The Eschenmoser coupling reaction under continuous-flow conditions

Article abstract of DOI:10.3762/bjoc.7.135

The Eschenmoser coupling is a useful carbon-carbon bond forming reaction which has been used in various different synthesis strategies. The reaction proceeds smoothly if S-alkylated ternary thioamides or thiolactames are used. In the case of S-alkylated s

Full text of DOI:10.3762/bjoc.7.135

The Eschenmoser coupling reaction under
continuous-flow conditions
Sukhdeep Singh, J. Michael Köhler, Andreas Schober
and G. Alexander Groß*
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2011, 7, 1164–1172.
Institute for Chemistry and Biotechnology, Technische Universität
Ilmenau, Weimarerstr. 32, D-98693-Ilmenau
doi:10.3762/bjoc.7.135
Received: 31 May 2011
Accepted: 28 July 2011
Published: 25 August 2011
Email:
G. Alexander Groß* - alexander.gross@tu-ilmenau.de
* Corresponding author
This article is part of the Thematic Series "Chemistry in flow systems II".
Guest Editor: A. Kirschning
Keywords:
activation energy; episulfide; flow chemistry; keto imine; kinetics;
S-alkylation; sulfide contraction; triisopropyl phosphite
© 2011 Singh et al; licensee Beilstein-Institut.
License and terms: see end of document.
Abstract
The Eschenmoser coupling is a useful carbon–carbon bond forming reaction which has been used in various different synthesis
strategies. The reaction proceeds smoothly if S-alkylated ternary thioamides or thiolactames are used. In the case of S-alkylated sec-
ondary thioamides or thiolactames, the Eschenmoser coupling needs prolonged reaction times and elevated temperatures to deliver
valuable yields. We have used a flow chemistry system to promote the Eschenmoser coupling under enhanced reaction conditions
in order to convert the demanding precursors such as S-alkylated secondary thioamides and thiolactames in an efficient way. Under
pressurized reaction conditions at about 220 °C, the desired Eschenmoser coupling products were obtained within 70 s residence
time. The reaction kinetics was investigated and 15 examples of different building block combinations are given.
Introduction
The Eschenmoser coupling [1,2] is a reaction method that yields applied many times as a useful reaction step in a variety of syn-
β-enaminocarbonyl derivatives of type 4 by the elimination of thesis strategies. Different natural products, such as diplodialid
sulfur (sulfide contraction) from an episulfide intermediate macrolactone- [5], sedamine alkaloid- [6], sparteine- [7], mersi-
(Scheme 1). The reaction was described for the first time by carpine- [8], batzelladine- [9], fuligocandin- [10] and vitamin
Knott in 1955 [3] and became prominent later on when it was B12-derivatives [11] were prepared with the aid of sulfide
applied to the total synthesis of vitamin B12 by Eschenmoser contraction steps. Pharmaceutically important substances, such
[4]. Since these early days the Eschenmoser coupling has been as methylphenidat [12] or the marine neurotoxin hemibreve-
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Scheme 1: Eschenmoser coupling reaction with secondary S-alkylated thioamide derivatives of type 3.
toxin [13], were prepared by utilization of the Eschenmoser tions, the thiophilic reagent must be carefully chosen in order to
coupling reaction. Recently, we explored the Eschenmoser overcome the difficulties in the separation of the desired pro-
coupling in order to produce Biginelli type dihydropyrimidine duct from phosphine sulfide byproducts.
(DHPM) derivatives as screening candidates for pharmaceu-
tical and crop science research [14]. Moreover, the Eschen- S-Alkylated ternary thioamides of type 7 usually undergo the
moser coupling is quite a valuable, metal free, carbon–carbon episulfide formation and subsequent sulfide contraction
bond forming reaction.
smoothly (Scheme 2). This is due to the strong electron
accepting nature of the thioiminium intermediate 8. Unfortu-
The necessary starting materials of type 3 can be prepared by nately, the S-alkylation is sometimes difficult in these cases [6].
