Mild, Fast, and Easy to Conduct MoCl5-Mediated Dehydrogenative Coupling Reactions in Flow

Article abstract of DOI:10.1021/acs.orglett.8b01664

A convenient and straightforward approach to performing oxidative coupling reactions in flow is presented. A collection of electron-rich benzene derivatives was subjected to this protocol, and the distinct utility of molybdenum pentachloride (MoCl₅) is established. Using this unexplored protocol, biphenyls could be obtained in 21-91% isolated yield. This simple protocol opens a new chapter in reagent-mediated dehydrogenative coupling reactions, and yields are compared to classical approaches.

Full text of DOI:10.1021/acs.orglett.8b01664

Letter
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Mild, Fast, and Easy To Conduct MoCl ‑Mediated Dehydrogenative
5
Coupling Reactions in Flow
Sebastian B. Beil,† Ise Uecker, Peter Franzmann, Timo Mu
,‡
†
†
ller, and Siegfried R. Waldvogel*
†
,†,‡
̈
†
Institute of Organic Chemistry, Johannes Gutenberg University Mainz, Duesbergweg 10-14, 55128 Mainz, Germany
MAterial Science IN MainZ (MAINZ), Graduate School of Excellence, Staudingerweg 9, 55128 Mainz, Germany
‡
*
S Supporting Information
ABSTRACT: A convenient and straightforward approach to performing
oxidative coupling reactions in flow is presented. A collection of electron-rich
benzene derivatives was subjected to this protocol, and the distinct utility of
molybdenum pentachloride (MoCl ) is established. Using this unexplored
5
protocol, biphenyls could be obtained in 21−91% isolated yield. This simple
protocol opens a new chapter in reagent-mediated dehydrogenative coupling
reactions, and yields are compared to classical approaches.
ehydrogenative or oxidative coupling reactions have
and flow rate, the reaction time can be easily adjusted and the
whole process is simplified. Since often only short reaction
times are necessary, no anhydrous solvents are required, which
increases the simplicity and utility of this protocol. Even
though oxidative coupling reactions in flow were reported to
be exothermic, no self-heating of the setup or further
precaution is necessary. The solid bed of MoCl5 is
considered as single-use only. To ensure no slow decom-
position of the oxidizer during storage between different runs
and to avoid contamination with other substrates, each bed is
freshly prepared for each reaction.
D
emerged as a powerful methodology to form new C−C
1
bonds between arenes. While thallium(III) reagents have
2
been applied in the past, today more environmentally friendly
3
reagents such as iron(III) chloride, molybdenum(V)
4
5
chloride, bis(trifluoroacetoxy) iodobenzene (PIFA), and
,3-dichloro-5,6-dicycano-1,4-benzoquinone (DDQ)/metha-
1
4
2
6
7
nesulfonic acid are described in this context. In particular,
4
MoCl exhibits high performance in establishing new C−C
5
8
and C−S bonds, respectively. More recently, several reagent-
free electrochemical protocols were investigated to efficiently
9
provide dehydrogenative coupling products. These systems
As a test and benchmark reaction, we investigated the
dehydrodimerization of 4-methyl veratrole (1) in dichloro-
methane. On a 1 mmol scale, the substrate was absorbed on
operate in 1,1,1,3,3,3-hexafluoroisopropanol using an active
molybdenum or BDD anode and can be considered even more
environmentally friendly since no stoichiometric amounts of
100 mg silica and charged in the precolumn together with
10
metal reagents are required or consumed.
MoCl . The empty space in the PP Buchi cartridge (12 × 75
mm) could be simply filled with sand. After elution, the
reaction mixture was directly purified on the silica column
̈
5
However, even though large amounts of oxidizers are
necessary in classical dehydrogenative coupling, these reactions
usually proceed rather quickly, which was recently highlighted
(
cartridge: 12 × 150 mm, 8 g silica). For collection, a fraction
4
b,8a
for MoCl5.
The high reaction rate for Mo(V) reagents is
collector was facilitated at a wavelength of 256 nm. Initially, we
observed that a flow rate of 2.5 mL/min is crucial (Table 1),
since a faster flow rate of 10 mL/min gave no conversion to 2.
