A Novel Cathode Material for Cathodic Dehalogenation of 1,1-Dibromo Cyclopropane Derivatives

Article abstract of DOI:10.1002/chem.201502064

Leaded bronze turned out to be an excellent cathode material for the dehalogenation reaction of cyclopropanes without affecting the strained molecular entity. With this particular alloy, beneficial properties of lead cathodes are conserved, whereas the corrosion of cathode is efficiently suppressed. The solvent in the electrolyte determines whether a complete debromination reaction is achieved or if the process can be selectively stopped at the monobromo cyclopropane intermediate. The electroorganic conversion tolerates a variety of functional groups and can be conducted at rather complex substrates like cyclosporine A. This approach allows the sustainable preparation of cyclopropane derivatives.

Full text of DOI:10.1002/chem.201502064

DOI: 10.1002/chem.201502064
Communication
&
Cyclopropanes
A Novel Cathode Material for Cathodic Dehalogenation of 1,1-
Dibromo Cyclopropane Derivatives
Christoph Gütz,[a] Maximilian Selt,[a] Markus Bänziger,[b] Christoph Bucher,[b]
Christina Rçmelt,[a] Nadine Hecken,[a] Fabrice Gallou,[b] Tomµs R. Galv¼o,[b] and
Siegfried R. Waldvogel*[a]
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Here, we report a sustainable and efficient electrolytic
method for a twofold dehalogenation at cyclopropanes. To cir-
cumvent the issue of corrosion of cathode we found leaded
bronze (CuSn7Pb15) to be a new, innovative, and stable cath-
ode material for electroorganic transformations. Leaded bronze
is an inexpensive alloy which is commonly used for bearings
and exhibits a pronounced higher chemical and mechanical
stability than lead.[12]
Abstract: Leaded bronze turned out to be an excellent
cathode material for the dehalogenation reaction of cyclo-
propanes without affecting the strained molecular entity.
With this particular alloy, beneficial properties of lead
cathodes are conserved, whereas the corrosion of cathode
is efficiently suppressed. The solvent in the electrolyte de-
termines whether a complete debromination reaction is
achieved or if the process can be selectively stopped at
the monobromo cyclopropane intermediate. The electro-
organic conversion tolerates a variety of functional groups
and can be conducted at rather complex substrates like
cyclosporine A. This approach allows the sustainable prep-
aration of cyclopropane derivatives.
For our studies, a collection of readily available cyclopro-
panes with a scope of functional groups was prepared
(Figure 1). This covers molecular entities like esters, aromatic
The cyclopropane moiety represents an important motif of
more than 100 pharmaceutical agents.[1] This is underlined by
4% of the 200 best-selling drugs exhibiting this particular
motif.[2] Furthermore, cyclopropanes are important starting ma-
terials in various synthetic transformations.[3] Consequently,
there is a significant need for efficient, inexpensive, and sus-
tainable protocols for the synthesis of such derivatives. A
common way for the synthesis on a technical scale is a twofold
dehalogenation of 1,1-dihalo cyclopropane derivatives, which
can be readily made from the corresponding alkenes and di-
halocarbenes.[3b,c,4] The dehalogenation reaction can be ach-
ieved by Birch reduction or a catalytic hydrogenolysis.[5] Both
methods are characterized by ring opening by-products, race-
mization a to carbonyl, and generation of waste from expen-
sive reagents.[5j,6]
Figure 1. Collection of different cyclopropane derivatives studied in the
cathodic dehalogenation reaction. Boc=tert-butoxycarbonyl,
TIPS=Si(CH(CH3)2)3.
In contrast, in the electrochemical reduction only electrons
serve as reagent and no reagent waste is generated. Conse-
quently, this methodology fulfils all requirements for “green
chemistry”.[7] Usually electrochemistry is only used for the syn-
thesis of commodities or, in a few cases, of specialty chemi-
cals.[7a,8] Although electrochemical dehalogenation reactions
are well-studied for simple halo alkanes,[9] so far only protocols
for the mono-dehalogenation of rather simple strained-ring
systems are reported,[10] whereas none are known for a cathodic
twofold dehalogenation at cyclopropanes. Furthermore, lead
or mercury are used as cathode material, which makes such an
electrolysis highly unattractive for the production of pharma-
ceutical ingredients, because corrosion of cathode is a serious
issue.[11]
systems, and alcohols. Additionally, we obtained two highly
functional pharmaceutically relevant structures. The reduction
of proline derivative 7 led to product 15, which is a key inter-
mediate for the synthesis of different drugs like NS5A inhibitor
compound, and therefore very attractive for pharmaceutical
applications.[13] This particular substrate is challenging due to
the plethora of functional groups and its stereochemistry,
which have to be conserved while electrolysis occurs. Further-
more, the derivative of cyclosporine A 8 or other polypeptides
represents an ideal substrate because of its size and the pepti-
dic nature.[14]
The electrolytic conversion was conducted in a divided cell
in order to avoid anodic degradation of substrate or product.
