reaction have emerged to overcome these
shortcomings.14, 26 One such reaction is the Rh(II) and the Ru(II)-
catalyzed coupling of thioamides with α-diazocarbonyl groups.14,
32-34
One problem associated with the Rh(II) and the Ru(II)-

yields (48–93%) (Table 2). The reaction of α-diazo acetophenone
2h with 1a also afforded the enaminone 3ah in 92% yield
without the addition of any triphenylphosphine. The same
transformation with Ru(II) requires 5 equivalents of PPh3.35
Formation of 3ag is also noteworthy as we are aware of only four
reports of enaminones containing Weinreb amides.40-43
11) failed to completely consume 1a in 26 hours. The use of
CuCl, CuBr and CuI gave reduced yields (Table 1, entries
12 14) and 1a did not undergo complete conversion into 3aa.
When anhydrous CuSO4 was used, only 15% conversion 1a into
3aa was observed (Table 1 entry 15). Use of (IPr)CuCl and
CuTC did not improve the yield ( Table 1, entries 16 and 17) and
Cu(acac)2 showed scarce conversion of 1a into 3aa (Table 1,
entry 18).
Table 2. Copper-Catalyzed Coupling Reaction of 1a with
Acceptor/Acceptor-Substituted Diazo Compounds
Table 1: Optimization of Reaction Conditionsa
Entry
Catalyst
Solvent
Time
(h)
26
26
26
19
18
12
11
26
26
26
26
26
26
26
26
26
26
26
Yield
(%)
40
1.b
Cu(OTf)2
Benzene
DCB
2.b
Cu(OTf)2
60
3.c
Cu(OTf)2
DCE
72
4.c
(CuOTf)2·Tol
(CuOTf)2·Tol
(CuOTf)2·Tol
(CuOTf)2·Tol
(CuOTf)2·Tol
Cu(CH3CN)4BF4
Cu(CH3CN)4BF4
Cu(CH3CN)4PF6
CuCl
Benzene
Toluene
DCB
DCE
DCM
DCE
67
5.c
70
6.c
74
7.c
92
8.d
<1
15
9.b
10.b
11.b
12.b
13.b
14.b
15.b
16.b
17.b
18.b
DCB
66
The diastereoselectivity was also probed for this coupling
reaction. Only a single diastereomer 3ah was obtained when 2h
was used. Such selectivity has been observed before and is
explained as a result of the greater stability of the Z isomer.14 The
exposure of other differently substituted diazo compounds to the
reaction conditions provided mixtures of diastereomers (3ab–
3ad, 3af and 3ag). The selectivity observed in the case of 3ab,
3ac and 3ag is similar to the ones observed in Eschenmoser type
reactions. Various explanations have been postulated for such
selectivity.14, 44
DCE
30
DCE
49
CuBr
DCE
39
CuI
DCE
41
CuSO4
DCE
15
(IPr)CuCl
CuTC
DCE
50
Next, we explored the scope of this copper-catalyzed
coupling reaction with various thioamides (Table 3). Primary,
secondary and tertiary thioamides were all converted into the
corresponding enaminones in moderate to excellent yields (32–
92%). Both cyclic (3fa, 3ea) and acyclic positioned thioamides
are viable substrates in this coupling reaction. The reaction also
shows excellent chemoselectivity. The α-diazocarbonyl
compounds, in the presence of copper catalysts, are known to
undergo N H insertion, C H insertion and Buchner reactions.1
While evaluating the substrate scope, N H insertion, C H
insertion or Buchner reaction products were never observed.
Such selectivity is suspected to be due to higher nucleophilicity
of sulfur compared to other functional groups and the highly
electrophilic nature of the copper carbene generated from Cu(I)
triflate.1 Table 3 (3da) also shows the first example of a metal-
DCE
24
Cu(acac)2
DCE
trace
aAll reactions were performed in
a pressure vessel under an argon
atmosphere. Reaction conditions: 1a (0.2 mmol), 2a (0.26 mmol), catalyst (5
mol%) in 2.0 ml solvent at 90˚C. bDetermined by 1H NMR with reference to
c
1a. Isolated yield. dReaction carried out at 50˚C; DCE = 1,2-dichloroethane;
DCB = 1,2-dichlorobenzene.
With the optimized reaction conditions in hand (Table 1,
entry 7), we next examined six different classes of
acceptor/acceptor-substituted diazo compounds– α-diazodiesters,
α-diazoketoesters, α-diazodiketones, α-diazoketoamides, α-
diazoesteramides and α-diazoketosulfones (Table 2) in this
reaction. These diazo compounds when reacted with thiolactam
1a, gave corresponding enaminones in moderate to excellent