This flow rate was kept for 15 min, to ensure that all of the
substrate was dissolved and the reaction went to completion.
The tubing length was about 60 cm, which corresponds to a
residence time of the reaction of about 12 s. With this setup in
hand, we tested different equivalents from 1.5 to 3.0 of MoCl5.
With 1.5 equiv a good yield of 71% was obtained (Table 1,
entry 1).
beneficial since many common side reactions occur on a slower
1
1
time scale. It is desirable to combine the fast reaction rate of
reagent-mediated coupling reactions with the easy purification
of the electrochemical protocol, which avoids an aqueous
workup. A straightforward solution would be the application of
flow conditions, which were reported for similar palladium-
1
2
catalyzed transformations previously. The solubility of
MoCl is either fairly poor in noncoordinating organic solvents
5
or the solvents are not stable under the strongly electrophilic
1
3
conditions. A simple protocol that can be easily implemented
into a flow chemical process is highly advantageous to generate
the desired compounds in an automated fashion.
This is the minimum amount required for the trans-
formation since an overoxidation is crucial in the reaction
15
mechanism, which can be observed when this reaction is
Here, we present the first example of a solid deposition of
the oxidizer in a reservoir and a slow dissolution of the
substrate and elution over the reagent (Figure 1). This reaction
mixture could then be directly purified from remaining metal
salt byproducts or impurities. Depending on the tubing length
conducted under inert batch conditions wherein 2 could be
Received: May 26, 2018
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b01664
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Figure 1. Schematic example of a MoCl -mediated oxidative coupling reaction under flow conditions (ERG = electron releasing group, newly
5
formed bond in bold).
Table 1. Optimization of the Flow Conditions Using MoCl5
to give 2
transformations. All of the reagents were reported to provide
biphenyl 2 in yields higher than 90% under batch
6c,17
conditions.
Surprisingly, only MoCl gave 2 in a sufficient
5
yield of 84%, whereas FeCl and PIFA gave no conversion in
3
flow (Table 2, entries 1−3).
Table 2. Comparison of the Efficiency of Different Oxidizers
in the Transformation of 4-Methylveratrole (1) into
Compound 2 under Flow Conditions
a
entry
solvent
equiv
yield (%)
b
1
2
3
4
5
6
7
8
CH Cl
1.5
2.0
3.0
2.0
2.0
2.0
2.0
2.0
71 (93)
84 (77)
2
2
2
2
b
CH Cl
2
CH Cl
38
−
26
3
−
7
2
MeCN
t-BuOCH3
THF
1,4-dioxane
toluene
a
entry
oxidant
MoCl5
yield (%)
1
2
3
4
84
−
a
b
Isolated yield. Yield in parentheses corresponds to the same
reaction under inert batch conditions, reaction time of 15 min.
FeCl3
PIFA
DDQ/MeSO H
−
57
b
3
isolated in 93% yield. We found that 2.0 equiv of MoCl is
required to give a high yield of 84% under flow conditions
a
b
5
Isolated yield. A second chromatography step (eluent: cyclo-
hexane/ethyl acetate) was required to remove DDQ/DDQH2.
(Table 1, entry 2). The slight excess comes along with the
avoidance of inert conditions and anhydrous solvents for this
flow-type reaction. When the amount of reagent (3.0 equiv) is
further increased, the yield drops down to 38% due to side
reactions such as overoxidation or chlorination (Table 1, entry
Nevertheless, the mixture of DDQ and MeSO H provided
3
product 2 in a good yield of 57%, but a second
chromatography purification step with different solvents
(cyclohexane and ethyl acetate) was required since DDQ
and the respective hydroquinone eluted together with the
product in CH Cl (Table 2, entry 4). This superior reactivity
3
). Interestingly, the isolated yields of 2 are inversed for 1.5
and 2.0 equiv when comparing the classical batch reaction with
the flow conditions, and only 77% yield was obtained using 2.0
equiv in batch, which could be explained by overoxidation and
oligomerization. Since dichloromethane is not desirable in
terms of sustainability and halogen-footprint, we tested the
effect of other solvents on the yield of 2. Strongly coordinating
solvents such as acetonitrile gave no conversion of 1 (Table 1,
entry 4).