As an inexpensive and available sacrificial compound for
anodic oxidation, methanol was added into the anodic half-
cell. For the optimization of the electrolysis, we screened differ-
ent parameters such as cathode and anode materials, electroly-
sis temperature, supporting electrolyte, solvent, different
proton sources, current densities, and applied electric charge
(see the Supporting Information). A galvanostatic versus po-
tentiostatic approach was chosen because an easier upscaling
to a technical scale is possible.[15]
[a] Dr. C. Gütz, M. Selt, Dr. C. Rçmelt, N. Hecken, Prof. Dr. S. R. Waldvogel
Department of Organic Chemistry
Johannes Gutenberg University Mainz
Duesbergweg 10-14, 55128 Mainz (Germany)
E-mail: waldvogel@uni-mainz.de
[b] Dr. M. Bänziger, Dr. C. Bucher, Dr. F. Gallou, T. R. Galv¼o
Chemical Research & Development
Novartis Pharma AG
Novartis Campus, Basel (Switzerland)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201502064.
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version for 1 resulting in a mixture of mono- and twofold de-
halogenated cyclopropanes. In the case of the reduction of 2
in DMF a mixture of the desired product and ring-opening
product (1,3-diphenylpropane) was isolated, which can be ra-
tionalized because the ring-opening of this molecule has been
previously discussed in the literature.[16]
After the successful reduction of the test substances we
started to convert the demanding, pharmaceutically relevant
compounds 7 and 8. Both could be reduced in excellent yield
to give 15 and 16 (Figure 2). The conversion occurs without
Scheme 1. Optimized conditions for the electrochemical dehalogenation of
cyclopropane derivatives. MTES=[Et3NMe]O3SOMe.
The best conditions are displayed in Scheme 1. Upon elec-
trolysis no loss of mass at the cathode was detected. A trace
analysis of the crude product revealed only a very low contam-
ination of lead (5 ppm), copper (4 ppm), and tin (1 ppm). This
amount of metal content is acceptable for pharmaceutical use,
because several synthetic steps will follow.
For most substrates 1–6 a complete conversion to the two-
fold dehalogenated derivative was observed in good to excel-
lent yield. Only in the case of the ester 6 did we observe
a transesterification caused by the diffusion of methanol from
the anolyte to the catholyte resulting in the methyl ester 13
(Table 1).
Table 1. Scope of the twofold debromination of cyclopropane deriva-
tives.
Figure 2. Demanding, pharmaceutically relevant compounds that were re-
duced electrochemically in high yield and selectivity.
Starting
material
Product
Applied
electricity [F]
Yield
the formation of any byproducts. This demonstrates the high
selectivity and applicability of this electrochemical process. It is
noteworthy that a large number of different bonds and stereo-
centers are tolerated. Furthermore, comparable classical meth-
ods for derivative 7, like the Birch reduction or the hydrogenol-
ysis, only gave significantly lower yields ranging from 48–
65%.[5j]
1
2
7
5
78%[a]
51%[b]
90%[a]
90%[b]
Moreover, for technical applications it is important to keep
in mind that purification of products is only feasible by aque-
ous work-up without the use of column chromatography. Fur-
thermore, the repetitive use of the supporting electrolyte and
solvent was studied (see the Supporting Information). After
stripping off the organic product by toluene extraction, the
supporting electrolyte was successfully reused for several elec-
trolyses.
3
4
7
6
68%[a]
68%[b]
82%[a]
80%[b]
5
6
5
5
Additionally, to broaden the scope, we selectively performed
the electrolysis to obtain the mono-dehalogenated derivative.
In order to stop the debromination reaction on the monohalo
species, the following features turned out to be the key: 1) use
of acetonitrile as solvent, 2) addition of phosphoric acid into
the catholyte, and 3) higher ratio of methanol in the anolyte
(Scheme 2). These changes all led to a higher proton concen-
tration in the catholyte, which promoted the hydrogen evolu-
tion as a side reaction instead of the second dehalogenation
process (see cyclic voltammetry data in the Supporting Infor-
mation).
only 13 (77%)[a,b]
[a] Electrolysis in N,N-dimethylformamide as solvent. [b] Electrolysis con-
ducted in acetonitrile as solvent.