S-alkylation of secondary thioamide or thiolactame building In the case of secondary thiolactames of type 5, sulfide contrac-
blocks of type 2 with α-bromoketones 1 (X = Br). The tion takes place as well, but prolonged reaction time and
carbon–carbon coupling occurs between these building blocks increased reaction temperature are necessary in most cases. In
as shown in Scheme 1. Due to the ease of accessibility of the contrast to this, secondary thioamide derivatives of type 5
building blocks and the usually high-yielding S-alkylation step, undergo the S-alkylation with α-bromoketones more readily
the Eschenmoser coupling is an interesting reaction for diver- than ternary thioamides. However, the specific reactivity of
sity-oriented combinatorial synthesis [15-17].
both reaction steps obviously depends on the building blocks
used and their specific reactivity. For the present work we chose
The new carbon–carbon bond formation occurs during the only commercially available α-bromoketone building blocks
construction of the episulfide intermediate 6, which requires and secondary thiolactame and thioamide derivatives. To
base catalysis (B ). The sulfur extraction from the episulfides 6 improve the long reaction times we investigated the Eschen-
or 8 yields the desired β-enaminocarbonyl derivative 4 or 9. moser coupling under process intensification conditions. There-
However, the detailed reaction mechanism for the sulfur extrac- fore, reaction temperatures far beyond the solvent boiling point
tion step has not yet been fully proven and obviously depends were applied under pressurized flow conditions for a minimum
on the applied reaction conditions. Experimental observations residence time. For small scale synthesis flow chemistry is of
show that the reaction can take place without the addition of a great advantage to realize these conditions on the laboratory
thiophilic agent or base. This is a strong hint that the sulfide bench safely [18].
extraction is of an intramolecular pericylic nature, as proposed
in Scheme 1. In the presence of a thiophilic agent, the mecha-
nism of extraction via intermediate ionic states also seems plau-
sible. Nevertheless, the Eschenmoser coupling reaction requires
the addition of a base and a thiophilic agent in the most cases.
Here, triphenylphosphine- or trialkyl-phosphite-derivatives are
usually employed to promote the sulfide contraction with valu-
able yield and selectivity. Eschenmoser himself made use of
Scheme 2: Eschenmoser coupling sequence of S-alkylated ternary
thioamides of type 7.
bi-functional reagents with dual thiophile and basic properties
in one molecule [2]. With regards to experimental considera-
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Results and Discussion
were formed when the reaction temperature exceeded 150 °C.
For the reaction optimization we have focused on a straightfor- As a result, only traces of the desired product 4aa were
ward procedure that finally prevents the isolation of the S-alky- observed by LC–MS analysis, along with multiple side prod-
lated intermediates 3 and avoids a change of the reaction ucts. The side products were not investigated in greater detail
solvent for the subsequent step. To establish the best conditions because of the complexity of the mixture. In the case of ethanol
we investigated the reaction of 2-bromo-1-phenylethanone (1a) as solvent, the solubility of the starting materials and S-alky-
with 2-mercapto-6-methyl-pyrimidin-4-ol (2a) in detail. There- lated intermediate 3aa was poor and the solutes tended to
fore, 2a was dissolved in different solvents and 2 equiv NEt3 precipitate. However, anhydrous 1,4-dioxane was found to be
were added. After 10 min, the dissolved α-bromoketone 1a was the best solvent for both reaction steps. Conversions, with anhy-
added dropwise. A concentration of about 0.1 mol/L was drous 1,4-dioxane as solvent, are shown in Figure 1. Only poor
achieved in this way. The reaction solutions were sonicated for conversion was observed up to 160 °C. The maximum conver-
about 1/2 h. Subsequently, the HNEt3Br precipitates were sion of about 98% was observed at 220 °C, with a flow rate of
filtered off. The precipitation and filtration was done with care 250 µL/min. At reaction temperatures beyond 220 °C the selec-
to prevent malfunctions of the feeding pumps. In the case of tivity of the reaction decreased dramatically and some unidenti-
chloroform as solvent no precipitation took place, but the fied decomposition products appeared. Nevertheless, the
LC–MS analysis indicated the S-alkylation clearly, with a increase of the flow rate, to about 500 or 750 µL/min at 230 °C,
purity of about 89%. To all filtered solutions 1.25 equiv of led to comparable good yields and high reaction selectivities. In
triisopropylphosphite (TIP) were added as thiophilic agent the case of higher flow rate, of 1000 µL/min and beyond, and
before the reaction solutions were fed through the flow chem- the corresponding shorter reaction time, a decreased conversion
istry setup. A flow rate of 1000 µL/min (RT: 55 s) was adjusted was observed due to the slow reaction kinetics (Figure 1).