2
2
and characteristics of MoCl compared to other oxidizers have
5
not been described before, which is surprising since all other
oxidizers were reported to proceed with short reaction
6
d,17
times.
Likewise, the performance of MoCl5 can be
rationalized by a distinct redox play under these particular
conditions. During the reaction, an overoxidized radical-
1
5
Ethereal solvents were previously reported to be less stable
cationic intermediate is formed, which is subsequently
reduced to the product by Mo(III) and Mo(IV) oxo-
1
6
with MoCl5, which was clearly confirmed by using methyl-
tert-butyl ether (MTBE), THF, or 1,4-dioxane (Table 1,
entries 5−7). Whereas MTBE gave a poor yield of 26% of 2, in
THF only traces of the product were isolated and dioxane
completely suppressed the syntheses of the biphenyl derivative
18
complexes. These reducing agents are generated by water
impurities within the silica gel, which was not dried prior to
use. In addition, silica acts as a trapping agent for HCl formed
during the reaction, which will otherwise decrease the
19
2
. Less polar solvents such as toluene gave product 2 in only
reactivity of the Mo(V) reagent. By these means, MoCl5
outperforms other common oxidizers under these flow
conditions.
7
% isolated yield, which corresponds to the diminished
solubility of MoCl in such solvents (Table 1, entry 8).
5
Furthermore, we investigated the impact of molybdenum
pentachloride on this reaction, since other oxidants such as
FeCl , PIFA, and DDQ/MeSO H are often applied in similar
To prove the utility of this new approach to conduct MoCl5-
mediated oxidative coupling reactions, we subjected a
collection of electron-rich benzene derivatives 3 to this
3
3
B
DOI: 10.1021/acs.orglett.8b01664
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
protocol. In addition, these results of the formed biphenyls 4
The para-dimethoxy derivative 3g again gave an improved
conversion in flow and provided the respective biphenyl in
73% yield.
were compared with classical batch reactions, whereas some of
1
1a,20
them were reported previously,
along with the electro-
9a
chemical approach we reported recently. Using our novel
We hereby developed an easy to perform molybdenum
pentachloride-mediated dehydrogenative coupling reaction
using flow conditions. Compared to batch reactions, no
anhydrous solvent is required, and products can be directly
isolated after column chromatography in high yields and
purity. The solvent can be redistilled and recycled, and the
applied amount can thereby be decreased and no additional
solvent change for chromatography is necessary. This protocol
not only provides biphenyls in good to excellent yields but also
flow conditions product 2 could be isolated in a yield of 84%
(Table 3). This result can easily compete with the high yields
Table 3. Scope of Intermolecular Oxidative Aromatic
Coupling for Electron-Rich Benzene Derivatives Using
a
MoCl under Flow Conditions
5
exceeds other commonly applied oxidants such as FeCl , PIFA,
3
or DDQ under flow conditions.
ASSOCIATED CONTENT
Supporting Information
■
*
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b01664.
General experimental procedures, synthetic details, and
characterization, including NMR and MS spectra for all
products and intermediate compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
■
*
E-mail: waldvogel@uni-mainz.de. Tel: +49 6131/39-26069.
ORCID
Sebastian B. Beil: 0000-0003-0373-3843
Siegfried R. Waldvogel: 0000-0002-7949-9638
Author Contributions
The manuscript was written through contributions of all
authors.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
S.R.W. acknowledges the DFG (Wa1276/15-1) and the
Center for INnovative and Emerging MAterials (CINEMA)
for financial support. S.B.B. thanks the Verband der
a
Flow conditions: MoCl (2.0 equiv), CH Cl , 20 °C. Flow rate: 2.5
5
2
2
Chemischen Industrie (VCI) for a Kekule Fellowship.
́
mL/min (15 min) → 7.0 mL/min (30−50 min). ERG: electron-
releasing group.
REFERENCES
1) (a) Grzybowski, M.; Skonieczny, K.; Butenscho
■
(
̈
n, H.; Gryko, D.
T. Angew. Chem., Int. Ed. 2013, 52, 9900−9930. (b) Li, C.-J. Acc.
Chem. Res. 2009, 42, 335−344.
of 93% and 67%, which were reported using batch and
(
2) (a) McKillop, A.; Turrell, A. G.; Young, D. W.; Taylor, E. C. J.