The solvent used in the electrolyte plays a significant role.
The derivatives 3–5 can be reduced in acetonitrile as well as
N,N-dimethylformamide (DMF) to form 11–13, whereas 1 and
2 can only be converted in acetonitrile or DMF, respectively, to
give 9 or 10. In acetonitrile we observed an incomplete con-
Subjecting the cyclopropanes 1–8 to these conditions re-
vealed that this protocol seems to be partly successful
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Nevertheless, most derivatives can be selectively mono de-
halogenated. In particular, the pharmaceutically relevant struc-
tures 23 and 24 could be obtained in very high yield
(Figure 3), which subsequently can be transformed into various
derivatives by bromide exchange and thus expand the range
of this class of biologically relevant compounds.
Scheme 2. Optimized conditions for the single electrochemical dehalogena-
tion of cyclopropane derivatives.
Table 2. Results of single debromination of cyclopropane derivatives.
Starting
material
Product
Applied
electricity [F]
cis/trans
Ratio[a]
Yield
1
2
3
4
4
2
4
3
60:40
94%
–
0%[b]
86%
0%
Figure 3. Successful reduced amino acid and peptide in a single electro-
chemical debromination.
60:40
In summary, we established an easy to perform, efficient,
and sustainable protocol for a mono- and twofold dehalogena-
tion of 1,1-dibromated cyclopropanes without concomitant
ring-opening product to gem-dimethyl derivatives. Except for
the esters, all employed functional groups are tolerated. The
key of this electrolytic conversion is the use of leaded bronze
instead of corrosion-prone lead, highly toxic mercury, or other
cathode materials (see the Supporting Information). Those
cathode materials led to complex product mixtures, low yield,
or significant corrosion of cathode. Leaded bronze is a new
cathode material for reductions that combines the high over-
potential towards hydrogen evolution of lead with an out-
standing chemical and mechanical stability. This reduces con-
tamination by traces of heavy metals to an acceptable level in
the crude product. In addition, the long-term stability of this
cathode material is ensured. Therefore, leaded bronze is an at-
tractive electrode material for all kinds of transformations
where lead is usually used but where its corrosion is a critical
issue.
–
5
6
3
3
50:50
50:50
90%
86%[c]
[a] Obtained from 1H NMR spectra integration. [b] Product is not stable
and undergoes a rearrangement. [c] 86% total yield, mixture of 21 (53%)
and 22 (33%).
(Table 2). In the case of the esters, the use of phosphoric acid
led to partial de-esterification and to a mixture of the corre-
sponding free acid and product 21 or 22. This problem was
solved by using no phosphoric acid. However, it is then impor-
tant to apply exactly the given amount of electricity, otherwise
a twofold dehalogenation is observed. Derivatives 2 and 4
could not be dehalogenated once under these conditions. For
derivative 2 we observed a ring opening because product 18
is prone to this reaction.[17] The same applies for 4 whereby an
unidentified mixture of different products was formed.
In combination with the possibility to recycle the used sol-
vent and supporting electrolyte, this electrochemical conver-
sion fulfils conditions for “green chemistry”. Therefore, this
electrochemical transformation is of high interest for a technical
use and represents the high potential of electrochemistry in
the synthesis of complex molecules.
Acknowledgements
Furthermore, we studied the stereoselectivity of the single
dehalogenation. The observed diastereoselectivity of the de-
halogenation is quite low. However, a mixture with a cis/trans
ratio between 50:50 and 60:40 was observed.
We thank Andreas Schneider for the discussion about the sep-
aration of cyclosporine derivatives.
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ghavachari, D. G. Peters, J. Electroanal. Chem. 2010, 647, 194–203;
e) D. G. Peters, Halogenated Organic Compounds in Organic Electrochem-
istry, 4th ed. (Eds.: H. Lund, O. Hammerich), Marcel Dekker, New York,
2001, 341–377; f) F. Beck, Kathodische Spaltung der Kohlenstoff-Halogen-
Bindung, in Elektroorganische Chemie, Akademie-Verlag, Berlin, 1974,
183–186; g) S. Torii, Electroreduction of Halogenated Compounds, in Elec-
troorganic Reduction Synthesis, Wiley-VCH, Weinheim, 2006, 331–337;
h) A. J. Fry, Cleavage of Single Bonds in Synthetic Organic Chemistry,
Wiley, Hoboken, 1989, 136–156.
Keywords: cyclopropanes · dehalogenation · electrochemical
reduction · leaded bronze · sustainable chemistry
[1] L. A. Wessjohann, W. Brandt, T. Thiemann, Chem. Rev. 2003, 103, 1625–
1648.