and the reaction temperature was increased stepwise from 120
to 240 °C. The backpressure regulator was set for all experi- The flow chemistry technique allows the determination of reac-
ments to about 100 bar. The received reaction products were tion kinetics data in a fast and efficient way, even under pres-
collected and analyzed by LC–MS analysis. In the case of THF surized process-identifying conditions. We investigated the
as solvent, precipitation took place in the capillary and the kinetics of the sulfide contraction of 3aa to 4aa in detail. For
backpressure regulator became blocked. In case of chloroform, this purpose, a 0.1 mol/L reaction solution was fed through the
the reaction solution turned black, and oily polymeric products reaction system at different flow rates and reaction tempera-
Figure 1: Conversion of 3aa to 4aa under different flow conditions.
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Beilstein J. Org. Chem. 2011, 7, 1164–1172.
tures. After each change in the reaction parameters the reaction
system was allowed to reach a steady state before a sample was
taken. After a change of the flow rate, samples were taken only
after a minimum waiting period of about three times the resi-
dence time to achieve system equilibration.
(1)
(2)
In order to compare the reaction performance of the flow reac-
tion with the conventional technique, the same reaction was For the analysis of the reaction kinetics the following workflow
carried out under batch conditions. The resulting product solu- was necessary: 1) Variation of the reaction parameters, 2) probe
tions were analyzed by LC–MS and isolated by the standard sampling, 3) HPLC analysis and 4) reaction kinetics calcula-
precipitation/recrystallization procedure. No conversion was tions for six different temperatures at five different flow rates.
observed in the batch reaction at ambient temperature within The determination of the complete reaction kinetics data was
48 h. Even heating up to the boiling point of 1,4-dioxane (101 complete within 6 h. A comparable analysis by a sequential
°C) for about 1 h did not furnish the desired product in any batch technique would take approximately 1 week. Hence, flow
significant amount. However, after refluxing overnight a yield chemistry is well suited to efficiently determine the kinetics for
of at least 43% 4aa was isolated.
reactions under unconventional reaction conditions.
The investigated Eschenmoser coupling under flow conditions To explore the scope of the sulfide-contraction reaction we
was found to be a first order reaction. Rate constants were varied both building blocks in a systematic manner under the
calculated using the first order kinetic Equation 1, where c following reaction conditions: 0.1 M reaction solution in anhy-
[mol/L] is the concentration of the product 4aa at the reaction drous 1,4-dioxane, 2 equiv NEt3, 1.25 equiv TIP at 220 °C and
temperature T [K] after the reaction solution was passed 250–750 µL/min flow rate. First, we varied the thiolactame
through the heater with the residence time τ [s]. The resulting building blocks 2 and kept the α-bromoketone 1a constant. In
kinetic plot is shown in Figure 2 (left). The determined rate Table 1, the investigated building blocks 2a–2i and the isolated
constants were used to prepare an Arrhenius plot and for calcu- yields are shown. For the product workup, 100% volume of
lation of the activation energy from Equation 2. The resulting water and 1% 1 M HCl were added to the product solution. If
Arrhenius plot is shown in Figure 2 (right). An activation precipitation took place after addition, the residues were
energy EA of about 91 kJ/mol, and a frequency factor A of filtered. If no precipitation took place, then the reaction solu-
about 3.73 × 109 s−1, were found. This activation energy is tion was extracted with ethyl acetate. The organic phase was
obviously the reason for the slow reaction kinetics at moderate separated and dried over MgSO4 and the ethyl acetate was
temperature. Hence, the application of pressurized high subsequently removed by evaporation. The resulting extracts or
temperature conditions should lead to significant reaction inten- precipitates were recrystallized from a solvent mixture of hot
sification.