9
a,15
electrochemical conditions.
Similar observations were
Am. Chem. Soc. 1980, 102, 6504−6512. (b) McKillop, A.; Turrell, A.
found for the halogenated veratrole derivatives 3a−c (F, Cl,
Br), and all of them gave significantly higher yields in flow
compared to the other two batch-type approaches. Hence,
almost quantitative yields of up to 91% were accessible. Only
G.; Taylor, E. C. J. Org. Chem. 1977, 42, 764−765.
(3) (a) Dossel, L.; Gherghel, L.; Feng, X.; Mullen, K. Angew. Chem.,
̈
̈
Int. Ed. 2011, 50, 2540−2543. (b) Danz, M.; Tonner, R.; Hilt, G.
Chem. Commun. 2012, 48, 377−379. (c) Feng, C.; Tian, X.-L.; Zhou,
J.; Xiang, S.-K.; Yu, W.-H.; Wang, B.-Q.; Hu, P.; Redshaw, C.; Zhao,
K.-Q. Org. Biomol. Chem. 2014, 12, 6977−6981. (d) Boden, N.;
Bushby, R. J.; Lu, Z.; Headdock, G. Tetrahedron Lett. 2000, 41,
4
-iodoveratrole (3d) gave a lower yield of only 25%, which is
most likely due to solubility issues of the newly formed
biphenyl on the silica column. More activated benzene
derivatives 3e and 3f gave surprisingly lower yields in flow,
compared to batch and Mo-anode mediated conversions. Due
1
(
0117−10120.
4) (a) Waldvogel, S. R.; Trosien, S. Chem. Commun. 2012, 48,
9
109−9119. (b) Schubert, M.; Waldvogel, S. R. Eur. J. Org. Chem.
to a high local MoCl concentration and the low oxidation
5
2016, 2016, 1921−1936.
(5) (a) King, B. T.; Kroulík, J.; Robertson, C. R.; Rempala, P.;
Hilton, C. L.; Korinek, J. D.; Gortari, L. M. J. Org. Chem. 2007, 72,
potential of the substrates, these could oligomerize and thereby
suppress the yields down to 21% and 45%, respectively.
C
DOI: 10.1021/acs.orglett.8b01664
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
2
279−2288. (b) Ormsby, J. L.; Black, T. D.; Hilton, C. L.; Bharat;
King, B. T. Tetrahedron 2008, 64, 11370−11378.
6) (a) Rose, P.; Emge, S.; Konig, C. A.; Hilt, G. Adv. Synth. Catal.
(
̈
̈
2017, 359, 1359−1372. (b) Little, M. S.; Yeates, S. G.; Alwattar, A.
A.; Heard, K. W. J.; Raftery, J.; Edwards, A. C.; Parry, A. V. S.; Quayle,
P. Eur. J. Org. Chem. 2017, 2017, 1694−1703. (c) Zhai, L.; Shukla, R.;
Wadumethrige, S. H.; Rathore, R. J. Org. Chem. 2010, 75, 4748−4760.
(
d) Zhai, L.; Shukla, R.; Rathore, R. Org. Lett. 2009, 11, 3474−3477.
(
5
(
7) Rempala, P.; Kroulík, J.; King, B. T. J. Org. Chem. 2006, 71,
067−5081.
8) (a) Franzmann, P.; Beil, S. B.; Winterscheid, P. M.; Schollmeyer,
D.; Waldvogel, S. R. Synlett 2017, 28, 957−961. (b) Spurg, A.;
Schnakenburg, G.; Waldvogel, S. R. Chem. - Eur. J. 2009, 15, 13313−
1
(
3317.
9) (a) Beil, S. B.; Mu
A.; Holtkamp, M.; Karst, U.; Schade, W.; Waldvogel, S. R. Angew.
Chem., Int. Ed. 2018, 57, 2450−2454. (b) Mohle, S.; Zirbes, M.;
Rodrigo, E.; Gieshoff, T.; Wiebe, A.; Waldvogel, S. R. Angew. Chem.,
Int. Ed. 2018, 57, 6018−6041. (c) Wiebe, A.; Gieshoff, T.; Mohle, S.;
Rodrigo, E.; Zirbes, M.; Waldvogel, S. R. Angew. Chem., Int. Ed. 2018,
7, 5594−5619.