catalyzed coupling of a thioformamide and a diazo compound for
the formation of an enaminone.
Scheme 1. Mechanistic Experiments
On the basis of these experimental observations and our
previous studies,34, 35 a mechanism is proposed for this copper-
catalyzed coupling reaction (Scheme 2). The reaction of a copper
complex with α-diazocarbonyl compounds generates the copper-
carbene complexe 8. The nucleophilic attack of thioamide to the
copper-carbene complex gives the copper-associated sulfur ylide
9. The metal-free ylide 10 can be obtained by the dissociation of
copper from 9. Both the metal associated ylide 9 and the metal
free ylide 10 can undergo electrocyclization to form episulfide
11. Copper(I) triflate assists in the formation of episulfide 11 and
the subsequent extrusion of sulfur to provide enaminones.
Mechanistic studies have been planned to test the validity of the
proposed mechanism.
Table 3. Copper-Catalyzed Coupling Reaction of Differently
Substituted Thioamides
R2
R2
R1
R3
CO2Et
CO2Et
(CuOTf) Tol, (5 mol%) R1
CO2Et
CO2Et
·
2
S
N2
+
DCE, 90oC
R3
N
N
R4
R4
2a
3
1
EtO2C
BnHN
CO2Et
EtO2C
Bn
CO2Et EtO2C
CO2Et
HN
NH2
PhHN
3ca
EtO2C
CO2Et
3ea
26 hrs, 71%
3ba
8hrs, 53%
3da
17hrs, 56%
9hrs, 74%
EtO2C CO2Et
EtO2C
CO2Et
N
, R= , 92%
3ga
, R=
3ha
H
N
N
, 79%
OMe
CO2Et
EtO2C
, R= , 60%
Me
3ia
, R=
3ja
R
N
, 75%
NO2
24hrs
3ka
26 hrs, 32%
3fa
21hrs, 63%
Thioethers are known to form when acceptor-only diazo
compounds react with thioamides in the presence of Ru(II)
catalysts. This suggests that ylides are present in this reaction.34,
35
We attempted to trap the intermediate thiocarbonyl ylide.
However, the reaction of 1g and 2a in the presence of a
dipolarophile 4 (DMAD; dimethylacetylenedicarboxylate) did
not yield cycloadduct 5 (Scheme 1A), and only 3ga was
obtained. Unlike the Ru(II) catalysts,35 with Cu(I)OTf, the
reaction of 1a with 2h only gave the enaminone 3ah (Table 2),
and formation of thioimino ether 6 was not observed (Scheme
1B). This suggests that, with Cu(I)OTf, the extrusion of sulfur is
not occurring just due to simple thermal activation. Furthermore,
the thioimino ether 6 could be converted into the enaminone 3ah
under the reaction conditions (Scheme 1B). These results support
the hypothesis that copper(I) triflate catalyzes the extrusion of
sulfur in this reaction. Although rarely reported, similar metal
and acid catalyzed -sulfur extrusions have been observed with
zinc, nickel, BF3 and TFA in the Eschenmoser sulfide contraction
reaction.14, 45-47
Scheme 2. Proposed Mechanism for Enaminone Formation
In conclusion, we have successfully developed an
unprecedented copper-catalyzed cross-coupling reaction of
thioamides with α-diazocarbonyl compounds for the
synthesis of enaminones.48 This reaction has a diverse
substrate scope. It also represents the synthesis of
enaminones containing the Weinreb amide, thioformamide,
and sulfone functionalities which can further broaden the
synthetic application of this reaction. We have also
discovered a new catalytic reactivity of copper(I) triflate that
enables the extrusion of sulfur from thioimino ether.
Currently, we are working on the utilization of
donor/acceptor-substituted diazo compounds and ester
diazoacetates in this coupling reaction.
Acknowledgments
Financial support was provided by The University of
Tulsa (TU). We thank Mrs. Jennifer Holland (TU) for her
help with the spectrometric measurements and Kun Miao,
Ashley Johnson and Maria Castaneda (TU) for their
assistance with the screening of catalysts. This work was
supported by the National Science Foundation under Grant
No. CHE 10487484.

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*Graphical Abstract

*Highlights




First report of copper-catalyzed coupling of thioamides and diazo compounds for the synthesis of enaminones
Thioformamide and primary, secondary and tertiary thiomamides can undergo this reaction
Acceptor/acceptor and acceptor-only substituted diazo compounds are coupling viable partners
Catalytic extrusion of sulfur is reported