[2] a) IMS Institue for healthcare informatics, A Review of the Use of Medi-
cines in the United States in 2012, 2013; b) Food and Drug Administra-
tion, 2013, report “Approved drugs 2013”.
[10] a) A. J. Fry, R. H. Moore, J. Org. Chem. 1968, 33, 1283–1284; b) A. J. Fry,
R. G. Reed, J. Am. Chem. Soc. 1972, 94, 8475–8484; c) S. Ikeda, G. Tsuka-
moto, I. Nishiguchi, T. Hirashima, Chem. Pharm. Bull. 1988, 36, 1976–
1981; d) R. E. Erickson, R. Annino, M. D. Scanlon, G. Zon, J. Am. Chem.
Soc. 1969, 91, 1767–1770; e) Y. M. Kargin, E. I. Gritsenko, V. V. Yanilkin,
V. V. Plemenkov, L. K. Dubovik, N. I. Maksimyuk, B. M. Garifullin, S. K. Le-
typov, A. V. Il’yasov, Russ. Chem. Bull. 1992, 41, 1572–1579; f) J. L. Webb,
C. K. Mann, H. M. Walborsky, J. Am. Chem. Soc. 1970, 92, 2042–2051;
g) H. M. Walborsky, C. Hamdouchi, J. Am. Chem. Soc. 1993, 115, 6406–
6408; h) S. Jaouannet, R. Hazard, A. Tallec, J. Electroanal. Chem. 1980,
111, 397–400.
[11] a) R. D. Armstrong, K. L. Bladen, J. Appl. Electrochem. 1977, 7, 345–353;
b) K. H. Roll, Ind. Eng. Chem. 1953, 45, 2210–2214; c) J. Tafel, Ber. Dtsch.
Chem. Ges. 1911, 44, 323–337; d) S. J. Stohs, D. Bagchi, Free Radical Biol.
Med. 1995, 18, 321–336.
[12] a) M. Aksoy, V. Kuzucu, H. Turhan, J. Mater. Process. Technol. 2002, 124,
113–119; b) K. M. Zohdy, M. M. Sadawy, M. Ghanem, Mater. Chem. Phys.
2014, 147, 878–883; cDIN EN 1982.
[13] a) J. O. Link, J. G. Taylor, L. Xu, M. Mitchell, H. Guo, H. Liu, D. Kato, T.
Kirschberg, J. Sun, N. Squires, J. Parrish, T. Keller, Z.-Y. Yang, C. Yang, M.
Matles, Y. Wang, K. Wang, G. Cheng, Y. Tian, E. Mogalian, E. Mondou, M.
Cornpropst, J. Perry, M. C. Desai, J. Med. Chem. 2014, 57, 2033–2046;
b) Y. L. Qiu, C. Wang, X. Peng, L. Ying, Y. S. Or, WO 2009/102325 AI,
2010; c) H. Cao, I. J. Kim, Y. Sun, X. Peng, Y.-L. Qiu, D. Tang, G. Wang, G.
Xu, WO 2012/158861A2, 2012; d) D. Tang, G. Xu, X. Peng, L. Ying, C.
Wang, H. Cao, J. Long, I. J. Kim, G. Wang, Y. L. Qiu, WO2013059281A2,
2013; e) R. Pfau, Nachr. Chem. 2015, 63, 293–294.
[14] a) S. Werkmeister, K. Junge, B. Wendt, E. Alberico, H. Jiao, W. Baumann,
H. Junge, F. Gallou, M. Beller, Angew. Chem. Int. Ed. 2014, 53, 8722–
8726; Angew. Chem. 2014, 126, 8867–8871; b) F. Gallou, L. G. Hamann,
Aldrichimica Acta 2015, 48, 12–14.
[15] H. Pütter, Industrial Electroorganic Chemistry in Organic Electrochemistry,
4th ed. (Eds.: H. Lund, O. Hammerich), Marcel Dekker, New York, 2001,
1259–1308.
[16] E. Cahard, F. Schoenebeck, J. Garnier, S. P. Y. Cutulic, S. Zhou, J. A.
Murphy, Angew. Chem. Int. Ed. 2012, 51, 3673–3676; Angew. Chem.
2012, 124, 3733–3736.