10) Frontana-Uribe, B. A.; Little, R. D.; Ibanez, J. G.; Palma, A.;
Vasquez-Medrano, R. Green Chem. 2010, 12, 2099−2119.
11) (a) Waldvogel, S. R.; Aits, E.; Holst, C.; Frohlich, R. Chem.
Commun. 2002, 1278−1279. (b) Waldvogel, S. R.; Frohlich, R.;
Schalley, C. A. Angew. Chem., Int. Ed. 2000, 39, 2472−2475.
c) Kramer, B.; Waldvogel, S. R. Angew. Chem., Int. Ed. 2004, 43,
446−2449. (d) Schubert, M.; Leppin, J.; Wehming, K.; Schollmeyer,
D.; Heinze, K.; Waldvogel, S. R. Angew. Chem., Int. Ed. 2014, 53,
494−2497.
12) (a) Cantillo, D.; Kappe, C. O. ChemCatChem 2014, 6, 3286−
305. (b) Erdmann, N.; Su, Y.; Bosmans, B.; Hessel, V.; Noel, T. Org.
̈
ller, T.; Sillart, S. B.; Franzmann, P.; Bomm,
̈
̈
5
(
(
̈
(
2
2
(
3
̈
Process Res. Dev. 2016, 20, 831−835. (c) Noel, T.; Buchwald, S. L.
Chem. Soc. Rev. 2011, 40, 5010−5029.
(
13) (a) Bartalucci, N.; Bortoluzzi, M.; Marchetti, F.; Pampaloni, G.;
Schoch, S.; Zacchini, S. New J. Chem. 2017, 41, 4329−4340.
(
b) Bortoluzzi, M.; Ferretti, E.; Hayatifar, M.; Marchetti, F.;
Pampaloni, G.; Zacchini, S. Eur. J. Inorg. Chem. 2016, 2016, 3838−
3
1
845. (c) Kauffmann, T. Angew. Chem., Int. Ed. Engl. 1997, 36, 1258−
275.
(
14) Gemoets, H. P. L.; Su, Y.; Shang, M.; Hessel, V.; Luque, R.;
Noel, T. Chem. Soc. Rev. 2016, 45, 83−117.
15) Schubert, M.; Franzmann, P.; Wunsche von Leupoldt, A.;
Koszinowski, K.; Heinze, K.; Waldvogel, S. R. Angew. Chem., Int. Ed.
016, 55, 1156−1159.
16) (a) Favero, L.; Marchetti, F.; Pampaloni, G.; Zacchini, S. Dalton
(
̈
2
(
Trans. 2014, 43, 495−504. (b) Maria, S.; Poli, R.; Gallagher, K. J.;
Hock, A. S.; Johnson, M. J., Ether Complexes of Molybdenum(III)
and Molybdenum(IV) Chlorides. In Inorganic Syntheses, Girolami, G.
S.; Sattelberger, A. P., Eds. John Wiley & Sons: 2014; Vol. 36.
(
c) Hayatifar, M.; Marchetti, F.; Pampaloni, G.; Pinzino, C.; Zacchini,
S. Polyhedron 2013, 61, 188−194.
17) (a) Jempty, T. C.; Miller, L. L.; Mazur, Y. J. Org. Chem. 1980,
5, 749−751. (b) Tohma, H.; Morioka, H.; Takizawa, S.; Arisawa, M.;
Kita, Y. Tetrahedron 2001, 57, 345−352.
18) (a) Hackeloer, K.; Schnakenburg, G.; Waldvogel, S. R. Org.
Lett. 2011, 13, 916−919. (b) Hackeloer, K.; Waldvogel, S. R.
Tetrahedron Lett. 2012, 53, 1579−1581.
19) Kramer, B.; Frohlich, R.; Waldvogel, S. R. Eur. J. Org. Chem.
003, 2003, 3549−3554.
20) Waldvogel, S. R. Synlett 2002, 2002, 622−624.
(
4
(
̈
̈
(
̈
2
(
D
DOI: 10.1021/acs.orglett.8b01664
Org. Lett. XXXX, XXX, XXX−XXX