methanol/dichloromethane. However, the crystallization process
Figure 2: Reaction kinetics analysis. Left: Rate constants with 0.1 M reaction solution. Right: Arrhenius-plot for the determined rate constants.
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Table 1: Product and yields received for different thio-substrates 2.
Structure of 2
Product 4
Yielda
48
2a
4aa
4ab
4ac
4ad
2b
2c
2d
55
78
–b
2e
4ae
82
2f
4af
69
92
2g
4ag
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Beilstein J. Org. Chem. 2011, 7, 1164–1172.
Table 1: Product and yields received for different thio-substrates 2. (continued)
2h
2i
4ah
4ai
5c
58
aIsolated yields; bDecomposition during sulfide contraction; cNo product precipitation or extraction of 4ah was possible; only 3ah was isolated in
smaller amount.
was not optimized and there is scope to increase yields further. choose only aromatic bromoketones because of their known
The desired products 3 were received in synthetically useful good reactivity and selectivity for the sulfide contraction [1].
yields in almost all cases. The NMR spectra of the resulting Recently, we investigated the reaction of dihydropyrimidine
products 4 mainly comprise two sets of signals with varying in- derivatives of type 11 with different aliphatic ketones 10 under
tensities (details can be found in the Supporting Information batch conditions. In that case the S-alkylated substrates 12 did
File 1). This is due to the two different possibilities for the not undergo the sulfide contraction but rather the thiazole for-
intramolecular H-bond formation caused by the keto–enol mation to 13 took place exclusively (Scheme 3) [19]. The
tautomerism of 4. In this scheme, the reaction of 2-mercapto- thiazol formation by condensation is a well known side reac-
pyrimidin-4-ol derivatives 2a, 2b and 2c proceeded smoothly tion of the sulfide contraction. Nevertheless, and in contrast to
with high yields. 6-Aza-2-thiothymine (2d) was quantitatively the batch reaction, no thiazole formation was observed under
S-alkylated but decomposed during the sulfide-contraction step the investigated flow conditions.
and subsequent workup. Therefore, we could not isolate the
desired product 4ad. The reaction of dihydropyrimidine
substrates 2e and 2f proceeded in a facile way, and the desired
products 3ae and 3af were isolated in good yields. Even the
mercapto hydantoin derivative 2g underwent the two step reac-
tion smoothly and yielded the desired product 4ag in good
quantity. In case of the 1H-benzoimidazole-2-thiol (2h), the
selective S-alkylation failed. The utilized alkylation conditions
favor the bis-alkylation, and hence the S-alkylated product was
produced in less than 10% yield (HPLC-peak area). LC–MS
Scheme 3: Exclusive formation of thiazol 13 with dihydropyrimidine
derivatives 11 take place in the case of aliphatic ketones 10 [19].
analysis after the sulfide contraction of this mixture showed that
the bis-S-alkylated intermediate was only partially converted.
Unfortunately, we could not isolate the product from the com-
plex reaction mixture by the standard precipitation and extrac- The influence of the bromoketone building blocks 1a–1g on the
tion/crystallization processes. The 2-thiobenzimidazol (2h) flow reaction performance was investigated (Table 2).
underwent the S-alkylation as well as the sulfide contraction 2-Mercapto-6-methylpyrimidin-4-ol (2a) was chosen as the
smoothly and showed good conversion to the desired product reaction partner for all bromoketones 1a–1g. High yields and
3ah. However, the applied precipitation technique yielded only reaction selectivities were observed in all cases at the investi-
a trace amount of the unconverted intermediate 3ah. gated temperature of 220 °C. The influence of the different
N-Phenylthioacetamide (2i) was additionally chosen as a aromatic bromoketones on the reaction seems to be negligible.
noncyclic secondary thioamide example. The desired product The electron accepting nature of the thio-substrate seems to
4ai was received in excellent yield.
have the dominating effect on the reaction performance.