[3] a) T. F. Schneider, J. Kaschel, D. B. Werz, Angew. Chem. Int. Ed. 2014, 53,
´
5504–5523; Angew. Chem. 2014, 126, 5608–5628; b) M. Fedorynski,
Chem. Rev. 2003, 103, 1099–1132; c) H. N. C. Wong, M. Y. Hon, C. W. Tse,
Y. C. Yip, J. Tanko, T. Hudlicky, Chem. Rev. 1989, 89, 165–198.
[4] F. Schuetz, H. Sauter, N. Goetz, J. Wild, H.-J. Wolf, R. Doetzer, G. Lorenz,
E. Ammermann, C. Kuenast, U. Kardorff, B. SE, US005371268A, 1994.
[5] a) T. S. Kuznetsova, O. V. Kokoreva, E. B. Averina, A. N. Zefirov, Y. K. Grish-
in, N. S. Zefirov, Russ. Chem. Bull. 1999, 48, 929; b) M. von Seebach, S. I.
Kozhushkov, R. Boese, J. Benet-Buchholz, D. S. Yufit, J. A. K. Howard, A.
de Meijere, Angew. Chem. Int. Ed. 2000, 39, 2495–2498; Angew. Chem.
2000, 112, 2617–2620; c) J. Martínez-PØrez, L. Sarandeses, J. Granja, J.
Palenzuela, A. MouriÇo, Tetrahedron Lett. 1998, 39, 4725–4728; d) T. Su-
gimura, T. Futagawa, T. Katagiri, N. Nishiyama, A. Tai, Tetrahedron Lett.
1996, 37, 7303–7306; e) W. Kraus, G. Klein, H. Sadlo, W. Rothenwçhrer,
Synthesis 1972, 485–487; f) Y. M. Sheikh, J. Leclercq, C. Djerassi, J. Chem.
Soc. Perkin Trans. 1 1974, 909–914; g) E. Vogel, W. Wiedemann, H. D.
Roth, J. Eimer, H. Günther, Justus Liebigs Ann. Chem. 1972, 759, 1–36;
h) M. S. Baird, P. Licence, V. V. Tverezovsky, I. G. Bolesov, W. Clegg, Tetra-
hedron 1999, 55, 2773–2784; i) R. J. de Lang, L. Brandsma, Synth.
Commun. 1998, 28, 225–232; j) M. Bänziger, C. Bucher, Chim. Oggi
2015, 33, 50–55.
[6] A. L. Schultz, J. Org. Chem. 1971, 36, 383–386.
[7] a) E. Steckhan, T. Arns, W. R. Heineman, G. Hilt, D. Hoormann, J. Jçrissen,
L. Krçner, B. Lewall, H. Pütter, Chemosphere 2001, 43, 63–73; b) P. Anas-
tas, N. Eghbali, Chem. Soc. Rev. 2010, 39, 301–312; c) R. A. Sheldon,
Green Chem. 2007, 9, 1273–1283; d) B. A. Frontana-Uribe, R. D. Little,
J. G. Ibanez, A. Palma, R. Vasquez-Medrano, Green Chem. 2010, 12,
2099–2119; e) H. J. Schäfer, M. Harenbrock, E. Klocke, M. Plate, A.
Weiper-Idelmann, Pure Appl. Chem. 2007, 79, 2047–2057; f) H. J. Schäfer,
C. R. Chim. 2011, 14, 745–765; g) J.-I. Yoshida, K. Kataoka, R. Horcajada,
A. Nagaki, Chem. Rev. 2008, 108, 2265–2299; h) S. R. Waldvogel, B.
Janza, Angew. Chem. Int. Ed. 2014, 53, 7122–7123; Angew. Chem. 2014,
126, 7248–7249.
[8] a) D. Pletscher, F. C. Walsh, Industrial Electrochemistry, Blackie Academic
& Professional, Glasgow, 1993; b) H. Lund, O. Hammerich, Organic Elec-
trochemistry, 4th ed., Marcel Dekker, New York, 2001; c) F. Beck, Elek-
troorganische Chemie, Akademie-Verlag, Berlin, 1974.
[9] For reviews and book chapters as examples for general electrochemical
dehalogantion, see: a) J. M. Saveant, Acc. Chem. Res. 1993, 26, 455–461;
b) P. W. Raess, M. S. Mubarak, M. A. Ischay, M. P. Foley, T. B. Jennermann,
K. Raghavachari, D. G. Peters, J. Electroanal. Chem. 2007, 603, 124–134;
c) N. L. Wolf, D. G. Peters, M. S. Mubarak, J. Electrochem. Soc. 2006, 153,
E1–E4; d) M. P. Foley, P. Du, K. J. Griffith, J. A. Karty, M. S. Mubarak, K. Ra-
[17] G. Rosocha, R. A. Batey, Tetrahedron 2013, 69, 8758–8768.
Received: May 27, 2015
Published online on August 6, 2015
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