However, all investigated combinations of the building blocks
Various α-bromoketone building blocks, as shown in Table 2, furnished the desired products in good yields within residence
were investigated in combination with the thiolactame 2a. We times of about 70 s.
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Table 2: Product and yields for various α-bromoketones 1.
Structure of 1
Product 4
Yielda
48
1a
4aa
4ba
1b
1c
1d
66
61
67
4ca
4da
1e
1f
4ea
4fa
72
61
1g
4ga
73
aIsolated yields.
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Conclusion
We found that Eschenmoser coupling can be performed at a
reaction temperature of 220 °C with residence times of about 70
s. 1,4-Dioxane was found to be the most effective solvent. The
reaction kinetics was determined in a fast and efficient way for
0.1 M reaction concentration. As a result, the flow chemistry
technique enabled the significant intensification of the reaction
kinetics, by application of enhanced process conditions on the
laboratory bench, in a safe and efficient way. The intensifica-
tion potential was investigated for demanding secondary thio-
lactames of type 5, and exemplary combinations of building
blocks, as shown in Table 1 and Table 2, were examined. In
almost all investigated cases the desired products were received
in synthetically useful yields.
Experimental
Flow chemistry system
A flow chemistry assembly consisting of two feeding pumps, a
capillary reactor, a heat controller and a backpressure regulator
was used, as shown in Figure 3. The capillary reactor consists
of a 2.1 m long steel capillary with 0.75 mm inner diameter
(~930 µL), which was wrapped around a brass cylinder with an
integrated heat-rod (hotset, HHP 200 W, 8 × 80 mm) and jack-
eted by a thermally isolated brass cover (Figure 4). Thermal
control was achieved by using a commercial process controller
(EMKO process controller ESM-4450) with adapted PT-100
temperature sensor. For pressure control a manual needle valve
(micro splitter, Upchurch) was integrated at the capillary outlet.
About 20 cm of the capillary between the heating cylinder and
the backpressure regulator was tempered by a water chiller to
ambient temperature. Feeds were delivered by the help of two
double piston HPLC-pumps (Shimadzu LC-9A, double inlet
check valves). The first pump was used to feed the reaction
solutions and the second pump was used to feed pure solvent
for purging and dilution. The maximum operational parameters
for the complete flow chemistry setup were proven up to 250 °C
and 200 bar. Residence times (τ) between 40 min and 60 s were
achieved by adjusting the flow rate from 20 to 2000 µL/min.
Figure 4: Capillary reactor with jacketed cover removed, and the
process controller.
Supporting Information
Supporting Information File 1
General procedures, analytical and spectral data.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-7-135-S1.pdf]
Acknowledgments
The support from K. Risch and S. Günther for compound
analysis is gratefully acknowledged. The authors thank
Figure 3: Flow chemistry setup scheme.
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Beilstein J. Org. Chem. 2011, 7, 1164–1172.
S. Schneider for the support during the development of the reac-
tion setup. This work was partially supported by different
BMBF projects: OPTIMI (FKZ: 16SV3701), BioMepSens
(FKZ: 03ZIK062) and Mikrokunststoffformen (FKZ:
03ZIK465).
License and Terms
This is an Open Access article under the terms of the
Creative Commons Attribution License
(http://creativecommons.org/licenses/by/2.0), which
permits unrestricted use, distribution, and reproduction in
any medium, provided the original work is properly cited.
References
1. Shiosaki, K. The Eschenmoser Coupling Reaction. In Comprehensive
Organic Synthesis; Trost, B. M., Ed.; Pergamon Press: Oxford, 1991;
Vol. 2, pp 865–892. doi:10.1016/B978-0-08-052349-1.00051-2
2. Roth, M.; Dubs, P.; Götschi, E.; Eschenmoser, A. Helv. Chim. Acta
1971, 54, 710–734. doi:10.1002/hlca.19710540229
The license is subject to the Beilstein Journal of Organic
Chemistry terms and conditions:
(http://www.beilstein-journals.org/bjoc)
3. Knott, E. B. J. Chem. Soc. 1955, 916–927. doi:10.1039/JR9550000916
4. Eschenmoser, A.; Wintner, C. E. Science 1977, 196, 1410–1426.
doi:10.1126/science.867037
The definitive version of this article is the electronic one
which can be found at:
5. Ireland, R. E.; Brown, F. R., Jr. J. Org. Chem. 1980, 45, 1868–1880.
doi:10.1021/jo01298a022
doi:10.3762/bjoc.7.135
6. Neto, B. A. D.; Lapis, A. A. M.; Bernd, A. B.; Russowsky, D.
Tetrahedron 2009, 65, 2484–2496. doi:10.1016/j.tet.2009.01.081
7. Wlodarczak, J.; Wysocka, W.; Katrusiak, A. J. Mol. Struct. 2010, 971,
12–17. doi:10.1016/j.molstruc.2010.02.050
8. Nakajima, R.; Ogino, T.; Yokoshima, S.; Fukuyama, T.
J. Am. Chem. Soc. 2010, 132, 1236–1237. doi:10.1021/ja9103233
9. Elliott, M. C.; Long, M. S. Org. Biomol. Chem. 2004, 2, 2003–2011.
doi:10.1039/b404679j
10.Pettersson, B.; Hasimbegovic, V.; Bergman, J. J. Org. Chem. 2011, 76,
1554–1561. doi:10.1021/jo101864n
11.Mulzer, J.; List, B.; Bats, J. W. J. Am. Chem. Soc. 1997, 119,
5512–5518. doi:10.1021/ja9700515
12.Russowsky, D.; da Silveira Neto, B. A. Tetrahedron Lett. 2003, 44,
2923–2926. doi:10.1016/s0040-4039(03)00420-9
13.Nicolaou, K. C.; Reddy, K. R.; Skokotas, G.; Sato, F.; Xiao, X. Y.;
Hwang, C. K. J. Am. Chem. Soc. 1993, 115, 3558–3575.
doi:10.1021/ja00062a021
14.Singh, S.; Schober, A.; Gebinoga, M.; Groß, G. A. Tetrahedron Lett.
2009, 50, 1838–1843. doi:10.1016/j.tetlet.2009.02.027
15.Groß, G. A.; Wurziger, H.; Schlingloff, G.; Schober, A.
QSAR & Comb. Sci. (Special Issue: Array Synthesis) 2006, 25,
1055–1062. doi:10.1002/qsar.200640120
16.Groß, G. A.; Mayer, G.; Albert, J.; Riester, D.; Osterodt, J.;
Wurziger, H.; Schober, A. Angew. Chem., Int. Ed. 2006, 118,
3174–3178. doi:10.1002/ange.200503041
17.Gebinoga, M.; Groß, G. A.; Albrecht, A.; Lübeck, T.; Henkel, T.;
Hoffmann, P.; Klemm, U.; Schlingloff, G.; Frank, T.; Schober, A.
QSAR & Comb. Sci. (Special Issue: Array Synthesis) 2006, 25,
1063–1068. doi:10.1002/qsar.200640113
18.Wegner, J.; Ceylan, S.; Kirschning, A. Chem. Commun. 2011, 47,
4583–4592. doi:10.1039/c0cc05060a
19.Singh, S.; Schober, A.; Gebinoga, M.; Groß, G. A. Tetrahedron Lett.
2011, 52, 3814–3817. doi:10.1016/j.tetlet.2011.05.067
1172